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Primacy of the research question, structure of the paper, writing a research article: advice to beginners.

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Thomas V. Perneger, Patricia M. Hudelson, Writing a research article: advice to beginners, International Journal for Quality in Health Care , Volume 16, Issue 3, June 2004, Pages 191–192,

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Writing research papers does not come naturally to most of us. The typical research paper is a highly codified rhetorical form [ 1 , 2 ]. Knowledge of the rules—some explicit, others implied—goes a long way toward writing a paper that will get accepted in a peer-reviewed journal.

A good research paper addresses a specific research question. The research question—or study objective or main research hypothesis—is the central organizing principle of the paper. Whatever relates to the research question belongs in the paper; the rest doesn’t. This is perhaps obvious when the paper reports on a well planned research project. However, in applied domains such as quality improvement, some papers are written based on projects that were undertaken for operational reasons, and not with the primary aim of producing new knowledge. In such cases, authors should define the main research question a posteriori and design the paper around it.

Generally, only one main research question should be addressed in a paper (secondary but related questions are allowed). If a project allows you to explore several distinct research questions, write several papers. For instance, if you measured the impact of obtaining written consent on patient satisfaction at a specialized clinic using a newly developed questionnaire, you may want to write one paper on the questionnaire development and validation, and another on the impact of the intervention. The idea is not to split results into ‘least publishable units’, a practice that is rightly decried, but rather into ‘optimally publishable units’.

What is a good research question? The key attributes are: (i) specificity; (ii) originality or novelty; and (iii) general relevance to a broad scientific community. The research question should be precise and not merely identify a general area of inquiry. It can often (but not always) be expressed in terms of a possible association between X and Y in a population Z, for example ‘we examined whether providing patients about to be discharged from the hospital with written information about their medications would improve their compliance with the treatment 1 month later’. A study does not necessarily have to break completely new ground, but it should extend previous knowledge in a useful way, or alternatively refute existing knowledge. Finally, the question should be of interest to others who work in the same scientific area. The latter requirement is more challenging for those who work in applied science than for basic scientists. While it may safely be assumed that the human genome is the same worldwide, whether the results of a local quality improvement project have wider relevance requires careful consideration and argument.

Once the research question is clearly defined, writing the paper becomes considerably easier. The paper will ask the question, then answer it. The key to successful scientific writing is getting the structure of the paper right. The basic structure of a typical research paper is the sequence of Introduction, Methods, Results, and Discussion (sometimes abbreviated as IMRAD). Each section addresses a different objective. The authors state: (i) the problem they intend to address—in other terms, the research question—in the Introduction; (ii) what they did to answer the question in the Methods section; (iii) what they observed in the Results section; and (iv) what they think the results mean in the Discussion.

In turn, each basic section addresses several topics, and may be divided into subsections (Table 1 ). In the Introduction, the authors should explain the rationale and background to the study. What is the research question, and why is it important to ask it? While it is neither necessary nor desirable to provide a full-blown review of the literature as a prelude to the study, it is helpful to situate the study within some larger field of enquiry. The research question should always be spelled out, and not merely left for the reader to guess.

Typical structure of a research paper

The Methods section should provide the readers with sufficient detail about the study methods to be able to reproduce the study if so desired. Thus, this section should be specific, concrete, technical, and fairly detailed. The study setting, the sampling strategy used, instruments, data collection methods, and analysis strategies should be described. In the case of qualitative research studies, it is also useful to tell the reader which research tradition the study utilizes and to link the choice of methodological strategies with the research goals [ 3 ].

The Results section is typically fairly straightforward and factual. All results that relate to the research question should be given in detail, including simple counts and percentages. Resist the temptation to demonstrate analytic ability and the richness of the dataset by providing numerous tables of non-essential results.

The Discussion section allows the most freedom. This is why the Discussion is the most difficult to write, and is often the weakest part of a paper. Structured Discussion sections have been proposed by some journal editors [ 4 ]. While strict adherence to such rules may not be necessary, following a plan such as that proposed in Table 1 may help the novice writer stay on track.

References should be used wisely. Key assertions should be referenced, as well as the methods and instruments used. However, unless the paper is a comprehensive review of a topic, there is no need to be exhaustive. Also, references to unpublished work, to documents in the grey literature (technical reports), or to any source that the reader will have difficulty finding or understanding should be avoided.

Having the structure of the paper in place is a good start. However, there are many details that have to be attended to while writing. An obvious recommendation is to read, and follow, the instructions to authors published by the journal (typically found on the journal’s website). Another concerns non-native writers of English: do have a native speaker edit the manuscript. A paper usually goes through several drafts before it is submitted. When revising a paper, it is useful to keep an eye out for the most common mistakes (Table 2 ). If you avoid all those, your paper should be in good shape.

Common mistakes seen in manuscripts submitted to this journal

Huth EJ . How to Write and Publish Papers in the Medical Sciences , 2nd edition. Baltimore, MD: Williams & Wilkins, 1990 .

Browner WS . Publishing and Presenting Clinical Research . Baltimore, MD: Lippincott, Williams & Wilkins, 1999 .

Devers KJ , Frankel RM. Getting qualitative research published. Educ Health 2001 ; 14 : 109 –117.

Docherty M , Smith R. The case for structuring the discussion of scientific papers. Br Med J 1999 ; 318 : 1224 –1225.

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  • Research Guides

Reading for Research: Social Sciences

Structure of a research article.

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Guide Acknowledgements

How to Read a Scholarly Article from the Howard Tilton Memorial Library at Tulane University

Strategic Reading for Research   from the Howard Tilton Memorial Library at Tulane University

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Academic writing has features that vary only slightly across the different disciplines. Knowing these elements and the purpose of each serves help you to read and understand academic texts efficiently and effectively, and then apply what you read to your paper or project.

Social Science (and Science) original research articles generally follow IMRD: Introduction- Methods-Results-Discussion


  • Introduces topic of article
  • Presents the "Research Gap"/Statement of Problem article will address
  • How research presented in the article will solve the problem presented in research gap.
  • Literature Review. presenting and evaluating previous scholarship on a topic.  Sometimes, this is separate section of the article. 

​Method & Results

  • How research was done, including analysis and measurements.  
  • Sometimes labeled as "Research Design"
  • What answers were found
  • Interpretation of Results (What Does It Mean? Why is it important?)
  • Implications for the Field, how the study contributes to the existing field of knowledge
  • Suggestions for further research
  • Sometimes called Conclusion

You might also see IBC: Introduction - Body - Conclusion

  • Identify the subject
  • State the thesis 
  • Describe why thesis is important to the field (this may be in the form of a literature review or general prose)


  • Presents Evidence/Counter Evidence
  • Integrate other writings (i.e. evidence) to support argument 
  • Discuss why others may disagree (counter-evidence) and why argument is still valid
  • Summary of argument
  • Evaluation of argument by pointing out its implications and/or limitations 
  • Anticipate and address possible counter-claims
  • Suggest future directions of research
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June 8, 2020 Editor's Note: The hypertension study (reference 5) is under investigation by the editor of the journal in which it was published due to inconsistencies in the data noted by others. Caution is warranted regarding applying these findings to clinical care.

Am Fam Physician. 2020;101(10):608-617

Author disclosure: Dr. Ebell is cofounder and editor-in-chief of Essential Evidence Plus. See Editor's Note . Dr. Grad has no relevant financial affiliations.

In 2019, regular surveillance of 110 English-language research journals identified 254 studies that met the criteria to become POEMs (patient-oriented evidence that matters). Physician members of the Canadian Medical Association rated these POEMs for their relevance to patients in their practices. This article summarizes the clinical questions and bottom-line answers from the top 20 POEMs of 2019. Taking blood pressure medications at night results in a large mortality reduction over six years compared with morning dosing. Automated devices are the best way to measure blood pressure. Nonfasting lipid profiles are preferred over fasting lipid profiles, and nonfasting and fasting lipid profiles are equally effective at predicting risk. The benefit of statins for primary prevention in people 75 years and older is uncertain at best. Aspirin has no net benefit for primary prevention of cardiovascular disease and has no effect on cancer outcomes. An Italian study found fecal immunochemical testing over five biennial screening cycles has a similar colorectal cancer yield as screening colonoscopy, whereas a meta-analysis found that taking aspirin, an anticoagulant, or a nonsteroidal anti-inflammatory drug has no impact on the positive predictive value of fecal immunochemical testing. Regarding infections, a meta-analysis showed that patients presenting with symptoms of acute respiratory tract infection are unlikely to have pneumonia if vital signs and the lung examination findings are normal. For streptococcal pharyngitis (strep throat), penicillin V at a dosage of 800 mg four times a day for five days is at least as effective as a dosage of 1,000 mg three times a day for 10 days. A primary care study in the United Kingdom reinforced that clinicians should counsel parents of children with lower respiratory tract symptoms to be patient, because these infections can take three weeks or more to fully resolve. Among direct oral anticoagulants, apixaban has the lowest bleeding risk, and cotreating with a proton pump inhibitor significantly reduces bleeding risk. Single ibuprofen doses from 400 to 800 mg significantly reduce acute pain to a similar degree. The two-dose recombinant zoster vaccine is much more effective than the single-dose live, attenuated vaccine but with a greater risk of injection site pain. Exercise helps reduce the risk of falls in older adults. Practice guidelines from 2019 on antithrombotics for atrial fibrillation, the management of type 2 diabetes mellitus, and screening for breast cancer were judged to be especially relevant.

Every year for the past 21 years, a team of experts in evidence-based medicine have systematically reviewed more than 110 English-language research journals to identify the original research most likely to change and improve primary care practice. The team includes experts in family medicine, pharmacology, hospital medicine, and women's health. 1 , 2

The goal of this process is to identify POEMs (patient-oriented evidence that matters). A POEM must report at least one patient-oriented outcome, such as improvement in symptoms, morbidity, or mortality. It should also be free of important methodologic bias, making the results valid and trustworthy. Finally, if applied in practice, the results would change what some family physicians do in patient care by prompting them to adopt a beneficial new practice or discontinue one that is ineffective or harmful. This should improve patient outcomes. Of more than 20,000 research studies published in 2019 in the journals reviewed by the POEMs team, 254 met criteria for validity, relevance, and practice change.

The Canadian Medical Association (CMA) purchases a subscription to POEMs for its members, many of whom receive the daily POEM by email. When members read a POEM, they can rate it with a validated questionnaire called the Information Assessment Method. POEM ratings address the domains of clinical relevance, cognitive impact, use in practice, and expected health benefits if that POEM were to be applied in patient care. 3 , 4 In 2019, each of the 254 POEMs were rated by an average of 1,530 physicians.

In this article, we present the 20 POEMs rated highest for clinical relevance by CMA members in 2019. This installment of our annual series ( ) summarizes the clinical question and bottom-line answer for each research study identified as a top 20 POEM, organized by topic and followed by a brief discussion. We also present the three most relevant practice guidelines identified by CMA members. The full text of the POEMs in this article are available at .


Hypertension is among the most common conditions managed by primary care physicians and is the topic of the two POEMs rated most relevant to readers in 2019 ( Table 1 ) . 5 , 6 Researchers randomized 19,168 adults with hypertension to take their antihypertensive medications at bedtime or first thing in the morning. 5 Patients were prescribed an antihypertensive from an approved list of the most common therapies. Patients taking their medications at bedtime had a lower likelihood of the composite outcome of myocardial infarction (MI), coronary revascularization, heart failure, stroke, or cardiovascular death (hazard ratio = 0.55; 95% CI, 0.50 to 0.61; number needed to treat to prevent one event over 6.3 years = 20). All-cause mortality was reduced to a similar extent. This is a large effect for a six-year study, and a practice-changer for many patients and physicians. Best of all, it costs nothing to make this change. See Editor's Note

How we measure blood pressure continues to be a subject of research. The next POEM was a meta-analysis of 31 studies, which included a total of 9,279 patients and compared automated in-office blood pressure readings with in-office manual measurements or ambulatory automated recordings during waking hours (the reference standard). 6 Automated in-office measurements were performed without anyone present to activate the machine and used three to five readings separated by one- to two-minutes. Ambulatory automated measurements were 13.4/5.9 mm Hg lower than the manual in-office measurements and were similar to the in-office automated measurements. To avoid starting or intensifying antihypertensive medication unnecessarily, it is critical to measure blood pressure using an automated device. Patients should also bring in their home device so that it can be calibrated with the office device.

Behavioral Medicine

Behavioral medicine POEMs are summarized in Table 2 . 7 – 9 The first POEM in this group was a well-executed network meta-analysis of medical therapy for generalized anxiety disorder. 7 A network meta-analysis includes studies comparing drugs with each other and with placebo, allowing for direct and indirect comparisons. The meta-analysis included 89 studies involving 25,000 patients and 22 different drugs; none of the studies were longer than 26 weeks. After excluding drugs that were poorly tolerated such as quetiapine (Seroquel), paroxetine (Paxil), and benzodiazepines, the most effective commercially available drugs overall were, in order of effectiveness, bupropion (Wellbutrin), duloxetine (Cymbalta), mirtazapine (Remeron), hydroxyzine, sertraline (Zoloft), pregabalin (Lyrica), venlafaxine, escitalopram (Lexapro), fluoxetine (Prozac), buspirone (Buspar), and citalopram (Celexa). Drugs that did not significantly decrease anxiety scores included imipramine, maprotiline, opipramol (not available in the United States), tiagabine (Gabitril), vilazodone (Viibryd), and vortioxetine (Trintellix). The drugs with the best combination of effectiveness and tolerability were duloxetine, pregabalin, venlafaxine, and escitalopram.

The next POEM included videotaped encounters between 252 patients and 15 English primary care physicians. 8 Patients were asked about the main reason for their visit beforehand, and this reason was almost always addressed during the visit. However, of the 139 patients who identified at least one symptom in the previsit interview, 43 failed to disclose a total of 67 symptoms during the visit, most often stress, worries or sadness; tiredness or sleep problems; problems passing urine; headache; and intimate or other personal problems. Although physicians cannot ask every patient about all of their problems during a visit, it is important to know that patients may not fully disclose symptoms. Physicians should make patients feel as safe as possible while looking for cues to undisclosed symptoms, and routinely asking, “Is there anything else I can help you with?”

The last POEM in the behavioral medicine group was an individual patient data meta-analysis of how early treatment response impacts later outcomes in patients with depression. 9 The researchers combined the individual patient data from 30 randomized trials, with 2,184 patients receiving placebo and 6,058 receiving active therapy. After six weeks of treatment, about 50% of patients in the active treatment group responded to treatment, with 32% achieving remission of symptoms. Response was defined as at least a 50% reduction in the Hamilton Rating Scale for Depression score, and remission was defined as a score of 7 points or less. By 12 weeks, the response rate was 68% in the active treatment group, with 49% achieving remission. Patients with improvement at two weeks were more likely to respond by six weeks, whereas among patients without early improvement, 33% responded by six weeks and 43% by 12 weeks. The absence of an early response does not preclude later response; therefore, physicians should not be too quick to change antidepressant medications.


Cardiovascular medicine POEMs are summarized in Table 3 . 10 – 14 The first two POEMs in this group address statin use. Many physicians and laboratory staff continue to insist that patients be fasting for lipid profile testing. The first POEM compared fasting and nonfasting lipid profiles in the same patients four weeks apart. 10 There was little difference between fasting and nonfasting measurements of low-density and high-density lipoprotein cholesterol levels and only a small increase in triglyceride levels (25 mg per dL [0.28 mmol per L]) with nonfasting measurements. Most importantly, the association between lipid levels and subsequent cardiovascular events was identical for fasting and nonfasting lipid measurements. Guidelines support nonfasting lipid measurements. 15 , 16 It is time to simplify our patients' lives and educate local laboratory staff, who often turn away patients who disclose that they are not fasting.

In the next POEM, data were pooled from 28 randomized trials of statins with more than 186,000 total patients. 11 This report focused on the 14,000 patients who were 75 years or older; the median follow-up was five years. There was only a small reduction in the composite outcome of MI and cardiovascular death among all patients (2.6% with statins vs. 3.0% with placebo; number needed to treat = 250 per year); the benefit was significant only in patients with preexisting cardiovascular disease. Statins had no effect on revascularization, stroke, cancer incidence, or cancer mortality.

This was a big year for aspirin studies. The next three POEMs, from two separate trials, examine the benefits and harms of aspirin therapy for primary prevention in contemporary populations. Prior studies that found a net benefit of aspirin for the primary prevention of cardiovascular disease and cancer (mostly colorectal) all recruited patients before 2002. In more recent years, fewer patients smoke or have uncontrolled hypertension, more are taking a statin, and we have widespread colorectal cancer screening. In this context, does aspirin still have a role?

Two aspirin POEMs were from the ASPREE (Aspirin in Reducing Events in the Elderly) trial, which included 19,114 adults 70 years and older in the United States and Australia (65 and older if black or Hispanic). Patients without known cardiovascular disease were randomized to aspirin, 100 mg, or placebo and were followed for a median of 4.7 years. The first POEM found no significant reduction in the likelihood of cardiovascular disease with aspirin, including fatal cardiovascular disease, fatal or nonfatal MI, and fatal or nonfatal ischemic stroke. However, they found a significant increase in major hemorrhages with aspirin. 12 The second POEM from the ASPREE trial found no difference between groups for disability-free survival, defined as a composite of death, dementia, or persistent physical disability. 13 A separate report from the ASPREE investigators (not one of the top 20 POEMs) found an increase in all-cause mortality with aspirin, primarily due to a significant increase in cancer-specific mortality (3.1% vs. 2.3%).

The third aspirin POEM was from the ASCEND (A Study of Cardiovascular Events in Diabetes) trial and included 15,480 adults 40 years and older with diabetes mellitus but no known cardiovascular disease. The patients were randomized to aspirin, 100 mg, or placebo and were followed for a median of 7.4 years. 14 There was a reduction in the composite of nonfatal MI, nonfatal stroke, or cardiovascular death with aspirin, but a corresponding increase in major hemorrhage with no effect on cardiovascular or all-cause mortality.

What do we tell our patients? A recent meta-analysis compared trials of aspirin therapy that recruited patients from 1978 to 2002 with four large trials that recruited patients since 2005. 17 The newer studies showed fewer cardiovascular benefits and no reduction in cancer incidence or mortality with aspirin as primary prevention. Based on a meta-analysis of the four most recent studies with a total of 61,604 patients, for every 1,200 patients taking aspirin instead of placebo for five years, there would be four fewer major cardiovascular events and three fewer ischemic strokes but eight more major hemorrhages, including three more intracranial hemorrhages. This study agrees with recent European guidelines that no longer recommend aspirin for primary prevention. 18 The 2016 U.S. Preventive Services Task Force (USPSTF) and 2019 American College of Cardiology guidelines recommend consideration of aspirin for primary prevention only in selected patients at high cardiovascular risk and low bleeding risk. 19 , 20 The USPSTF recommendation is currently being updated. 21

Cancer Screening

The three POEMs on cancer screening ( Table 4 ) address colorectal cancer. 22 – 24 Fecal immunochemical testing (FIT) is the recommended method for colorectal cancer screening in most countries that have screening programs and is the subject of the first two POEMs in this group. The first POEM is an Italian study that reported the diagnostic yield of five rounds of biennial FIT in persons 50 to 69 years of age submitting a single specimen. 22 The highest rates of detection occurred in the first round, as prevalent cancers were detected, and declined and then stabilized in later rounds. Over the 10-year study, about 25% of men and 18% of women had a positive test result requiring a follow-up colonoscopy. The cumulative rate was 6% for advanced adenoma and 0.85% for colorectal cancer, which are similar to findings in studies of colonoscopy in Italy and the United States. 25 , 26 These results mean we can have confidence in FIT as a screening test while we wait for the results of ongoing randomized trials of FIT vs. colonoscopy-based screening.

The second POEM about FIT was a meta-analysis evaluating the impact of aspirin, nonsteroidal anti-inflammatory drugs, and anticoagulants on the positive predictive value of the test. 23 It could theoretically go in either direction, increasing false positives by making noncancerous lesions more likely to bleed or increasing true positives by making cancers and adenomas more likely to bleed. The researchers found that the use of any of these medications had almost no effect on the positive predictive value, which was approximately 6% for colorectal cancer and 40% for advanced neoplasia. FIT requires only a single specimen and no dietary preparation, and now we know that patients undergoing FIT can continue to take medications that increase bleeding risk.

Finally, a study used a Swedish cancer registry with 173,796 patients to determine the impact of family history on the risk of colorectal cancer. 24 The relative risk of colorectal cancer using no affected relatives as the reference was 1.2 for a single second-degree relative with a history of colorectal cancer, 1.6 for a single first-degree relative or two second-degree relatives, 2.3 for one first-degree relative and one second-degree relative, 2.5 for two first-degree relatives, and 5.4 for one first-degree and two second-degree relatives. However, a previous study found that this family history–related risk is attenuated once patients reach 55 years of age. 27

POEMs on managing infections are summarized in Table 5 . 28 – 30 The first POEM is a meta-analysis of studies that recruited outpatients with acute respiratory tract infections who received chest radiography. 28 The goal was to identify the best sign, symptom, or combination that allows clinicians to rule out community-acquired pneumonia (CAP). The researchers found that for patients with the combination of normal vital signs and normal lung examination findings, the likelihood of CAP is low at 0.4%. This could help reduce unnecessary chest radiography if applied consistently.

The second POEM in this group was selected as one of the top three research studies out of more than 400 presented at the 2019 North American Primary Care Research Group meeting. 29 This Swedish study included 422 adults and children presenting to a primary care physician with moderately severe streptococcal pharyngitis (strep throat). Patients were randomized to penicillin V at a dosage of 800 mg four times a day for five days or 1,000 mg three times a day for 10 days. Those receiving the higher dose over a shorter course of treatment had similar cure rates as those receiving longer-duration therapy, with quicker symptom resolution and no increase in recurrence. Many other studies have found similar results with antibiotics for a range of infections.

An accurate prognosis can potentially help patients avoid unnecessary antibiotic use and return visits. The third POEM in this group recruited 485 healthy children in the United Kingdom, and parents were instructed to contact the researchers every time the child had a respiratory tract infection. 30 One-half of the children had at least one infection, with a median duration of nine days; 90% recovered by day 23. Lower respiratory tract infections were associated with a longer duration of symptoms and ear infections were associated with a shorter duration. This reinforces that clinicians should counsel parents of children with lower respiratory tract symptoms to be patient.


Four additional POEMs are summarized in Table 6 . 31 – 34 The first is a cohort study of more than 1.6 million Medicare beneficiaries who started an anticoagulant between 2011 and 2015. 31 Bleeding rates were compared, adjusting for available covariates using propensity score matching (i.e., matching patients who were similar other than choice of anticoagulant). The adjusted incidence of hospitalization for upper gastrointestinal tract bleeding was significantly higher in those who received rivaroxaban (Xarelto) compared with those who received dabigatran (Pradaxa), warfarin (Coumadin), or apixaban (Eliquis); 144 per 10,000 person-years vs. 120, 113, and 73, respectively). For all agents combined, adding a proton pump inhibitor significantly reduced bleeding risk (76 out of 10,000 per year vs. 115 out of 10,000 per year; number needed to treat = 256), although rivaroxaban still had the highest bleeding rate.

The next POEM identified 225 adults presenting to the emergency department with acute pain (mostly musculoskeletal); the average pain score was 6 to 7 out of 10. 32 They were then randomized to a single dose of 400-mg, 600-mg, or 800-mg ibuprofen. An hour after taking the medication, there was no difference between groups, which all had pain scores between 4.4 and 4.5.

The third POEM in this group is a meta-analysis of studies comparing two doses of the recombinant zoster vaccine (Shingrix) with one dose of the live, attenuated vaccine (Zostavax) for the prevention of shingles. 33 Shingrix was more effective but caused more systemic adverse events, although mild, and more injection site pain.

Finally, a systematic review identified 46 studies of the impact of exercise on fall risk in patients 59 years or older. 34 Most of the programs used moderate-intensity exercise, with about one hour of exercise three times per week. The researchers found that exercise significantly decreased the overall risk of falls and resulting injuries but did not affect the risk of multiple falls, hospitalization, or mortality. Fractures were less likely in the exercise group but not significantly.

Practice Guidelines

POEMs sometimes summarize high-impact practice guidelines from important organizations. Key messages from the three highest-rated guidelines are summarized in Table 7 . 35 – 37

The American College of Chest Physicians recommends initiating direct oral anticoagulant therapy in patients with newly diagnosed atrial fibrillation, avoiding aspirin or aspirin plus clopidogrel (Plavix) to prevent thromboembolism, using risk scores for stroke and bleeding, and avoiding cotreatment with aspirin and an anticoagulant if possible. 35

The American Diabetes Association/European Association for the Study of Diabetes guideline for type 2 diabetes mellitus continues to recommend educating patients about diabetes self-management and providing support as the cornerstone of therapy, and metformin as the preferred initial therapy. 36 If a second agent is needed, there are many options, although glucagon-like peptide 1 receptor antagonists or sodium-glucose cotransporter 2 inhibitors are recommended for patients with established heart disease; sodium-glucose cotransporter 2 inhibitors are preferred for patients with heart failure or chronic kidney disease.

The American College of Physicians recommendations for breast cancer screening generally parallel those of the USPSTF, which are supported by the American Academy of Family Physicians. Recommendations include shared decision-making in women 40 to 49 years of age, biennial mammography from 50 to 74 years of age or until the woman's life expectancy is less than 10 years, and eliminating the clinical breast examination as a screening test for women who undergo regular mammography. 37 – 39

The full text of the POEMs discussed in this article is available at .

A list of top POEMs from previous years is available at .

Editor's Note: This article was cowritten by Dr. Mark Ebell, who is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell, Inc. Because of Dr. Ebell's dual roles and ties to Essential Evidence Plus, the concept for this article was independently reviewed and approved by a group of AFP 's medical editors. In addition, the article underwent peer review and editing by three of AFP 's medical editors. Dr. Ebell was not involved in the editorial decision-making process.—Sumi Sexton, MD, Editor-in-Chief.

The authors thank Wiley-Blackwell, Inc., for giving permission to excerpt the POEMs; Drs. Allen Shaughnessy, Henry Barry, David Slawson, Nita Kulkarni, and Linda Speer for their work in selecting and writing the original POEMs; the academic family medicine fellows and faculty of the University of Missouri–Columbia for their work as peer reviewers; Pierre Pluye, PhD, for his work in codeveloping the Information Assessment Method; and Maria Vlasak for her assistance with copyediting the POEMs for the past 26 years.

Shaughnessy AF, Slawson DC, Bennett JH. Becoming an information master: a guidebook to the medical information jungle. J Fam Pract. 1994;39(5):489-499.

Ebell MH, Barry HC, Slawson DC, et al. Finding POEMs in the medical literature. J Fam Pract. 1999;48(5):350-355.

Grad RM, Pluye P, Mercer J, et al. Impact of research-based synopses delivered as daily e-mail: a prospective observational study. J Am Med Inform Assoc. 2008;15(2):240-245.

Pluye P, Grad RM, Johnson-Lafleur J, et al. Evaluation of email alerts in practice: Part 2. Validation of the information assessment method. J Eval Clin Pract. 2010;16(6):1236-1243.

  • Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial [published online October 22, 2019]. Eur Heart J . 2019. Accessed March 10, 2020.

Roerecke M, Kaczorowski J, Myers MG. Comparing automated office blood pressure readings with other methods of blood pressure measurement for identifying patients with possible hypertension. A systematic review and meta-analysis. JAMA Intern Med. 2019;179(3):351-362.

Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder [published correction appears in Lancet . 2019;393(10182):1698]. Lancet. 2019;393(10173):768-777.

Paskins Z, Sanders T, Croft PR, et al. Non-disclosure of symptoms in primary care: an observational study. Fam Pract. 2018;35(6):706-711.

de Vries YA, Roest AM, Bos EH, et al. Predicting antidepressant response by monitoring early improvement of individual symptoms of depression: individual patient data meta-analysis. Br J Psychiatry. 2019;214(1):4-10.

Mora S, Chang CL, Moorthy MV, et al. Association of nonfasting vs fasting lipid levels with risk of major coronary events in the Anglo-Scandinavian Cardiac Outcomes Trial–lipid lowering arm. JAMA Intern Med. 2019;179(7):898-905.

Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407-415.

McNeil JJ, Wolfe R, Woods RL, et al.; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509-1518.

McNeil JJ, Woods RL, Nelson MR, et al.; ASPREE Investigator Group. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379(16):1499-1508.

Bowman L, Mafham M, Wallendszus K, et al.; ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529-1539.

Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile—a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016;37(25):1944-1958.

Grundy SM, Stone NJ. 2018 cholesterol clinical practice guidelines: Synopsis of the 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline. Ann Intern Med. 2019;170(11):779-783.

Moriarty F, Ebell MH. A comparison of contemporary versus older studies of aspirin for primary prevention [published online November 21, 2019]. Fam Pract . 2019. Accessed March 10, 2020.

Piepoli MF, Hoes AW, Agewall S, et al.; The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2016;37(29):2315-2381.

Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in J Am Coll Cardiol . 2019;74(10):1429–1430]. J Am Coll Cardiol. 2019;74(10):e177-e232.

Bibbins-Domingo K. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164(12):836-845.

U.S. Preventive Services Task Force. Aspirin use to prevent cardiovascular disease and colorectal cancer: preventive medication. April 2016. Accessed February 14, 2010.

Zorzi M, Hassan C, Capodaglio G, et al. Long-term performance of colorectal cancer screening programmes based on the faecal immunochemical test. Gut. 2018;67(12):2124-2130.

Nieuwenburg SAV, Vuik FER, Kruip MJHA, et al. Effect of anticoagulants and NSAIDs on accuracy of faecal immunochemical tests (FITs) in colorectal cancer screening: a systematic review and meta-analysis. Gut. 2019;68(5):866-872.

Tian Y, Kharazmi E, Sundquist K, et al. Familial colorectal cancer risk in half siblings and siblings: nationwide cohort study. BMJ. 2019;364:l803.

Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.

Segnan N, Senore C, Andreoni B, et al. Comparing attendance and detection rate of colonoscopy with sigmoidoscopy and FIT for colorectal cancer screening. Gastroenterology. 2007;132(7):2304-2312.

Schoen RE, Razzak A, Yu KJ, et al. Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer. Gastroenterology. 2015;149(6):1438-1445.e1.

Marchello CS, Ebell MH, Dale AP, et al. Signs and symptoms that rule out community-acquired pneumonia in outpatient adults: a systematic review and meta-analysis. J Am Board Fam Med. 2019;32(2):234-247.

Skoog Ståhlgren G, Tyrstrup M, Edlund C, et al. Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study. BMJ. 2019;367:l5337.

Hay AD, Anderson E, Ingle S, et al. Respiratory tract infections in children in the community: prospective online inception cohort study. Ann Fam Med. 2019;17(1):14-22.

Ray WA, Chung CP, Murray KT, et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA. 2018;320(21):2221-2230.

Motov S, Masoudi A, Drapkin J, et al. Comparison of oral ibuprofen at three single-dose regimens for treating acute pain in the emergency department: a randomized controlled trial. Ann Emerg Med. 2019;74(4):530-537.

Tricco AC, Zarin W, Cardoso R, et al. Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50 and older: systematic review and network meta-analysis. BMJ. 2018;363:k4029.

de Souto Barreto P, Rolland Y, Vellas B, et al. Association of long-term exercise training with risk of falls, fractures, hospitalizations, and mortality in older adults. A systematic review and meta-analysis. JAMA Intern Med. 2019;179(3):394-405.

Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest. 2018;154(5):1121-1201.

Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.

Qaseem A, Lin JS, Mustafa RA, et al. Screening for breast cancer in average-risk women: a guidance statement from the American College of Physicians. Ann Intern Med. 2019;170(8):547-560.

U.S. Preventive Services Task Force. Breast cancer: screening. January 2016. Accessed February 14, 2020.

American Academy of Family Physicians. Clinical preventive service recommendation. Breast cancer. Accessed February 14, 2020.

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Expert Commentary

5 common research designs: A quick primer for journalists

If you're not sure how a cross-sectional analysis differs from a randomized, controlled clinical trial, keep reading. We offer a broad overview of five of the most common research designs journalists encounter.

types research design explainer journalists

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by Denise-Marie Ordway, The Journalist's Resource July 9, 2021

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Journalists who read and cover academic research know scholars take a variety of approaches to investigate a problem, trend or intervention. But if you’re not familiar with research methods, it can be difficult to know what scientists mean when they say they have conducted, for example, a cross-sectional analysis or a randomized, controlled clinical trial.

Researchers often do not explain why they picked a particular study design or how it differs from others they could have chosen to interrogate the topic at hand.

We created this brief explainer to offer journalists a broad overview of five of the most common research designs they will encounter: longitudinal, cross-sectional, correlational, experimental and clinical trials. We’d like to point out that some research falls into more than one category — a study can be both longitudinal and correlational, for instance.

It’s also worth noting these five study types generally are considered quantitative research , which employs a mathematical analysis of the data collected to try to explain what’s being observed. Qualitative research , on the other hand, usually examines some aspect of human behavior by observing and interacting with people and their environments.


Longitudinal study

Here’s what it is: This type of study allows scholars to follow the same group of people over time, whether a few dozen people over a few weeks or millions of people over decades. Researchers monitor and measure changes through observation or by analyzing information gathered at regular intervals, often with surveys or in-person interviews.

Keep in mind: Longitudinal studies can be helpful for collecting data on a single topic or a wide array of topics across time. Some of these studies follow groups of people from childhood into and through adulthood, asking questions about their health, employment, relationship status and opinions on certain issues along the way.

An example: The Pre-Elementary Education Longitudinal Study followed a nationally representative sample of children with disabilities as they progressed from preschool into their early elementary school years. The study offers insights into special education services available to young children at the time, the family characteristics of kids with disabilities and the academic performance of students with disabilities during this stage of their lives.

Cross-sectional study

Here’s what it is: A cross-sectional study provides a snapshot of a group of people at a point in time. Researchers use cross-sectional studies to examine such things as U.S. doctors’ attitudes toward euthanasia or the prevalence of soda consumption among women over age 40. These studies often allow scholars to compare subgroups of the study population — for instance, comparing soda consumption among women over age 40 according to their race, country of origin, household income and education level.

Keep in mind: Because a cross-sectional study captures data from a single moment in time, its timing can affect results. People might behave or answer questions differently after a major event such as a natural disaster or international controversy.

An example: A paper published in the BMJ Open medical journal in 2019 examines the characteristics that police reporting symptoms of professional burnout have in common. The authors of “ Associations Between Shift Work Characteristics, Shift Work Schedules, Sleep and Burnout in North American Police Officers: A Cross-Sectional Study ,” learned that of the 3,140 North American police officers who participated in the study, those working irregular schedules were most at risk of burnout.

Correlational study

Here’s what it is: Scientists perform correlational studies to determine whether a relationship exists between two or more variables — weather and indoor air quality, for instance, or exercise and mental acuity. Correlation can tell researchers if the relationship is positive, meaning the variables being studied increase or decrease together, or whether it is negative, meaning one variable decreases as the other increases.

This research design can provide some insight into how strong that relationship is. However, scientists must use more advanced statistical analysis methods such as regression to determine the strength and nature of the relationship. They also can extrapolate data to make predictions about how the variables will behave in each other’s presence over time or as conditions change.

Keep in mind: Just because scholars find a relationship exists between two variables does not mean one variable causes the other to behave in a certain way.Establishing causation requires additional research and analysis. Researchers can use an experimental study design, which we explain below, to determine causal relationships between variables in a controlled environment.

An example: An article that appeared last year in Human Behavior and Emerging Technologies looks at the relationship between social media use and the mental health of Latinos living in southern California.  In the paper, “ Social Media Use and Depression, Anxiety, and Stress in Latinos: A Correlational Study ,” researchers find that social media “is a significant predictor of stress but not of depression or anxiety” for study participants and that the impact of social media varied depending on how long they and their families had lived in the U.S.

Experimental study

Here’s what it is: Experimental research, which employs one of the most rigorous research designs, is best suited for examining cause-and-effect relationships. When conducting this type of study, scholars typically introduce an intervention of some sort into a controlled environment that allows scholars to isolate and investigate the effect of the intervention. The intervention could be a new program, product or procedure. Researchers also can use an experimental study to test how people react to stimuli such as violence in news videos or changes to food labels.

Keep in mind: Often in experimental studies, researchers create a control group for comparison purposes. The control group will be similar to the group testing the intervention but won’t be exposed to the intervention. By including the control group, researchers can more accurately determine whether the intervention led to changes.

An example: A study published in 2019 in Political Behavior features three experiments aimed at gauging how white voters in the U.S. respond to seeing Democratic presidential candidates courting Latino voters. As the author explains in “ The New White Flight?: The Effects of Political Appeals to Latinos on White Democrats ,” white voters viewed presidential campaign ads or read news headlines about the election and then responded to questions about how they felt about the candidates, including who they planned to support in the election.

Clinical trial

Here’s what it is: If scientists want to evaluate the safety and effectiveness of a health-related intervention, they conduct clinical trials. “Clinical trials are research studies performed in people that are aimed at evaluating a medical, surgical, or behavioral intervention ,” according to the U.S. Department of Health and Human Services. “They are the primary way that researchers find out if a new treatment, like a new drug or diet or medical device (for example, a pacemaker) is safe and effective in people.”

Clinical trials of new treatments have four phases, beginning with testing the safety of a new treatment and ending with monitoring its use after the U.S. Food and Drug Administration licenses and approves it.

Keep in mind: Randomized controlled trials are widely considered the gold standard in research, but they’re also expensive . For these studies, patients are randomly assigned to groups that usually are the same or similar in size. One group receives or participates in the intervention. The group that serves as the control receives a placebo or participates in an activity unrelated to the intervention being tested. Researchers compare what happened with the intervention group against what they learned about the control group.

An example: Researchers tested whether tailored messaging would encourage U.S. mothers who expressed concerns about the human papillomavirus vaccine to get their adolescent children immunized. Their findings are described in “ Tailored Messages Addressing Human Papillomavirus Vaccination Concerns Improves Behavioral Intent Among Mothers: A Randomized Controlled Trial ,” published in the Journal of Adolescent Health in August 2020.

If you found this explainer helpful, please check out our tip sheets on covering scientific failures , spotting bias in clinical trials and differentiating between good and flawed research .

The Journalist’s Resource would like to thank Anne M. Cafer , an assistant professor of sociology and co-director of the University of Mississippi’s Community First Research Center for Wellbeing & Creative Achievement , for offering her guidance and insights in creating this explainer.

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Denise-Marie Ordway


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Sat / act prep online guides and tips, 113 great research paper topics.

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General Education


One of the hardest parts of writing a research paper can be just finding a good topic to write about. Fortunately we've done the hard work for you and have compiled a list of 113 interesting research paper topics. They've been organized into ten categories and cover a wide range of subjects so you can easily find the best topic for you.

In addition to the list of good research topics, we've included advice on what makes a good research paper topic and how you can use your topic to start writing a great paper.

What Makes a Good Research Paper Topic?

Not all research paper topics are created equal, and you want to make sure you choose a great topic before you start writing. Below are the three most important factors to consider to make sure you choose the best research paper topics.

#1: It's Something You're Interested In

A paper is always easier to write if you're interested in the topic, and you'll be more motivated to do in-depth research and write a paper that really covers the entire subject. Even if a certain research paper topic is getting a lot of buzz right now or other people seem interested in writing about it, don't feel tempted to make it your topic unless you genuinely have some sort of interest in it as well.

#2: There's Enough Information to Write a Paper

Even if you come up with the absolute best research paper topic and you're so excited to write about it, you won't be able to produce a good paper if there isn't enough research about the topic. This can happen for very specific or specialized topics, as well as topics that are too new to have enough research done on them at the moment. Easy research paper topics will always be topics with enough information to write a full-length paper.

Trying to write a research paper on a topic that doesn't have much research on it is incredibly hard, so before you decide on a topic, do a bit of preliminary searching and make sure you'll have all the information you need to write your paper.

#3: It Fits Your Teacher's Guidelines

Don't get so carried away looking at lists of research paper topics that you forget any requirements or restrictions your teacher may have put on research topic ideas. If you're writing a research paper on a health-related topic, deciding to write about the impact of rap on the music scene probably won't be allowed, but there may be some sort of leeway. For example, if you're really interested in current events but your teacher wants you to write a research paper on a history topic, you may be able to choose a topic that fits both categories, like exploring the relationship between the US and North Korea. No matter what, always get your research paper topic approved by your teacher first before you begin writing.

113 Good Research Paper Topics

Below are 113 good research topics to help you get you started on your paper. We've organized them into ten categories to make it easier to find the type of research paper topics you're looking for.


  • Discuss the main differences in art from the Italian Renaissance and the Northern Renaissance .
  • Analyze the impact a famous artist had on the world.
  • How is sexism portrayed in different types of media (music, film, video games, etc.)? Has the amount/type of sexism changed over the years?
  • How has the music of slaves brought over from Africa shaped modern American music?
  • How has rap music evolved in the past decade?
  • How has the portrayal of minorities in the media changed?


Current Events

  • What have been the impacts of China's one child policy?
  • How have the goals of feminists changed over the decades?
  • How has the Trump presidency changed international relations?
  • Analyze the history of the relationship between the United States and North Korea.
  • What factors contributed to the current decline in the rate of unemployment?
  • What have been the impacts of states which have increased their minimum wage?
  • How do US immigration laws compare to immigration laws of other countries?
  • How have the US's immigration laws changed in the past few years/decades?
  • How has the Black Lives Matter movement affected discussions and view about racism in the US?
  • What impact has the Affordable Care Act had on healthcare in the US?
  • What factors contributed to the UK deciding to leave the EU (Brexit)?
  • What factors contributed to China becoming an economic power?
  • Discuss the history of Bitcoin or other cryptocurrencies  (some of which tokenize the S&P 500 Index on the blockchain) .
  • Do students in schools that eliminate grades do better in college and their careers?
  • Do students from wealthier backgrounds score higher on standardized tests?
  • Do students who receive free meals at school get higher grades compared to when they weren't receiving a free meal?
  • Do students who attend charter schools score higher on standardized tests than students in public schools?
  • Do students learn better in same-sex classrooms?
  • How does giving each student access to an iPad or laptop affect their studies?
  • What are the benefits and drawbacks of the Montessori Method ?
  • Do children who attend preschool do better in school later on?
  • What was the impact of the No Child Left Behind act?
  • How does the US education system compare to education systems in other countries?
  • What impact does mandatory physical education classes have on students' health?
  • Which methods are most effective at reducing bullying in schools?
  • Do homeschoolers who attend college do as well as students who attended traditional schools?
  • Does offering tenure increase or decrease quality of teaching?
  • How does college debt affect future life choices of students?
  • Should graduate students be able to form unions?


  • What are different ways to lower gun-related deaths in the US?
  • How and why have divorce rates changed over time?
  • Is affirmative action still necessary in education and/or the workplace?
  • Should physician-assisted suicide be legal?
  • How has stem cell research impacted the medical field?
  • How can human trafficking be reduced in the United States/world?
  • Should people be able to donate organs in exchange for money?
  • Which types of juvenile punishment have proven most effective at preventing future crimes?
  • Has the increase in US airport security made passengers safer?
  • Analyze the immigration policies of certain countries and how they are similar and different from one another.
  • Several states have legalized recreational marijuana. What positive and negative impacts have they experienced as a result?
  • Do tariffs increase the number of domestic jobs?
  • Which prison reforms have proven most effective?
  • Should governments be able to censor certain information on the internet?
  • Which methods/programs have been most effective at reducing teen pregnancy?
  • What are the benefits and drawbacks of the Keto diet?
  • How effective are different exercise regimes for losing weight and maintaining weight loss?
  • How do the healthcare plans of various countries differ from each other?
  • What are the most effective ways to treat depression ?
  • What are the pros and cons of genetically modified foods?
  • Which methods are most effective for improving memory?
  • What can be done to lower healthcare costs in the US?
  • What factors contributed to the current opioid crisis?
  • Analyze the history and impact of the HIV/AIDS epidemic .
  • Are low-carbohydrate or low-fat diets more effective for weight loss?
  • How much exercise should the average adult be getting each week?
  • Which methods are most effective to get parents to vaccinate their children?
  • What are the pros and cons of clean needle programs?
  • How does stress affect the body?
  • Discuss the history of the conflict between Israel and the Palestinians.
  • What were the causes and effects of the Salem Witch Trials?
  • Who was responsible for the Iran-Contra situation?
  • How has New Orleans and the government's response to natural disasters changed since Hurricane Katrina?
  • What events led to the fall of the Roman Empire?
  • What were the impacts of British rule in India ?
  • Was the atomic bombing of Hiroshima and Nagasaki necessary?
  • What were the successes and failures of the women's suffrage movement in the United States?
  • What were the causes of the Civil War?
  • How did Abraham Lincoln's assassination impact the country and reconstruction after the Civil War?
  • Which factors contributed to the colonies winning the American Revolution?
  • What caused Hitler's rise to power?
  • Discuss how a specific invention impacted history.
  • What led to Cleopatra's fall as ruler of Egypt?
  • How has Japan changed and evolved over the centuries?
  • What were the causes of the Rwandan genocide ?


  • Why did Martin Luther decide to split with the Catholic Church?
  • Analyze the history and impact of a well-known cult (Jonestown, Manson family, etc.)
  • How did the sexual abuse scandal impact how people view the Catholic Church?
  • How has the Catholic church's power changed over the past decades/centuries?
  • What are the causes behind the rise in atheism/ agnosticism in the United States?
  • What were the influences in Siddhartha's life resulted in him becoming the Buddha?
  • How has media portrayal of Islam/Muslims changed since September 11th?


  • How has the earth's climate changed in the past few decades?
  • How has the use and elimination of DDT affected bird populations in the US?
  • Analyze how the number and severity of natural disasters have increased in the past few decades.
  • Analyze deforestation rates in a certain area or globally over a period of time.
  • How have past oil spills changed regulations and cleanup methods?
  • How has the Flint water crisis changed water regulation safety?
  • What are the pros and cons of fracking?
  • What impact has the Paris Climate Agreement had so far?
  • What have NASA's biggest successes and failures been?
  • How can we improve access to clean water around the world?
  • Does ecotourism actually have a positive impact on the environment?
  • Should the US rely on nuclear energy more?
  • What can be done to save amphibian species currently at risk of extinction?
  • What impact has climate change had on coral reefs?
  • How are black holes created?
  • Are teens who spend more time on social media more likely to suffer anxiety and/or depression?
  • How will the loss of net neutrality affect internet users?
  • Analyze the history and progress of self-driving vehicles.
  • How has the use of drones changed surveillance and warfare methods?
  • Has social media made people more or less connected?
  • What progress has currently been made with artificial intelligence ?
  • Do smartphones increase or decrease workplace productivity?
  • What are the most effective ways to use technology in the classroom?
  • How is Google search affecting our intelligence?
  • When is the best age for a child to begin owning a smartphone?
  • Has frequent texting reduced teen literacy rates?


How to Write a Great Research Paper

Even great research paper topics won't give you a great research paper if you don't hone your topic before and during the writing process. Follow these three tips to turn good research paper topics into great papers.

#1: Figure Out Your Thesis Early

Before you start writing a single word of your paper, you first need to know what your thesis will be. Your thesis is a statement that explains what you intend to prove/show in your paper. Every sentence in your research paper will relate back to your thesis, so you don't want to start writing without it!

As some examples, if you're writing a research paper on if students learn better in same-sex classrooms, your thesis might be "Research has shown that elementary-age students in same-sex classrooms score higher on standardized tests and report feeling more comfortable in the classroom."

If you're writing a paper on the causes of the Civil War, your thesis might be "While the dispute between the North and South over slavery is the most well-known cause of the Civil War, other key causes include differences in the economies of the North and South, states' rights, and territorial expansion."

#2: Back Every Statement Up With Research

Remember, this is a research paper you're writing, so you'll need to use lots of research to make your points. Every statement you give must be backed up with research, properly cited the way your teacher requested. You're allowed to include opinions of your own, but they must also be supported by the research you give.

#3: Do Your Research Before You Begin Writing

You don't want to start writing your research paper and then learn that there isn't enough research to back up the points you're making, or, even worse, that the research contradicts the points you're trying to make!

Get most of your research on your good research topics done before you begin writing. Then use the research you've collected to create a rough outline of what your paper will cover and the key points you're going to make. This will help keep your paper clear and organized, and it'll ensure you have enough research to produce a strong paper.

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Christine graduated from Michigan State University with degrees in Environmental Biology and Geography and received her Master's from Duke University. In high school she scored in the 99th percentile on the SAT and was named a National Merit Finalist. She has taught English and biology in several countries.

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6 Common Flaws To Look Out For in Peer Review

common research article

Joanna Wilkinson

It’s not always easy to spot flaws in research papers. Sometimes an error is glaringly obvious – like a vague abstract with no aim and little data – and other times it’s like finding a needle in a stack of pins. (Like, really, really sharp pins that leave you dreaming of haystacks). Luckily, the solution isn’t all that prickly. The trick is knowing what to look for during peer review, where to find it and, importantly, how severe the error is.

To help with this, we’ve pulled together a list of six common flaws you can watch out for as a reviewer.

Here are the 6 common flaws to look out for in peer review:

1) Inappropriate study design for the study aims 2) Unexplained deviations from standard/best practice and methodologies 3) Over-interpretation of results 4) Commenting beyond the scope of the article 5) Lack of evidence to support conclusions 6) Too many words

This blog post is informed by a module within our free peer review training course, the  Publons Academy . Join today to learn the core competencies of peer review. With one-to-one support from your mentor, you’ll write reviews of real papers, gain access to our Review Template and review examples, and by the end of it, we’ll put you in front of journal editors in your field as a certified peer reviewer.

We discuss each common flaw to watch out for below, but first, a quick recap about the importance of peer review and how it can improve your own research.

Why peer review is important

As a peer reviewer, you play a vital role in protecting the quality and integrity of scientific research. Your peers rely on this work to understand what research to trust and build on, leading to better, faster science.

Your manuscripts will also improve because, over time, you’ll learn how to use your knowledge in peer review to fine-tune your own research.

Peer reviewing will help you evaluate the importance and accuracy of your research question; the appropriateness of methodological and statistical approaches; and build up a set of best-practice tips to prepare and organize your research project. And finally, by learning common errors to watch out for when peer reviewing, you’ll inevitably learn to avoid the same mistakes in your own research, which will increase your chances of getting published.

6 Common Research Flaws and How to Spot them in a Manuscript

A quick caveat:  this isn’t an extensive list! Research errors differ for every field as do the types of studies conducted. This is a helpful starting point, however, that will enable you to guard against the more common mistakes made in a manuscript. Once you start accepting more invites to review and become more confident reading a manuscript critically, you can build on this list with more specialized examples.

1. Inappropriate study design for the study aims

A study’s design is crucial to obtaining valid and scientifically sound results. Familiarise yourself with those commonly used in your field of research. If you come across an uncommon study design, read the researchers’ use and justification of it carefully, and question how it might affect their data and analysis. Review the study design critically but also remember to be open-minded. Just because something is new and unfamiliar it does not automatically mean it is incorrect or flawed.

2. Unexplained deviations from standard/best practice and methodologies

Similar to the above. The methods section, for example, should explain the steps taken to produce the results. If these are not clear or you’re left questioning their validity, it’s important to make your concerns known. And if they are unusual then, as with the study design, examine the researchers’ justification carefully with the view to ask more questions if necessary. Non-academic discourse, whereby opinionated and biased statements are used throughout the study, is another deviation from best practice

3. Over-interpretation of results

Over-interpretation has no place in research. Ensure the conclusions drawn in the paper are based on the data presented and are not extrapolated beyond that (to a larger population or ecological setting, for example). You should also watch out for studies that focus on seemingly important differences where none exist.

4. Commenting beyond the scope of the article

“That’s beyond the scope of this paper” is a common phrase in academic writing. As a reviewer, watch out for papers that include comments or statements not pertaining to the research project and data at hand.

5. Lack of evidence to support conclusions

A research paper’s concluding statements must be justified and evidence-based. If you’re not convinced of the results, it could mean the researchers need to clarify aspects of their methodological procedure, add more references to support their claims, or include additional data or further analysis.

6. Too many words

A common pain point in manuscripts is that it’s too wordy. It’s important to keep check on this scenario and encourage clear, concise and effective text where possible. Too many words can be distracting for the reader, which at best could cause them to lose interest and at worst could lead to them misinterpreting the research.

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105 Questions to Ask When Reviewing a Research Article

Poring over the pages of a research article can feel like navigating a labyrinth. You’re in pursuit of the truth, but the path is winding, and each choice of direction is pivotal. As a critic, a peer reviewer, or simply an inquisitive reader, you understand the potential impact that a well-conducted study can have on the world.

Unlocking that potential begins with a meticulously critical review guided by questions—questions that cut through the data like a surgeon’s scalpel, revealing the heart of the study’s validity and value.

Let’s prime your inquisitive mind with essential inquiries to illuminate the strengths and shortcomings of any research article.

Table of Contents

Understanding the Research Foundation

  • What is the primary research question the article is addressing?
  • Is the literature review relevant and comprehensive?
  • How does this study contribute to the existing body of knowledge?
  • Does the research address a significant problem in the field?
  • Are the research objectives clearly stated?
  • How well does the study formulate its hypotheses or research questions?
  • Are the theoretical framework and background context well articulated?
  • Does the article sufficiently justify the relevance of the research?
  • Are there any apparent biases in the way the research question is framed?
  • How does the research build upon or challenge existing theories?
  • Is there a clear connection between the research question and the methodology?
  • Does the article clearly state its aims and scope?
  • Are any assumptions made in the research explicitly stated?
  • Is the importance of the research question evident to non-specialists?
  • Are there areas within the research foundation that could benefit from further clarification?

Assessing the Research Methods

  • Are the methods appropriate for the research question?
  • Is the study design clearly explained and appropriate?
  • Have the instruments used for data collection been adequately described?
  • Are the methods of data analysis suitable for answering the research question?
  • Were any controls used to prevent bias, and are they effective?
  • Is there a clear explanation of how participants or samples were selected?
  • Does the study acknowledge and account for any limitations in the methodology?
  • Are procedures described in enough detail to replicate the study?
  • Is the choice of statistical tests clearly justified?
  • Were all methods ethically sound?
  • Does the author explain the steps taken to ensure data reliability and validity?
  • Have the methods been presented transparently?
  • Does the article discuss the generalizability of the methods to other contexts?
  • Are there any potential confounding variables, and how are they addressed?
  • Is the sampling method adequately justified and explained?

Analyzing the Results

  • Are the results presented in a clear and organized way?
  • Do tables and figures effectively communicate the findings?
  • Are all claimed results supported by the data?
  • Does the study appropriately discuss any unexpected or unusual findings?
  • Are the results contextually interpreted with sufficient caution?
  • Is there evidence of data saturation in qualitative studies?
  • Does the author distinguish between correlation and causation where applicable?
  • Are percentages and numerical results given with appropriate precision?
  • Have the results been discussed in relation to the research question?
  • Are any findings that do not support the hypotheses adequately acknowledged and discussed?
  • Is the variability in the data acknowledged and explained?
  • Has the study reported the effect sizes where relevant?
  • Are the results consistent with the results from similar studies?
  • Does the author avoid overgeneralizing the findings?
  • Are all the results derived from the methodology described, or are there unaccounted-for results?

Evaluating the Discussion and Conclusions

  • Do the discussion and conclusions logically follow from the results?
  • Are the implications of the results clearly spelled out?
  • Does the discussion acknowledge the study’s limitations?
  • How well does the article relate the findings to the broader context of the field?
  • Are all findings integrated into the conclusion, including those that don’t fully support the hypotheses?
  • Are the conclusions well-reasoned and supported by evidence?
  • Does the discussion consider alternative explanations for the findings?
  • Are recommendations for future research made?
  • Does the author overstate the significance of the results?
  • Has the study’s contribution to new knowledge been articulated well?
  • Do the conclusions address the aims stated at the beginning of the paper?
  • Is there evidence of reflexivity in acknowledging the researcher’s role?
  • Are conclusions kept within the bounds of the research design and data?
  • How does the research advance the field or influence practice?
  • Is there a call to action or practical application identified in the conclusions?

Considering the Practical Implications

  • Are the practical implications of the research clearly outlined?
  • How does the research address real-world issues?
  • Are recommendations for practitioners or policymakers discussed?
  • Is the impact on society or the environment considered?
  • Is there potential for the research to influence public policy or regulations?
  • How might the results be applied in the field?
  • Does the study provide insights that could lead to technological innovations?
  • Are ethical considerations in applying the research findings addressed?
  • Is there a clear audience or beneficiary of the research implications?
  • How can the findings be used to inform future research or professional practice?
  • Does the research suggest new areas for practical experimentation or implementation?
  • Are the financial or economic implications of the research evaluated?
  • Does the article suggest any changes to current standards or protocols?
  • How accessible are the implications to stakeholders outside of academia?
  • Do the practical implications take into account diverse contexts and populations?

Reviewing the Structure and Presentation

  • Is the article structured logically and systematically?
  • Does the title accurately describe the content of the article?
  • Are all sections of the paper, including the abstract and keywords, effectively presented?
  • Is the writing clear, concise, and easy to follow?
  • Does the paper avoid unnecessary jargon and define essential terms?
  • Is there a smooth flow and transitions between sections?
  • Are any graphs, charts, or images appropriate and clearly labeled?
  • Does the paper meet the scholarly standards for formatting and style?
  • Is the quality of English language usage appropriate for publication?
  • Are all necessary acknowledgments or disclaimers included?
  • Does the introduction effectively set up the importance of the research and outline the paper?
  • Is the conclusion concise and does it summarize the key findings?
  • Are the table of contents and/or index clear and correct?
  • Is the overall presentation appealing to the journal’s readership?
  • Does the paper adhere to the targeted journal’s guidelines for authors?

Checking for Ethical Compliance and Citation Integrity

  • Are the sources of funding and any potential conflicts of interest disclosed?
  • Is evidence of informed consent or IRB approval mentioned for studies with human participants?
  • Are raw data and materials available as per ethical guidelines?
  • Is proper attribution given to all sources and previous research?
  • Are the citations up-to-date and relevant to the content of the article?
  • Is there any sign of plagiarism or self-plagiarism?
  • Does the article adhere to ethical standards regarding animal research if applicable?
  • Have the authors been transparent about their contribution to the research?
  • Are the limitations regarding the ethical aspects of the research acknowledged?
  • Are quotes and figures from other works properly cited?
  • Does the work avoid undue harm in the presentation of graphic or sensitive material?
  • Is there a declaration of any data manipulation or image enhancement?
  • Are citation practices consistent throughout the document?
  • Has the article avoided sensationalism or overstating research findings?
  • Are appropriate permissions documented for copyrighted material?

Frequently Asked Questions

Why is it important to review a research article critically.

Reviewing a research article critically is crucial because it ensures the integrity, reliability, and impact of academic work. It helps to identify strengths and weaknesses within a study, improve research quality, and foster scientific progress.

What should I focus on when assessing a research article’s methodology?

When assessing methodology, focus on whether the methods are suitable for the research question, the study design is solid, and the procedures are meticulously described and ethical. It’s also vital to consider the data analysis, selection of participants, and the method of reporting results.

How do I know if the results of the article are credible?

Results are credible if they are clear, logically presented, supported by the data, and statistically validated. They should align with the methodology and address the research question effectively.

What if I find ethical issues in the research article?

Ethical issues should be addressed by evaluating the transparency of funding, conflicts of interest, adherence to ethical research guidelines, and whether there is informed consent if applicable. If ethical issues are present, they should be reported to the journal or relevant authorities.

Final Thoughts

Evaluating a research article is not dissimilar to assembling a jigsaw puzzle, where every question you pose helps piece the narrative together, giving clarity to blurred lines and bringing context into sharper focus.

Remember, the right questions don’t just lead to answers—they challenge assumptions, push boundaries, and pave the way for innovation and improvement. With this list of questions, you’re equipped to traverse the intricate layers of any research work and emerge with insights as powerful as the studies they scrutinize.

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Bea Mariel Saulo

April 16, 2024

10 min read

New Prostate Cancer Treatments Offer Hope for Advanced Cases

Major discoveries during the past 10 years have transformed prostate cancer treatment, enabling it to proceed even for the most advanced form of the disease

By Marc B. Garnick

Cutaway illustration shows the position of the prostate, a walnut-size gland in the pelvic cavity. It generates fluid that mixes with sperm from the testes and seminal vesicle fluid to make semen, which exits the body through the urethra.

David Cheney

D eciding how to diagnose and treat prostate cancer has long been the subject of controversy and uncertainty. A prime example involves prostate-specific antigen (PSA) testing, a blood test for a telltale protein that can reveal cancer even when the patient has no symptoms. After its introduction in the early 1990s, PSA testing was widely adopted—millions of tests are done in the U.S. every year. In 2012, however, a government task force indicated that this test can lead to overtreatment of cancers that might have posed little danger to patients and so might have been best left alone.

While arguments for and against PSA testing continue to seesaw back and forth, the field has achieved a better grasp on what makes certain prostate cancers grow quickly, and those insights have paved the way for better patient prognoses at every stage of the disease, even for the most advanced cases. A prostate cancer specialist today has access to an enhanced tool set for treatment and can judge when measures can be safely deferred.

The importance of these advances cannot be overstated. Prostate cancer is still one of the most prevalent malignancies. Aside from some skin cancers, prostate cancers are the most common cancers among men in the U.S. Nearly 270,000 people in America will be diagnosed with prostate cancer this year, and it is the fourth most common cancer worldwide. Fortunately, the vast majority of patients will live for years after being diagnosed and are more likely to die of causes unrelated to a prostate tumor.

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At its most basic level, prostate cancer is a malignancy that occurs in the prostate gland, which produces fluid that mixes with sperm from the testicles to make semen. The prostate is located in front of the rectum, below the bladder and above the penis, and cancer in the gland has four major stages.

Early on, localized tumors show no evidence of extension beyond the prostate gland. A second, “regionally advanced” form of the disease remains close to the prostate. Then there are metastatic prostate cancers, which spread outside the gland to other parts of the body. Treatment of tumors in this category has benefited from improved diagnostic imaging tests. In fact, with these tests, cancer specialists have characterized the fourth category, oligometastatic prostate cancer, a disease stage on a continuum between localized prostate cancer and more broadly dispersed metastatic disease. Major discoveries in the past 10 years have transformed the way we approach each type of prostate cancer, and these advances are likely to continue for decades to come.

The first treatment steps for people with localized cancer involve risk stratification. Through this process, a physician gauges the likelihood of a cancer’s being eliminated or cured by local treatment (usually surgery or radiation) and, if it does abate, of its returning. A physician determines the risk based on PSA results, physical examination of the prostate gland and inspection of cells from the biopsied tumor.

The right course of action for a patient with elevated PSA levels continues to undergo constant revision. Until five to seven years ago, a physician evaluated a person with high PSA by feeling their prostate gland for potentially cancerous abnormalities. Invariably, the next step would be a needle biopsy—an uncomfortable procedure in which the physician obtains snippets of prostate tissue through the rectum.

But we now have a way to biopsy through the perineum—the area between the back of the scrotum and the anal-rectal area. Thanks to technical improvements, it can be done in an outpatient setting without general anesthesia or sedation. The technique reduces the patient’s risk of infection and need for antibiotics because it doesn’t disrupt the bacterial flora in the rectum. In a recent study, researchers compared outcomes in patients who underwent a trans­rectal biopsy and received antibiotics with those for people who had a transperineal biopsy with minimal to no antibiotics. They found the two approaches comparable in terms of complications from infections.

Even more exciting is the prospect of eliminating biopsies altogether. When a patient has an abnormal PSA value but their rectal examination shows no obvious evidence of cancerous deposits, physicians can now use magnetic resonance imaging (MRI) to look at the prostate and surrounding tissue. MRI scans are best for identifying clinically significant cancers—those that, if left untreated or undiagnosed, could eventually spread. MRI can also uncover more extensive cancer spread or tumors in unusual locations such as the front of the prostate.

Cutaway illustration shows the position of the prostate, a walnut-size gland in the pelvic cavity. It generates fluid that mixes with sperm from the testes and seminal vesicle fluid to make semen, which exits the body through the urethra.

Another benefit of MRI procedures is that they identify fewer clinically insignificant cancers—those that are unlikely to cause problems and might best be left alone. In this case, failure to detect certain cancers is a good thing because it spares people unnecessary treatment. In some medical centers in the U.S. and many in Europe, a physician will perform a biopsy only if the MRI scan does reveal evidence of clinical significance. Studies that have compared the two diagnostic approaches—routine biopsy for all patients with elevated PSA levels versus biopsies based on abnormal MRI findings—found they are similarly effective at detecting clinically significant cancers.

Once a patient is diagnosed with prostate cancer, what happens next? For decades the debate over treatment has been just as contentious as the debate over diagnosis. Fortunately, new research from the U.K. has provided some clarity. Investigators there studied several thousand people with elevated PSA levels whose prostate biopsies showed cancer. These patients were randomized to receive surgical removal of the cancerous gland, radiation treatments or no active treatment at all. At the end of 15 years of comprehensive follow-up, about 3 percent of patients in each group had died of prostate cancer, and nearly 20 percent in each group had died of unrelated causes.

Based on the results of this study and others, more people are now being offered “active surveillance” after a prostate cancer diagnosis, in which treatment is either delayed or avoided altogether. Careful monitoring of patients who have not undergone surgery or radiation is becoming more common; it is now being extended even to those with more worrisome tumors. The monitoring involves a range of measures: PSA testing every three to six months, physical examination of the prostate gland and assessment of the patient’s urinary symptoms. Those tests are followed by repeat biopsies at increasing intervals, as long as there are no significant pathological changes.

If a cancer is identified as having either intermediate- or high-risk features, doctors need to track its progression, usually with bone scans using radio­­pharma­ceut­i­cals and with abdominal-pelvic computed tomography (CT) scans, which may show any spread in the areas to which prostate cancer most often metastasizes. Unfortunately, these techniques are not sensitive enough to reliably detect cancer in structures less than a centimeter in diameter, such as lymph nodes. Consequently, small areas of metastatic disease may go undetected. These cases are said to be “understaged.”

Understaging can now be studied through more precise diagnostic testing. Typically patients whose disease is understaged are not treated until the cancer becomes detectable through symptoms such as urination problems or pain. The disease then may require intensive therapies, and there is less of a chance of long-term remission. One technology that can help address understaging is advanced scanning that combines radiodiagnostic positron-emission tomography (PET) with CT.

These scans can detect molecules commonly found in prostate cancer cells, such as prostate-specific membrane antigen (PSMA). If PSMA is present outside the prostate gland, such as in pelvic lymph nodes, the affected areas can be identified, and a plan can be made for targeted radiation treatments or surgical removal.

Let’s consider how PET-CT scanning can be used in clinical practice. One of my patients, a 68-year-old man, was diagnosed with prostate cancer that was localized but had high-risk features. The traditional diagnostic bone and CT scans did not show any evidence of cancer spread outside the prostate. A PET-CT scan for PSMA, however, did reveal the presence of several small deposits of cancer cells in well-defined areas of the pelvis, indicating the cancer had spread to the lymph nodes. This finding prompted treatment that included radiation therapy in the prostate gland and the cancerous lymph nodes, as well as androgen-deprivation therapy (ADT), a treatment that reduces levels of testosterone, the hormone that enables prostate cancer to grow and progress.

The more precise identification of small tumor deposits in a limited number of pelvic lymph nodes—diagnosed as oligometastatic prostate cancer—enabled a new use for an old technology in oncology called metastasis-directed therapy (MDT), which targets cancer-containing lymph nodes or bony areas with radiation. At times, surgical removal of the abnormal lymph nodes may also be incorporated into MDT. Recently published studies on the use of MDT in conjunction with conventional treatments show, in some cases, long-term remission lasting through years of follow-up. Until recently, such a scenario was unthinkable for people whose prostate cancer had spread to their lymph nodes. My patient had the PSMA scan and MDT, as well as a relatively short course of ADT. He is cancer-free for now.

Precise identification of small metastatic deposits has other positive benefits. ADT has for decades been the mainstay for treating many forms of prostate cancer. Patients must continue the therapy for years, sometimes for the rest of their lives. Side effects of ADT are similar to those experienced during menopause. In fact, “andropause” is the term that captures the effects of ADT. Lower levels of testosterone are accompanied by a multitude of symptoms, including but not limited to loss of libido, erectile dysfunction, weight gain, hot flashes, bone loss, cognitive impairment, mood changes, diminished energy, and worsening of preexisting heart and vascular problems.

Studies of MDT for oligometastatic prostate cancer have raised the question of whether ADT could be delayed, administered for a shorter duration or even omitted in patients who otherwise would have required it. By strategically deploying traditional forms of localized treatment—usually surgery to remove the prostate gland or radiation—with added MDT for oligometastatic disease, doctors can significantly shorten the duration of ADT or potentially eliminate it. Such an approach would have been difficult to imagine five years ago. Longer-term follow-up studies will help scientists determine whether some people diagnosed in this fashion can go into an extended remission.

F or advanced forms of prostate cancer that have spread to other parts of the body, ADT has been the main treatment. Physicians historically have generally recommended surgical removal of the testicles—the primary source of testosterone—or the administration of other hormones that block the production and action of testosterone. In the mid-1980s I was involved with research on drugs called luteinizing hormone–releasing hormone analogues that lowered testosterone by shutting off the signal in the brain that instructs the testicles to make testosterone. Today newer agents have been added that further lower and block testosterone’s action.

The goal of prostate cancer treatment at later stages is to eliminate multiple sources of testosterone. As noted earlier, testosterone in the body comes predominantly from the testicles; the adrenal glands also produce a small amount. But prostate cancer cells can evolve to produce their own androgens. Testosterone and its active form, dihydrotestosterone (DHT), traverse the membranes of prostate cancer cells and interact with androgen receptors in the cytoplasm, a cell’s liquid interior. The receptors then transport DHT to the nucleus, where it instructs the cancer cell to grow, replicate and spread.

Traditional ADT does little to affect either the production of testosterone by the adrenal glands or androgen-producing prostate cancer cells, and it doesn’t block the activity of androgen receptors. But new approaches to ADT may address these shortcomings. Drug combinations that affect all these processes have substantially improved survival in people with metastatic prostate cancer—and, more important, patients are able to tolerate these more intensive treatment programs.

Instead of just one drug to decrease testosterone, new standards for treatment prescribe combinations of two or even three drugs. In addition to traditional ADT, there are medications such as do­cetaxel, a chemotherapy, and other new drugs that can block the production of testosterone by the adrenal glands or cancer cells or stop it by interfering with the activity of androgen receptors. All these drug combinations have resulted in meaningful improvements in survival.

Yet another therapy for advanced disease involves the identification of PSMA-expressing cancer cells that can be targeted with pharmaceuticals designed to deliver radioactive bombs. An injectable radiopharmaceutical can be delivered selectively to these cells, leaving healthy cells mostly unaffected. This therapy, lutetium-177-­PSMA-617 (marketed as Pluvicto), has been approved by the U.S. Food and Drug Administration for the treatment of prostate cancer that has become resistant to other forms of ADT and chemotherapy. It is likely to become an important therapy for even earlier stages of prostate cancer.

Genetics and genomic testing of patients and cancers have also helped in the quest for improvement of symptoms and longer survival. Some genetic mutations that are known to increase the risk of breast and ovarian cancer have also been associated with a heightened risk of prostate cancer. Testing for such mutations is becoming much more common, and patients who have them can be treated with specific therapies that block their deleterious effects, leading to better outcomes.

An understanding of the type of mutation is also critical—for both patients and their family members. Germline mutations are inherited from a patient’s biological parents by every cell in the body. These mutations can be passed along to the patient’s children. A somatic mutation, in contrast, is not inherited but develops in the cancer itself. Targeted therapies designed specifically to correct the effects of either germline or somatic mutations have produced significant improvements in patient longevity. Some of the most commonly recognized cancer mutations—either somatic or germline—are those in BRCA genes, which have been associated with early-onset breast and ovarian cancer.

When researchers studied cancer in families with BRCA mutations, they uncovered many cases of prostate cancer. This finding led to the discovery that BRCA mutations appeared in both men and women in these families. The mutations change the way DNA is repaired, introducing defects that can result in cancer formation. Drugs have now been developed that treat cancers linked to the BRCA mutations. Several such drugs—those in a class called poly­(ADP-ribose) polymerase (PARP) inhibitors—have recently received FDA approval for use as a treatment in people with these mutations. This research has led to more widespread genetic testing of patients with prostate cancer and, when germline mutations are found, family genetic counseling.

All these advances have occurred over the past decade—an incredibly short interval in the context of cancer oncology. Current options for early-stage prostate cancer enable physicians and patients to feel more at ease with conservative choices rather than immediate interventions with negative side effects. For patients whose cancers are advanced at initial diagnosis or progress and become metastatic, the treatment of oligometastases now often leads to long-term remission and requires fewer treatments with harmful systemic side effects. For those with more widespread metastatic disease, their cancer can now be managed with improved therapeutics based on a better understanding of disease biology. These new strategies have begun to transform this once rapidly fatal disease into a chronic condition that people can live with for years or even for their full life expectancy.

Marc B. Garnick is Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston. He is editor in chief of Harvard Medical School’s 2024–2025 Report on Prostate Diseases.

Scientific American Magazine Vol 330 Issue 5

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Urinary tract infections: epidemiology, mechanisms of infection and treatment options

Associated data.

Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host–pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.

Urinary tract infections (UTIs) are some of the most common bacterial infections, affecting 150 million people each year worldwide 1 . In 2007, in the United States alone, there were an estimated 10.5 million office visits for UTI symptoms (constituting 0.9% of all ambulatory visits) and 2–3 million emergency department visits 2 – 4 . Currently, the societal costs of these infections, including health care costs and time missed from work, are approximately US$3.5 billion per year in the United States alone. UTIs are a significant cause of morbidity in infant boys, older men and females of all ages. Serious sequelae include frequent recurrences, pyelonephritis with sepsis, renal damage in young children, pre-term birth and complications caused by frequent antimicrobial use, such as high-level antibiotic resistance and Clostridium difficile colitis.

Clinically, UTIs are categorized as uncomplicated or complicated. Uncomplicated UTIs typically affect individuals who are otherwise healthy and have no structural or neurological urinary tract abnormalities 5 , 6 ; these infections are differentiated into lower UTIs (cystitis) and upper UTIs (pyelonephritis) 5 , 7 . Several risk factors are associated with cystitis, including female gender, a prior UTI, sexual activity, vaginal infection, diabetes, obesity and genetic susceptibility 3 , 7 . Complicated UTIs are defined as UTIs associated with factors that compromise the urinary tract or host defence, including urinary obstruction, urinary retention caused by neurological disease, immunosuppression, renal failure, renal transplantation, pregnancy and the presence of foreign bodies such as calculi, indwelling catheters or other drainage devices 8 , 9 . In the United States, 70–80% of complicated UTIs are attributable to indwelling catheters 10 , accounting for 1 million cases per year 4 . Catheter-associated UTIs (CAUTIs) are associated with increased morbidity and mortality, and are collectively the most common cause of secondary bloodstream infections. Risk factors for developing a CAUTI include prolonged catheterization, female gender, older age and diabetes 11 .

UTIs are caused by both Gram-negative and Gram-positive bacteria, as well as by certain fungi ( FIG. 1 ). The most common causative agent for both uncomplicated and complicated UTIs is uropathogenic Escherichia coli (UPEC). For the agents involved in uncomplicated UTIs, UPEC is followed in prevalence by Klebsiella pneumoniae , Staphylococcus saprophyticus , Enterococcus faecalis , group B Streptococcus (GBS), Proteus mirabilis , Pseudomonas aeruginosa , Staphylococcus aureus and Candida spp. 3 , 6 , 12 , 13 ( FIG. 1 ). For complicated UTIs, the order of prevalence for causative agents, following UPEC as most common, is Enterococcus spp., K. pneumoniae , Candida spp., S. aureus , P. mirabilis , P. aeruginosa and GBS 9 , 14 – 16 ( FIG. 1 ).

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Urinary tract infections (UTIs) are caused by a wide range of pathogens, including Gram-negative and Gram-positive bacteria, as well as fungi. Uncomplicated UTIs typically affect women, children and elderly patients who are otherwise healthy. Complicated UTIs are usually associated with indwelling catheters, urinary tract abnormalities, immunosuppression or exposure to antibiotics. The most common causative agent for both uncomplicated and complicated UTIs is uropathogenic Escherichia coli (UPEC). For uncomplicated UTIs, other causative agents are (in order of prevalence) Klebsiella pneumoniae , Staphylococcus saprophyticus , Enterococcus faecalis , group B Streptococcus (GBS), Proteus mirabilis , Pseudomonas aeruginosa , Staphylococcus aureus and Candida spp. For complicated UTIs, the other causative agents are (in order of prevalence) Enterococcus spp., K. pneumoniae , Candida spp., S. aureus, P. mirabilis , P. aeruginosa and GBS.

Patients suffering from a symptomatic UTI are commonly treated with antibiotics; these treatments can result in long-term alteration of the normal micro-biota of the vagina and gastrointestinal tract and in the development of multidrug-resistant microorganisms 17 . The availability of niches that are no longer filled by the altered microbiota can increase the risk of colonization with multidrug-resistant uropathogens. Importantly, the ‘golden era’ of antibiotics is waning, and the need for rationally designed and alternative treatments is therefore increasing. Recent studies have used RNA sequencing to directly analyse uropathogens from the urine of women experiencing symptomatic UTIs. These studies, together with basic science and improved animal models, have been crucial in enabling us to understand the molecular details of how uropathogens adhere, colonize and adapt to the nutritionally limited bladder environment; evade immune surveillance; and persist and disseminate in the urinary tract. These studies have therefore revealed key virulence factors that can be targeted to prevent and counteract the pathogenic mechanisms that are important in UTIs 7 , 17 , 18 . In this Review, we discuss the molecular mechanisms of pathogenesis during bladder and kidney infection, comparing and contrasting the virulence factors used by the major uropathogens UPEC, K. pneumoniae , P. mirabilis , E. faecalis and P. aeruginosa . Furthermore, we discuss current antibiotic treatments, antibiotic resistance mechanisms, new combination therapies and future therapeutic interventions that use vaccines and small molecules to target virulence factors.

Adherence and colonization

Adherence is a key event initiating each step in UTI pathogenesis. A UTI typically starts with periurethral contamination by a uropathogen residing in the gut, followed by colonization of the urethra and subsequent migration of the pathogen to the bladder, an event that requires appendages such as flagella and pili ( FIG. 2 ). In the bladder, the consequences of complex host–pathogen interactions ultimately determine whether uropathogens are successful in colonization or eliminated.

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a | Uncomplicated urinary tract infections (UTIs) begin when uropathogens that reside in the gut contaminate the periurethral area (step 1) and are able to colonize the urethra. Subsequent migration to the bladder (step 2) and expression of pili and adhesins results in colonization and invasion of the superficial umbrella cells (step 3). Host inflammatory responses, including neutrophil infiltration (step 4), begin to clear extracellular bacteria. Some bacteria evade the immune system, either through host cell invasion or through morphological changes that result in resistance to neutrophils, and these bacteria undergo multiplication (step 5) and biofilm formation (step 6). These bacteria produce toxins and proteases that induce host cell damage (step 7), releasing essential nutrients that promote bacterial survival and ascension to the kidneys (step 8). Kidney colonization (step 9) results in bacterial toxin production and host tissue damage (step 10). If left untreated, UTIs can ultimately progress to bacteraemia if the pathogen crosses the tubular epithelial barrier in the kidneys (step 11). b | Uropathogens that cause complicated UTIs follow the same initial steps as those described for uncomplicated infections, including periurethral colonization (step 1), progression to the urethra and migration to the bladder (step 2). However, in order for the pathogens to cause infection, the bladder must be compromised. The most common cause of a compromised bladder is catheterization. Owing to the robust immune response induced by catheterization (step 3), fibrinogen accumulates on the catheter, providing an ideal environment for the attachment of uropathogens that express fibrinogen-binding proteins. Infection induces neutrophil infiltration (step 4), but after their initial attachment to the fibrinogen-coated catheters, the bacteria multiply (step 5), form biofilms (step 6), promote epithelial damage (step 7) and can seed infection of the kidneys (steps 8 and 9), where toxin production induces tissue damage (step 10). If left untreated, uropathogens that cause complicated UTIs can also progress to bacteraemia by crossing the tubular epithelial cell barrier (step 11).

Multiple bacterial adhesins recognize receptors on the bladder epithelium (also known as the uroepithelium) and mediate colonization ( TABLE 1 ). Uropathogens such as UPEC survive by invading the bladder epithelium, producing toxins and proteases to release nutrients from the host cells, and synthesizing siderophores to obtain iron ( FIG. 2 ; TABLE 1 ). By multiplying and overcoming host immune surveillance, the uropathogens can subsequently ascend to the kidneys, again attaching via adhesins or pili to colonize the renal epithelium and then producing tissue-damaging toxins ( FIG. 2 ; TABLE 1 ). Consequently, the uropathogens are able to cross the tubular epithelial barrier to access the blood stream, initiating bacteraemia.

Virulence factors used by the main uropathogens

AipA, adhesion and invasion mediated by the Proteus autotransporter; CNF1, cytotoxic necrotizing factor 1; Ebp, endocarditis- and biofilm-associated; Epa, enterococcal polysaccharide antigen; Esp, enterococcal surface protein; ExoS, exoenzyme S; F1C pili, type 1-like immunological group C pili; HlyA, α-haemolysin; HpmA, haemolysin; MR/P, mannose-resistant Proteus -like; Msr, methionine sulfoxide reductase; NAF, non-agglutinating fimbria; ND, not determined; PMF, P. mirabilis -like fimbria; P pili, pyelonephritis-associated pili; Pta, Proteus toxic agglutinin; TaaP, trimeric autoagglutinin autotransporter of Proteus ; UPEC, uropathogenic Escherichia coli .

The uropathogens that cause uncomplicated UTIs, including UPEC, K. pneumoniae and S. saprophyticus , have the ability to bind directly to the bladder epithelium, which is composed of the umbrella cells (also known as superficial facet cells), intermediate cells and basal cells 19 ( TABLE 1 ). UPEC and K. pneumoniae bind to uroplakins, which are the major protein components of the umbrella cell apical membrane 19 and which form a crystalline array protecting the mammalian bladder tissue from damaging agents in urine 20 . In addition to uroplakins, α 3 β 1 integrins, which are expressed at the surface of uroepithelial cells, can also serve as receptors for UPEC 21 . By contrast, complicated UTIs are initiated when the bacteria bind to a urinary catheter, a kidney stone or a bladder stone, or when they are retained in the urinary tract by a physical obstruction. Some pathogens (for example, UPEC) can cause both uncomplicated and complicated UTIs. However, others such as P. mirabilis , P. aeruginosa and Enterococcus spp. predominantly cause complicated UTIs ( FIG. 2 ). Subsequently, these uropathogens often form biofilms that are responsible for colonization and persistence 22 , 23 ( BOX 1 ).

Biofilms and morphological plasticity

Uropathogens use different mechanisms for survival in response to stresses in the bladder such as starvation and immune responses. By forming biofilms and undergoing morphological changes, uropathogens can persist and cause recurrent infections 40 , 129 , 130 .

Biofilm formation

Extracellular DNA (eDNA), exopolysaccharides called extracellular polymeric substances, pili, flagella and other adhesive fibres create a scaffold to form a multicellular bacterial community that is protected from immune responses, antimicrobial agents and other stresses 40 . The antimicrobial recalcitrance of uropathogens increases on biofilm maturation, as the biofilm provides a physical barrier to antibiotic entry. Therefore, understanding species-specific biofilm formation and dispersal mechanisms is crucial for the development of novel therapies that prevent colonization, such as biofilm inhibitors, anti-adhesive molecules and molecules that induce bacterial dispersion.

Uropathogenic Escherichia coli (UPEC) forms biofilm-like intracellular bacterial communities (IBCs) that protect their members from neutrophils, antibiotics and other stresses 38 ( FIG. 3 ). Type 1 pili, antigen 43 and adhesive surface fibres called curli induce biofilm formation by mediating interbacterial interactions and attachment to surfaces. Transcription of antigen 43 is regulated by oxidative stress regulator (OxyR; also known as hydrogen peroxide-inducible genes activator) 131 , whereas type 1 pilus and curli fibre genes are regulated by polymyxin-resistant protein B (PrmB; also known as BasS) on iron sensing 3 , leading to phosphorylation of polymyxin-resistant protein A (PmrA; also known as BasR) and quorum sensing regulator B (QseB) 131 . UPEC biofilm formation on catheters is dependent on type 1 pili 35 .

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a | In the bladder, uropathogenic Escherichia coli (UPEC) expression of type 1 pili is essential for colonization, invasion and persistence. The type 1 pilus adhesin, FimH, binds mannosylated uroplakins and integrins that coat the surface of umbrella cells. Uroplakin binding by FimH induces actin rearrangement and bacterial internalization via unknown mechanisms. FimH–α 3 β 1 integrin interactions induce actin rearrangement via activation of RHO-family GTPases (such as RAC proteins), resulting in bacterial invasion. Inside the host cell, UPEC can subvert host defences and resist antibiotic treatment. However, lipopolysaccharide (LPS) released by UPEC is sensed by Toll-like receptor 4 (TLR4), which induces cyclic AMP (cAMP) production via adenylyl cyclase 3 (AC3) activation, resulting in exocytosis of vesicular UPEC across the apical plasma membrane. UPEC subverts this innate defence mechanism by escaping into the cytoplasm, where it then multiplies to form intracellular bacterial communities (IBCs). Maturation of IBCs causes bacterial dispersal and allows the invasion of other host cells, which enables UPEC to re-enter the IBC cycle. Alternatively, UPEC can establish quiescent intracellular reservoirs (QIRs) in the underlying transitional cells. QIRs consist of 4–10 non-replicating bacteria within membrane-bound compartments encased in F-actin and can remain viable for months. In addition, UPEC survives within the harsh bladder environment by secreting several factors that are important for nutrient acquisition. The toxin α-haemolysin (HlyA) promotes host cell lysis through pore formation, facilitating iron release and nutrient acquisition. The siderophores expressed by UPEC allow the bacterium to scavenge iron and thus promote survival during a urinary tract infection (UTI). HlyA also triggers epithelial exfoliation to promote the spread of UPEC to other hosts following urine expulsion or to expose deeper layers of the uroepithelium for QIRs. Cytotoxic necrotizing factor 1 (CNF1) is also important for host cell remodelling and functions by binding to the receptor basal cell adhesion molecule (BCAM) on host cells to induce constitutive activation of the RHO GTPases RAC1, RHOA and cell division control 42 (CDC42), resulting in actin cytoskeletal rearrangements and membrane ruffling. Activation of RAC1 also induces the host cell anti-apoptotic and pro-survival pathways, preventing apoptosis of colonized epithelial cells and allowing the UPEC population to expand. The extracellular survival of UPEC also requires evasion of the innate immune system by the adoption of a filamentous morphology, which renders the bacterium more resistant to neutrophil killing than their bacillary form. b | UPEC colonization of the kidneys is dependent on expression of pyelonephritis-associated (P) pili, which bind globoside-containing glycolipids lining the renal tissue. The P pilus adhesin, PapG, also interacts with TLR4, reducing the expression of polymeric immunoglobulin receptor (PIGR). This results in impaired immunoglobulin A (IgA) transport across the epithelium, thereby modulating the local secretory antibody immune response and preventing UPEC opsonization and clearance.

Proteus mirabilis produces urease, which hydrolyses urea to carbon dioxide and ammonia. This increases the urine pH and generates calcium crystals and magnesium ammonium phosphate precipitates, which are incorporated into polysaccharide capsules, forming crystalline biofilms on the catheter ( FIG. 4 ). The phosphotransferase regulator of swarming behaviour (RsbA) upregulates polysaccharide expression, represses swarming 23 and enhances biofilm formation. Mannose-resistant Proteus -like (MR/P) pili intimately associate with the crystal layers, promoting biofilm formation. Oxygen limitation in the biofilm activates the expression of MR/P pili by inducing the recombinase MrpI to reorient the promoter of the pilus genes. Similarly, expression of the fimbrial operon regulator MrpJ leads to decreased motility, promoting biofilm formation 53 , 132 .

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a | Catheter-associated urinary tract infections (CAUTIs) mediated by Proteus mirabilis depend on the expression of mannose-resistant Proteus -like (MR/P) pili for initial attachment, and for biofilm formation on the catheter and in the bladder. Subsequent urease production induces the formation of calcium crystals and magnesium ammonium phosphate precipitates in the urine through the hydrolysis of urea to carbon dioxide and ammonia, resulting in a high pH. The production of extracellular polymeric substances by bacteria attached to the catheter traps these crystals, allowing the formation of a crystalline biofilm, which protects the community from the host immune system and from antibiotics. In addition, these structures prevent proper urine drainage, resulting in reflux and promoting the progression to pyelonephritis, septicaemia and shock. Finally, production of the bacterial toxins haemolysin (HpmA) and Proteus toxic agglutinin (Pta) is important for tissue destruction and bacterial dissemination to the kidneys. HpmA induces pore formation by inserting itself into the cell membrane and destabilizing the host cell, causing tissue damage, exfoliation and nutrient release. Pta punctures the host cell membrane, causing cytosol leakage and resulting in osmotic stress and depolymerization of actin filaments, thus compromising the structural integrity of the cell. The release of nutrients via these toxins also allows the bacteria to scavenge iron using siderophores. b | Enterococcus faecalis pathogenesis during CAUTIs depends on catheter implantation, which results in bladder inflammation and causes fibrinogen release, deposition onto the catheter, and accumulation. E. faecalis takes advantage of the presence of fibrinogen and uses it as a food source through the production of proteases. E. faecalis also binds fibrinogen through the endocarditis- and biofilm-associated (Ebp) pilus, allowing the formation of biofilms that protect the bacteria against the immune system.

Pseudomonas aeruginosa has the ability to form biofilms on catheters and damaged bladder tissue 82 through several mechanisms, including quorum sensing autoinducers that bind to the transcriptional regulators LasR (which regulates elastase (LasB) expression) and RhlR (which regulates the synthesis of rhamnolipids). Quorum sensing induces the production of eDNA, rhamnolipids, lectins, elastases and toxins. The amphiphilic rhamnolipids allow microcolony formation by changing the hydrophobicity of the P. aeruginosa surface 133 . Biofilm maturation is promoted by lectin adhesins, which are important for bacterial cell–cell interactions 134 . The production of alginates and extracellular polymeric substances is activated when cyclic di-GMP binds to the transcriptional regulators alginate biosynthesis 44 (Alg44) and pellicle formation regulator D (PelD) 135 . Small RNAs from the regulator of secondary metabolites ( rsm ) family, such as rsmZ and rsmY , regulate exopolysaccharide production by reducing the availability of RsmA, which is the transcriptional repressor for exopolysaccharide-encoding genes 81 , 136 , 137 .

Morphological changes

Uropathogens also adopt morphological changes, such as filamentation, to circumvent the host immune system 130 , 138 . During IBC maturation, expression of suppressor of lon (SulA) inhibits FtsZ polymerization in a subpopulation of UPEC, blocking septation ring formation and cell division 138 . When the resulting filamentous bacterial cells emerge from epithelial cells, they are resistant to killing by neutrophils and can colonize other naive uroepithelial cells and re-enter the IBC cycle 129 , 138 ( FIG. 3 ). Alternatively, during colonization by P. mirabilis , the bacteria adopt a filamentous morphology as a result of the sensor activities of flagella on contact with a urinary catheter. Contact creates a torsional change in the outer membrane, and this is sensed by upregulator of the flagellar master operon (Umo) proteins, which induce the expression of flagella to produce the highly flagellated cells that are required for swarming during a UTI 6 , 23 , 53 , 139 ( FIG. 4 ).

Chaperone–usher pathway pili

Many uropathogens initiate a UTI using pili that mediate adhesion to host and environmental surfaces, facilitate invasion into the host tissues and promote interbacterial interactions to form biofilms 24 – 27 . For example, numerous Gram-negative pathogenic bacteria — including E. coli , Klebsiella spp., Proteus spp., Pseudomonas spp., Haemophilus spp., Salmonella spp. and Yersinia spp. 16 , 27 – 29 — express a large, highly conserved family of adhesive fibres called chaperone–usher pathway (CUP) pili 25 , 26 . CUP pili are assembled by the chaperone–usher molecular machinery 24 , 25 and are composed of pilin subunits with incomplete immunoglobulin-like folds that lack the typical carboxy-terminal seventh β-strand 30 , 31 . Briefly, in a process termed donor-strand complementation, a dedicated periplasmic chaperone ‘donates’ a β-strand to complete the immunoglobulin fold of the subunits, forming a complex with each subunit and ensuring their proper folding and stabilization. The chaperone–subunit complex is then targeted to the usher assembly protein in the outer membrane, where the usher selectively differentiates chaperone–subunit complexes and catalyses the ordered assembly of pili on the cell surface via a mechanism termed donor-strand exchange. During donor-strand exchange, the final folding of a subunit occurs as the donated β-strand of the chaperone is replaced by an amino-terminal extension on the next incoming subunit 32 . Importantly, understanding the most basic principles of molecular biology — such as how a protein folds into domains that serve as assembly modules for building large supramolecular structures, and how an outer-membrane macromolecular machine (the usher) assembles these structures from individual subunits, which are delivered as chaperone–subunit complexes and then transported in a regulated manner across a biological membrane — has led to the development of anti-virulence compounds that block CUP pilus assembly or function and that result in the dysregulation of virulence factors. These compounds have the potential for broad-spectrum activity against numerous Gram-negative bacteria (see below).

Uropathogenic Escherichia coli

Thirty-eight distinct CUP pilus operons have been identified in E. coli genomes, and a single UPEC strain can encode more than 12 different CUP pili 25 . However, the distribution of CUP operons is not uniform across different UPEC isolates; some operons are found ubiquitously in UPEC, whereas others are present in only a handful of strains. The multitude of CUP pili encoded by UPEC are tipped with different adhesins, some of which are known to mediate distinct tropisms in the lower and upper urinary tract by recognizing receptors with stereochemical specificity, notably in the bladder or kidney epithelium 33 .

Type 1 pili and pyelonephritis-associated (P) pili are the better characterized CUP pili. Type 1 pili are essential for colonization, invasion and persistence of UPEC in the mouse bladder 34 ( FIG. 3 ). Type 1 pili are tipped with the adhesin FimH 7 , which recognizes mannosylated uroplakins and α 1 β 3 integrins with stereochemical specificity 21 , 35 to initiate colonization and invasion into umbrella cells 7 , 21 . Type 1 pili binding to these cells triggers a signal transduction cascade that activates Rho GTPases, such as those from the Rac family, to cause actin rearrangement and internalization of UPEC by a zippering mechanism consisting of a plasma membrane sheathe that engulfs the bacterium 36 ( FIG. 3 ). Invasion allows UPEC to subvert certain host defences and become recalcitrant to antibiotic treatments. However, an innate defence expulsion mechanism defends the uroepithelium from UPEC invasion; this expulsion mechanism depends on Toll-like receptor 4 (TLR4) expression by uroepithelial cells. Lipopolysaccharide (LPS)-mediated activation of TLR4 stimulates adenylyl cyclase 3 (AC3) to produce cyclic AMP, which induces the exocytosis of vesicular UPEC into the apical plasma membrane of the umbrella cells 37 ( FIG. 3 ). Importantly, by escaping into the cytoplasm (through an unknown mechanism), UPEC can subvert the expulsion pathway and rapidly multiply, forming transient biofilm-like intracellular bacterial communities (IBCs) 38 , 39 ( BOX 1 ; FIG. 3 ). After their maturation, bacteria disperse from the IBC to invade other cells, where the IBC cycle is repeated 38 – 40 . IBC formation is a common mechanism for clinical UPEC isolates and has been observed in multiple mouse backgrounds and also in exfoliated uroepithelial cells in the urine of patients with acute UTIs but not in the cells in urine from healthy controls 41 , 42 . The process of invasion and IBC formation provides UPEC with the ability to survive stringent bottlenecks in the urinary tract, including TLR4-mediated expulsion, umbrella cell exfoliation, ascension to the kidneys, urination and inflammation 7 , 43 . UPEC also establishes quiescent intracellular reservoirs (QIRs) in underlying transitional cells, within membrane-bound compartments enmeshed in F-actin ( FIG. 3 ). In contrast to the metabolically active IBCs, QIRs typically contain 4–10 non-replicating bacteria that can remain viable for months and can be re-activated to serve as seeds that initiate a recurrent UTI 7 . It has been proposed that during uroepithelial turnover, in which the underlying immature cells terminally differentiate into umbrella cells, the redistribution of actin and perhaps other associated signals might trigger UPEC revival from QIRs, releasing the bacteria back into the bladder lumen 44 .

Unlike the mannose-binding adhesin FimH of type 1 pili, the adhesin of P pili, PapG, binds globosides containing glycolipids that are present in the human kidneys 33 ( FIG. 3 ). In addition, PapG modulates the local secretory-antibody immune response by interacting with TLR4 to reduce polymeric immunoglobulin receptor (PlGR) expression, thus impairing immunoglobulin A transport through the lamina propria and epithelial cells to the kidney lumen 45 ( FIG. 3 ). By inhibiting immunoglobulin A transport into the urinary space, UPEC evades a key host protective mechanism, allowing the establishment of ascending infection 45 , 46 .

Importantly, the initial innate host response to UPEC colonization and invasion not only dictates the outcome of the original infection but is also crucial for determining host susceptibility to subsequent infections 39 . An increased susceptibility to recurrent UTIs can occur not because of a deficient host response to UPEC infection, as is commonly accepted, but rather as a result of an unrestrained lymphocyte-dependent innate inflammatory response to acute infection, leading to severe acute injury to the mucosal uroepithelium and potentiating subsequent infections 39 .

Klebsiella pneumoniae

Similarly to UPEC, K. pneumoniae uses type 1 pili for biofilm formation and bladder colonization 47 ( TABLE 1 ). Interestingly, although the K. pneumoniae adhesin FimH is highly homologous to UPEC FimH, they have different binding specificities 48 . K. pneumoniae FimH-mediated biofilm formation is inhibited by heptyl mannose, as opposed to the methyl mannose-mediated inhibition of UPEC FimH. Moreover, K. pneumoniae FimH has a weaker adherence to the bladder than UPEC FimH, resulting in significantly lower K. pneumoniae titers in the mouse bladder and fewer IBCs than are seen for UPEC. Despite the relatively poor adhesive properties of K. pneumoniae FimH in the urinary tract, it remains an important virulence factor for K. pneumoniae during colonization, biofilm formation and persistence in both UTIs and CAUTIs 48 – 50 . In addition , K. pneumoniae encodes numerous other CUP pili, including type 3 pili, which also play an important part in colonization, biofilm formation and persistence during UTIs and in biofilm formation during CAUTIs 35 , 51 , 52 .

Proteus mirabilis

Following initial attachment, P. mirabilis produces mannose-resistant Proteus -like (MR/P) pili, which are CUP pili that facilitate biofilm formation and colonization of the bladder and kidneys, and are crucial for catheter-associated biofilm formation 6 , 16 , 23 , 53 ( BOX 1 ; FIG. 4 ). Other CUP pili encoded by P. mirabilis include P. mirabilis -like fimbriae (PMFs), which are important for bladder and kidney colonization 53 , and non-agglutinating fimbriae (NAFs), which are able to attach to uroepithelial cells in vitro 53 . However, the in vivo mechanistic roles of PMFs, NAFs and their receptors have not yet been established.

In addition to CUP pili, P. mirabilis encodes two autotransporters, TaaP (trimeric autoagglutinin autotransporter of Proteus ) and AipA (adhesion and invasion mediated by the Proteus autotransporter), which are important for bladder and kidney infection, respectively 53 . AipA can adhere to human bladder and kidney cell lines in vitro but is only required for kidney infection (and not for bladder infection) in mice. Conversely, TaaP is required for bladder infection by P. mirabilis in mice. Importantly, both autotransporters bind to extracellular-matrix proteins in vitro: AipA preferentially binds to collagen I, and TaaP to laminin, which might provide an explanation for their different tissue tropisms.


Enterococci encode several adhesion factors, including the collagen adhesin Ace, enterococcal surface protein (Esp), enterococcal polysaccharide antigen (Epa), and endocarditis- and biofilm-associated (Ebp) pili 54 ( TABLE 1 ). Of these, Ebp pili contribute to CAUTIs 54 – 56 and are required for persistence during infection 55 , 56 . Clinical studies have shown that mechanical stress induced by urinary catheterization produces histological and immunological changes in the bladder, resulting in a robust inflammatory response, exfoliation, oedema, and mucosal lesions of the uroepithelium and kidneys 57 , 58 . Importantly, a mouse model of CAUTI seems to recapitulate these immunological changes that are induced by urinary catheterization, exhibiting catheter-induced inflammation, severe uroepithelial damage, exfoliation and the onset of bladder wall oedema, which is exacerbated by increased catheterization time 59 . Urinary catheters provide a surface for E. faecalis attachment and biofilm formation, which promotes E. faecalis persistence in the bladder and further dissemination to the kidneys 55 ( FIG. 4 ). However, E. faecalis is unable to bind to catheter material in vitro and is unable to grow in urine 60 . This apparent paradox was resolved by the finding that urinary catheterization induces fibrinogen release into the bladder as part of the inflammatory response; this fibrinogen subsequently accumulates in the bladder and is deposited on the implanted catheter 60 ( FIGS 2 , ​ ,4). 4 ). Following fibrinogen deposition, the Ebp pilus adhesin — EbpA, which contains an N-terminal fibrinogen-binding domain — mediates catheter colonization and biofilm formation during CAUTIs caused by E. faecalis 60 , 61 ( FIG. 4 ). Furthermore, E. faecalis can use fibrinogen for growth, enhancing biofilm formation on the catheter 60 ( FIG. 4 ). This resolution of the paradox has been recapitulated in vitro by the demonstration that E. faecalis attaches to fibrinogen-coated catheters and grows in urine supplemented with fibrinogen 60 .

Other virulence factors

The bladder environment is limited in nutrients; thus, in order to survive and grow within the urinary tract, uropathogens produce proteases and toxins that damage the host tissue to release nutrients, while also providing a niche for bacterial invasion and dissemination ( TABLE 1 ).

Proteases and toxins

UPEC secretes high concentrations of α-haemolysin (HlyA), which oligomerizes and integrates in the cholesterol-rich microdomains in the host cell membrane in a Ca + -dependent manner 62 , 63 . This results in pore formation in the umbrella cells and promotes their lysis, which facilitates iron and nutrient acquisition by the bacteria ( FIG. 3 ). HlyA also triggers exfoliation, exposing deeper layers of the uroepithelium for colonization and promoting bacterial spread to other hosts following cell expulsion in the urine 62 – 65 ( FIG. 3 ). Furthermore, HlyA is highly expressed in IBCs, suggesting that it is important during this stage of infection 39 , 63 , 66 .

UPEC also secretes cytotoxic necrotizing factor 1 (CNF1), which affects actin remodelling in the host cell through three small RHO GTPases: RAC1, RHOA and cell division control 42 (CDC42) 67 , 68 . CNF1 enters the host cell in endocytic vesicles, by binding to the receptor basal cell adhesion molecule (BCAM; also known as LU) 69 , and then constitutively activates RHO GTPases via deamination of a glutamine residue; this causes actin cytoskeletal rearrangements and membrane ruffling, leading to increased levels of bacterial internalization 67 , 70 . In addition, the activation of RAC1–GTP induces the host cell anti-apoptotic and pro-survival pathways (through the interaction of phosphoinositide 3-kinase (PI3K), AKT (also known as PKB) and nuclear factor-κB (NF-κB)); this prevents apoptosis of the colonized uroepithelium, thus facilitating UPEC survival and protecting the niche 67 , 71 ( FIG. 3 ).

P. mirabilis produce two toxins, haemolysin (HpmA) and Proteus toxic agglutinin (Pta), which are implicated in tissue damage and dissemination to the kidneys, initiating acute pyelonephritis 16 , 72 . HpmA is a Ca + -dependent pore-forming cytolysin that destabilizes the host cell by inserting itself into the cell membrane and causing a Na + efflux 16 ( FIG. 4 ). By contrast, the surface-associated cytotoxic protease Pta is functional only in an alkaline pH, such as that induced by the activity of P. mirabilis urease 73 . In the proposed mode of action, Pta punctures the host cell membrane, causing leakage of the cytosol, osmotic stress and depolymerization of actin filaments; the structural integrity of the cell is therefore compromised, resulting in bladder and kidney damage 53 , 73 ( FIG. 4 ). Pta also induces bacterial cell–cell interaction via autoaggregation 53 , 73 .

P. aeruginosa produces elastases, exoenzyme S (ExoS) and haemolytic phospholipase C, all of which have been implicated in UTI initiation and dissemination, and subsequent pyelonephritis 74 , 75 ( TABLE 1 ). The GTPase activity of ExoS downregulates macrophage RAC1 function, interfering with lamellopodium formation and inducing membrane ruffle formation. The ADP-ribosyltransfease activity of ExoS targets RHO family proteins (RAS proteins and RalA), affecting cell adherence and morphology 76 . Elastase induces tissue destruction through its protease activity, releasing nutrients (including iron) for continued bacterial growth 77 . Phospholipase C is an α-toxin that hydrolyses phosphatidylcholine from the host cell membrane, compromising cell integrity and resulting in organ damage 78 – 80 . The expression of all of these virulence factors is regulated by the quorum sensing system 81 . Quorum sensing is activated at high cell density by the accumulation of small molecules called autoinducers. When a threshold level of autoinducers is reached, they bind to transcriptional activator proteins and activate the expression of virulence factors 81 , 82 ( BOX 1 ).

Urease is encoded by several uropathogens, including P. mirabilis 53 , 83 , S. saprophyticus 84 , K. pneumoniae 85 and P. aureginosa 86 , and is important for colonization and persistence during P. mirabilis and S. saprophyticus UTIs 83 , 84 ( FIG. 4 ; TABLE 1 ). This enzyme catalyses the hydrolysis of urea to carbon dioxide and ammonia 87 , resulting in elevated urine pH and the production of calcium crystals (apatite) and magnesium ammonium phosphate ammoprecipitates (struvite) in urine and on catheters 53 ( FIG. 4 ). Importantly, the accumulation of ammonia becomes toxic for the uroepithelial cells, inducing direct tissue damage 88 . The P. mirabilis urease, one of the best studied ureases involved in UTIs, is a Ni 2+ -dependent metalloenzyme that is essential for colonization of the bladder and kidneys and promotes the formation of stones 23 , 53 , 87 . The P. mirabilis urease is induced by urea and is constitutively expressed during growth in urine 89 . This urease is highly active, hydrolysing urea several times faster than those produced by other species, such as Providencia stuartii , Providencia rettgeri , Proteus vulgaris and Morganella morganii 90 . The high activity level of the P. mirabilis enzyme induces rapid crystal formation, and these crystals become trapped within the polysaccharides produced by attached bacterial cells, forming crystalline biofilms on catheters 23 , 89 , 91 . The crystalline biofilms provide P. mirabilis with protection from the host immune system and antibiotics 88 ( BOX 1 ; FIG. 4 ). These structures also block urine drainage from the ureters, potentially resulting in reflux and promoting progression to pyelonephritis, septicaemia and shock 53 .

Iron scavenging

The bladder environment is limited in iron. Thus, to be able to grow in human urine, uropathogens utilize siderophore systems for iron (Fe 3+ ) scavenging; these systems are composed of the siderophore assembly machinery, a siderophore responsible for binding iron and a membrane receptor that internalizes the iron bound to the siderophore 92 ( TABLE 1 ).

UPEC produces several siderophores 93 , of which two — aerobactin and yersiniabactin — are essential in the urinary tract 93 ( FIG. 3 ). Aerobactin is highly expressed, stable at low pH and displays higher levels of iron binding than enterobactin 94 , 95 . Yersiniabactin is important in bio-film formation in urine and has a protective role against intracellular killing by copper stress, as it sequesters host-derived copper 96 .

Numerous iron-scavenging siderophore systems are utilized by other uropathogens: K. pneumoniae produces enterobactin and aerobactin 85 ; P. mirabilis uses proteobactin and yersiniabactin-related 97 ; and P. aeruginosa produces pyochelin and pyoverdin 86 ( TABLE 1 ). Siderophore systems are important potential targets for vaccine development 98 and for designing small molecules that interfere with their function.

Treatment of urinary tract infections

UTIs result in considerable economic and public health burdens and substantially affect the life quality of afflicted individuals 17 . Currently, antibiotics — such as trimethoprim sulfamethoxazole, ciprofloxacin and ampicillin — are the most commonly recommended therapeutics for UTIs 4 . However, increasing rates of antibiotic resistance and high recurrence rates threaten to greatly enhance the burden that these common infections place on society. Ideally, alternative therapies will be established that will be recalcitrant to the development of resistance. Many promising approaches are being developed, from leveraging what we have learned about the basic biology of UTI pathogenesis to specifically target virulence pathways. These antivirulence therapeutics should theoretically allow us to effectively neutralize, or ‘disarm’, the capacity of UTI pathogens to cause disease, without altering the gut commensal microbiota, because antivirulence therapeutics target processes that are critical for UTI pathogenesis but that are not required for the essential processes of growth and cell division (which are the targets of conventional antibiotics).

Below, we discuss the current challenges that have arisen from the emergence of multidrug-resistant bacterial strains and highlight the progress that is being made towards the development of antivirulence therapeutics for UTIs. We also discuss how an understanding of the evolution of bacterial resistance mechanisms and their spread is providing new approaches for the modification and improvement of current therapeutic options.

Multidrug resistance

UTIs are becoming increasingly difficult to treat owing to the widespread emergence of an array of antibiotic resistance mechanisms 3 , 4 , 15 , 99 – 102 (see Supplementary information S1 (table) ). Of particular concern are members of the family Enterobacteriaceae, including E. coli and K. pneumoniae , which have both acquired plasmids encoding extended-spectrum β-lactamases (ESBLs). These plasmids rapidly spread resistance to third-generation cephalosporins as well as other antibiotics 15 , 99 – 103 ( BOX 2 ). Other Enterobacteriaceae family members produce the class C β-lactamases (AmpC enzymes) that are active against cephamycin in addition to third-generation cephalosporins, and are also resistant to β-lactamase inhibitors 99 – 102 . The expression of AmpC enzymes is also associated with carbapenem resistance in K. pneumoniae strains lacking a 42 kDa outer-membrane protein 15 , 99 – 102 ( BOX 2 ).

Antibiotic resistance

Multidrug-resistant uropathogenic organisms are becoming an expanding public health threat, as Enterobacteriaceae family members increasingly acquire extended-spectrum β-lactamases (ESBLs) such as cefotaximases (CTX-Ms) and oxacillinases (OXAs), AmpC-type β-lactamases and carbapenemases.

Originating in Klebsiella pneumoniae and Escherichia coli , ESBLs are now prevalent throughout the Enterobacteriaceae family, as frequent use of cephalosporins in the nosocomial setting and the carriage of ESBL-encoding genes on transferrable elements together create an ideal environment for the selection of antibiotic resistance 99 , 102 . ESBLs are plasmid-encoded or chromosomally encoded β-lactamases with broad activity against penicillins and cephalosporins. They function by splitting the amide bond of the β-lactam ring, thus inactivating β-lactam antibiotics 102 . Troublingly, ESBLs are encoded on plasmids that typically carry other resistance genes which provide activity against aminoglycosides, sulfonamides and quinolones, making the bacteria that acquire these plasmids multidrug resistant 101 , 102 .

The plasmids encoding the ESBLs CTX-Ms form a new plasmid phylum that is phylogenetically distinct from other plasmid-encoded β-lactamases. CTX-Ms are active against narrow-, broad- and extended-spectrum penicillins, classical and extended-spectrum cephalosporins, and monobactams 99 , 102 , 103 . Notably, they also confer high-level cefotaxime resistance 99 , 103 . CTX-Ms are the most prevalent β-lactamases in community-associated isolates and are typically encoded on plasmids with other resistance genes 102 . CTX-Ms efficiently hydrolyse the β-lactam ring via nucleophilic attack of a ring carbonyl carbon by a conserved serine in the β-lactamase, resulting in a ring-opened product that is inactive 140 .

OXAs are ESBLs that are typically encoded by plasmids and mediate resistance to ampicillin, cephalothin, oxacillin and cloxacillin by hydrolysing the β-lactam rings 99 , 103 . In addition, OXAs are characterized by their ability to resist the β-lactamase inhibitor clavulante 103 . To date, OXAs have been shown to be expressed only in Pseudomonas aeruginosa 99 , 103 .

AmpC enzymes

The chromosomally encoded AmpC enzymes hydrolyse penicillins, third-generation and extended-spectrum cephalosporins, and cephamycins, and are resistant to β-lactamase inhibitors, including clavulanate 99 , 102 . AmpC expression is induced in response to β-lactams, cephamycin and cephalosporin exposure.


Carbapenemases are ESBLs that confer the ability to inactive carbapenems in addition to penicillins and extended-spectrum cephalosporins 99 , 101 , 102 . The two most clinically relevant carbapenemases, K. pneumoniae (serine) carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM-1), originated in K. pneumoniae and rapidly spread throughout the Enterobacteriaceae family, creating carbapenem-resistant Enterobacteriaceae (CRE) 15 , 99 , 101 , 102 . The broad activity of carbapenemases confers resistance against a wide range of extended-spectrum β-lactam antibiotics, particularly carbapenem.

Multidrug resistance is also common among enterococci, as they are naturally resistant to trimethoprim, clindamycin, cephalosporins and penicillins 15 , 101 , 102 . Recently, Enterococcus spp. have developed high-level resistance to glycopeptides, including vancomycin, which is considered to be one of the last lines of defence against multidrug-resistant organisms. Specifically, enterococci evolved resistance to glycopeptides through the expression of vancomycin and teicoplanin A-type resistance ( van ) genes that encode the penicillin-binding proteins (PBPs) VanA, VanB, VanD, VanE, VanG and VanL 101 , 102 . The mechanism of resistance for VanA, the most common PBP expressed by enterococci, is to replace the cell wall precursor D-alanine–D-alanine with D-alanine–D-lactose, effectively reducing the binding affinity of vancomycin 104 . The troubling trend towards a high prevalence of multi-drug-resistant uropathogens has spurred the development of alternative control measures and treatment options.

Combination therapies

New antimicrobials that are resistant to inactivation by ESBLs are under development for use in combination with new classes of β-lactamase inhibitors, which target both β-lactamases and K. pneumoniae carbapenemases (KPCs) 105 – 107 . These combination therapies have been shown to be effective in vitro against carbapenem-resistant members of the family Enterobacteriaceae. Furthermore, clinical trials involving complicated UTIs revealed that ceftazidime, a third-generation cephalosporin that is active against Gram-positive and Gram-negative organisms, is effective against ESBL- and carbapenemase-producing Gram-negative bacteria when combined with the β-lactamase inhibitor avibactam 105 . Future studies are needed to test the efficacy of ceftazidime–avibactam against ESBL-, KPC- and AmpC-producing Gram-negative pathogens during infection, as the drug combination has the potential to be effective against a broad range of cephalosporin-resistant Enterobacteriaceae family members. Although these antibiotic–inhibitor combinations are promising, the development of resistance to β-lactamase inhibitors is not well characterized 105 . Moreover, the effectiveness of specific antibiotic–inhibitor therapies is dependent on the antimicrobial-resistance patterns encoded by each pathogen, as the expression of certain combinations of ESBLs and carbapenemases can provide resistance to an antibiotic–inhibitor therapy 105 – 107 . For example, the combination of {"type":"entrez-protein-range","attrs":{"text":"BAL30072-BAL29880","start_term":"BAL30072","end_term":"BAL29880","start_term_id":"359272553","end_term_id":"359272361"}} BAL30072-BAL29880 –clavulanate (two β-lactam antibiotics and a β-lactamase inhibitor) is effective against many carbapenem-resistant Enterobacteriaceae family members, but K. pneumoniae strains that typically produce KPCs and SHVs (another type of ESBL), or AmpC enzymes are resistant 106 . Therefore, it is crucial to know which antibiotic mechanisms are available to a specific uropathogen in order to determine an effective treatment.

Vaccines targeting bacterial adhesion

As adherence has a key role at nearly every step of UTI pathogenesis, one attractive strategy for the development of antivirulence therapies, including vaccines, has been to target CUP pili. As a general rule, vaccination with whole pili has been ineffective at generating an antibody response that can protect against UTIs. However, adhesin-based vaccines have been shown to be effective at blocking host–pathogen interactions, thus preventing the establishment of disease 108 – 112 . Experiments using mouse and cynomolgus monkey models of UTIs determined that immunization with PapD–PapG or FimC–FimH chaperone–adhesin complexes protected against UTIs 108 – 112 . The effectiveness of the FimC–FimH vaccine was shown to be due, in large part, to antibodies that block the function of FimH in bladder colonization 110 . Furthermore, the anti-FimH antibodies did not seem to alter the E. coli niche in the gut microbiota 109 . Modifications of this vaccine are currently under development, with the aim of inducing greater immune stimulation 108 , 112 . For example, one approach has been to fuse FimH to the flagellin FliC in order to induce a more substantial acute inflammatory response, which functions through TLR4 signalling via the MYD88 pathway 112 . A Phase I clinical trial began in January 2014 to evaluate the efficacy of a FimC–FimH vaccine using a synthetic analogue of monophosphoryl lipid A as the adjuvant.

In addition to the UPEC adhesins, adhesins from P. mirabilis and E. faecalis have also been used as vaccine targets 60 , 113 . In a mouse model of UTI, vaccination with the P. mirabilis MR/P pilus adhesin, MrpH, reduced bacterial burdens compared with those of unvaccinated controls, similar to the results observed with UPEC in the FimH vaccine trials 110 , 113 . Moreover, a vaccine strategy that is efficacious against E. faecalis CAUTIs is being developed based on vaccination with the Ebp pilus adhesin, EbpA. This strategy induced high antibody titers and reduced bacterial burdens in a mouse model of CAUTI 60 . In conclusion, adhesin-based vaccines represent a promising area for the development of therapeutics against uropathogens. Thus, understanding the molecular basis of host–pathogen interactions is crucial for vaccine development strategies.

Vaccines targeting bacterial toxins and proteases

The UPEC pore-forming toxin HlyA has also received attention as a potential vaccine target and was evaluated in a mouse model of pyelonephritis to assess protection against renal damage 114 , 115 . Vaccination with HlyA reduced the incidence of renal scaring compared with controls; however, it did not protect against UPEC colonization of the kidneys 115 . In addition, in a mouse model of UTI, vaccination with the P. mirabilis haemolysin, HpmA, did not provide protection against bacterial colonization 116 . However, vaccination with Pta, an alkaline protease with toxic effects towards epithelial cells, displayed promising results in a mouse model of UTI, protecting against upper UTI, although bacterial burdens in the bladder remained unaffected 116 . Thus, although haemolysins and proteases might provide effective vaccine targets for preventing upper UTIs, additional studies are needed to determine the effectiveness of these enzymes as targets for vaccines.

Vaccines targeting siderophores

Iron acquisition systems have shown great promise as targets for vaccine development because uropathogens require a source of iron during colonization and persistence. Furthermore, siderophore and haem acquisition systems have been shown to be upregulated during experimental infection, as well as in the urine of women with a UTI 86 , 94 , 97 , 98 . These parameters sparked vaccine development based on ferric yersiniabactin uptake receptor (FyuA), haem acquisition protein (Hma), iron uptake transport aerobactin receptor (IutA) and the siderophore receptor iron-responsive element A (IreA) 98 . Vaccination with FyuA and Hma protected mice against pyelonephritis 98 , 117 , whereas vaccination with IutA and IreA reduced bladder colonization in mice, confirming the importance of these proteins during infection 98 , 117 . Interestingly, the differential tissue-specific protection seen with these four proteins suggests that these systems have different roles or expression profiles in different niches, including the bladder or kidneys.

Vaccinations with other siderophore systems in mouse models of UTI, including the iron receptors FitA and ChuA 98 , were not protective against infection and were correlated, to a large extent, with lower antigen-specific humoral responses during experimental UTI. These studies suggest that effective siderophore-based vaccines function in part by preventing cognate siderophore uptake, as is the case with FyuA, Hma, IutA and IreA 98 , 117 , making this an exciting area of therapeutic development against UTIs.

Small molecules targeting urease

Several urease inhibitors have been developed as potential drugs for UTI treatment, with varying results 89 . Many of the early inhibitors were active against ureases from several different bacterial species, including Helicobacter pylori, P. mirabilis and S. saprophyticus , and many of these inhibitors showed great promise, as they had low binding and inhibitory concentrations. The best characterized urease inhibitor, acetohydroxamic acid (AHA), even had some success in treating UTIs caused by urease-producing organisms; this inhibitor works by preventing urine alkalization and was approved by the FDA in 1983 (REF. 89 ). However, many of these inhibitors had severe side effects related to toxicity. For example, AHA resulted in teratogenicity, as well as psychoneurological and musculo-integumentary effects. Subsequent studies showed that derivatives of AHA also had considerable inhibitory properties, but again, these compounds had mutagenic properties that made them undesirable therapeutics 89 . Another group of urease inhibitors, the phosphoramidites, exhibited potent activity against P. mirabilis urease and were effective in a mouse model of infection. However, this class of compounds displayed low stability in the low pH of gastric juice, making them impractical 89 . Finally, the heterocyclic compounds termed benzimidazoles have garnered much attention because they function as proton pump inhibitors that irreversibly inactivate ATPase systems 118 . These compounds are currently the standard treatment for peptic ulcers and gastroesophageal reflux disease 89 . Benzimidazoles interact with the gastric hydrogen potassium ATPase, thereby inactivating them and effectively limiting the disease 118 . Interestingly, benzimidazoles also bind to the urease metallocentre, effectively blocking the active site of the enzyme through steric hindrance 89 . Benzimidazoles also have a bactericidal activity against H. pylori , and this is not mediated by urease inhibition, indicating that these compounds have a more general bactericidal effect 89 , 119 . Great strides have been made to identify and characterize urease inhibitors, but more work is needed to bring these potential treatments to the market.

Small molecules targeting bacterial adhesion

Our detailed understanding of pilus assembly and pilus–receptor binding has opened the door to the development of two classes of small, rationally designed synthetic compounds to inhibit pili: mannosides, which inhibit pilus function; and pilicides, which inhibit pilus assembly. Targeting CUP pilus function or assembly has therapeutic potential, as it should block UPEC colonization, invasion and biofilm formation, thus preventing disease 30 , 31 , 120 , 121 .

Pilicides were originally developed to specifically inhibit the assembly of UPEC type 1 pili. They have a 2-pyridone scaffold 28 , 30 , 31 , 120 and function by selectively targeting and interfering with crucial chaperone–usher interactions. Further studies have been carried out to investigate their broad spectrum of activity against other CUP pili 122 . A recent analysis of 35 Escherichia spp. genomes and 132 plasmids identified a total of 458 CUP operons, representing 38 distinct CUP pilus types on the basis of usher phylogeny 25 . A single Escherichia sp. genome can have as many as 16 distinct, intact CUP oper-ons 25 , suggesting that compounds which target CUP pili by disrupting their assembly would potentially exhibit broad-spectrum activity. For example, pilicide ec240 was found to disrupt several virulence-associated pili, including type 1 pili, P pili and S pili, as well as flagellar motility 122 . The effect of ec240 on the transcriptome and proteome of the cystitis isolate E. coli UTI89 revealed that the most downregulated genes after growth in the presence of ec240 were the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the type 1 fimbriae promoter element ( fimS ), which can oscillate between phase ON and phase OFF orientations. ec240 induced the fimS phase OFF orientation and increased the expression of the transcriptional regulators S-fimbrial switch regulatory protein (SfaB) and P pilus regulatory protein PapB, which have been shown to promote a fimS phase OFF orientation 122 . Thus, the potency of pilicide ec240 is largely due to its ability to induce a phase OFF orientation of the type 1 pilus promoter, rather than any interference with chaperone–usher interactions. Additional work revealed that other pilicides also inhibit the production of Dr pili, another type of UPEC CUP pili that are known to be important in pyelonephritis in mice and humans 30 , 33 . Furthermore, pilicides have been shown to disrupt CUP pilus biogenesis in K. pneumoniae and also in Haemophilus influenzae (a finding that has important implications for otitis media) 24 , 29 . Thus, pilicides represent an exciting class of antivirulence molecules with the potential to target a broad spectrum of pathogens that utilize CUP pili in attachment and the establishment of infection. Future studies using mouse models of UTIs and CAUTIs to investigate the role of CUP pili in Gram-negative bacterial infections, as well as the efficacy and bioavailability of pilicides as therapeutics, will unravel the potential of this class of molecules.

Mannosides, which are FimH receptor analogues, have been developed to bind FimH with high affinity and block FimH binding to mannosylated receptors 35 , 121 , 123 – 125 . Mannosides are potent FimH antagonists that offer a promising therapeutic opportunity for the treatment and prevention of UTIs by interrupting key host–pathogen interactions 123 – 125 . Studies in mouse models have demonstrated the potential of mannosides as novel therapeutic strategies against UTIs: mannosides are orally bioavailable; they are potent and fast-acting therapeutics in treating and preventing UTIs; they function by preventing bladder colonization and invasion; they are effective against multidrug-resistant UPEC; they potentiate antibiotic efficacy; and they are effective against established UTIs and CAUTIs 35 , 121 , 124 , 125 .

Interestingly, the adhesin FimH undergoes a substantial structural change during transit across the usher pore, such that the receptor-binding lectin domain bends approximately 37° with respect to the pilin domain. Thus, FimH adopts an elongated conformation before transport across the usher pore 32 , 126 , whereas the lectin domain swings closer to the pilin domain after transport 32 . The two forms of the lectin domain have important implications for binding and pathogenesis: the elongated conformation binds mannose with a significantly higher affinity than the compact form 126 . Residues that control these conformational transitions have been shown to be under positive selection, and pathoadaptive alleles of FimH have subsequently been identified 126 – 128 . Thus, we now understand how protein–protein interactions and ligand binding can regulate a dynamic conformational equilibrium in the receptor-binding domain of FimH, and this is revealing unexpected insights into UTI pathogenesis and potentiating mannoside development. This unravelling of the dynamics of how allostery governs CUP pilus assembly and function is providing valuable information about macromolecular protein assembly and virulence in Gram-negative pathogens and is spawning new ways of thinking about drug development.

UTIs are some of the most common bacterial infections, resulting in billions of dollars in health care costs annually 1 . Both the numerous uropathogens, which encode a wide range of virulence factors, and the spread of antimicrobial resistance threaten the only effective treatment option available — antibiotics 15 , 17 . Moreover, high rates of recurrent UTIs suggest that antibiotics are not an effective therapy for all UTIs. Intensive studies have laid the foundations for conducting translational research that can identify essential mechanisms of virulence and provide evidence to guide the development of UTI treatments and prophylactics that are optimized against uropathogens and that do not alter the normal microflora. The identification of virulence determinants — specifically, those that are essential for initial attachment, including adhesins, and for the subsequent establishment of disease, including siderophores and urease — has allowed the development of targeted therapies that effectively neutralize pathogenic bacteria and prevent disease in animal models. By targeting the initial steps of infection — either through chemical compounds, such as mannosides and pilicides, or by vaccination with adhesins or siderophore receptors — these therapies aim to prevent uropathogens from gaining a foothold in the urinary tract.

Although great strides have been made in developing new strategies that might one day be of value in the treatment and prevention of UTIs, more work is needed. Although the FimH vaccine is in Phase I clinical trials, many of the other potential therapies, including mannosides, pilicides, and vaccines against siderophores, toxins and pili, are still in the preclinical stages of development and have been tested only in animal models. Importantly, the impact of these strategies on the endogenous microbiota should be considered. For example, although these antivirulence therapeutics are not expected to greatly affect the microbiota (as Enterobacteriaceae family members make up only a small portion of the gut flora), only the FimH vaccine has so far been demonstrated to have no effect on the normal composition of the gut microbiota 109 .

Finally, substantial effort should be put into setting up future clinical trials, which will be essential for translating these novel antivirulence therapies into new treatments that reduce the suffering associated with UTIs.

Supplementary Material


The authors apologize to researchers whose work could not be included in this Review owing to space limitations. They thank members of S.J.H.’s and M.G.C.’s laboratories, especially K. W. Dodson, for their suggestions and comments. This work was supported by the 1F32DK104516-01 grant to A.L.F.-M. and the R01-DK051406, R01-AI108749-01 and P50-DK0645400 grants from the US National Institute of Allergy and Infectious Diseases (NIAID) and US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Competing interests statement

The authors declare no competing interests.


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This glossary is intended to assist you in understanding commonly used terms and concepts when reading, interpreting, and evaluating scholarly research. Also included are common words and phrases defined within the context of how they apply to research in the social and behavioral sciences.

  • Acculturation -- refers to the process of adapting to another culture, particularly in reference to blending in with the majority population [e.g., an immigrant adopting American customs]. However, acculturation also implies that both cultures add something to one another, but still remain distinct groups unto themselves.
  • Accuracy -- a term used in survey research to refer to the match between the target population and the sample.
  • Affective Measures -- procedures or devices used to obtain quantified descriptions of an individual's feelings, emotional states, or dispositions.
  • Aggregate -- a total created from smaller units. For instance, the population of a county is an aggregate of the populations of the cities, rural areas, etc. that comprise the county. As a verb, it refers to total data from smaller units into a large unit.
  • Anonymity -- a research condition in which no one, including the researcher, knows the identities of research participants.
  • Baseline -- a control measurement carried out before an experimental treatment.
  • Behaviorism -- school of psychological thought concerned with the observable, tangible, objective facts of behavior, rather than with subjective phenomena such as thoughts, emotions, or impulses. Contemporary behaviorism also emphasizes the study of mental states such as feelings and fantasies to the extent that they can be directly observed and measured.
  • Beliefs -- ideas, doctrines, tenets, etc. that are accepted as true on grounds which are not immediately susceptible to rigorous proof.
  • Benchmarking -- systematically measuring and comparing the operations and outcomes of organizations, systems, processes, etc., against agreed upon "best-in-class" frames of reference.
  • Bias -- a loss of balance and accuracy in the use of research methods. It can appear in research via the sampling frame, random sampling, or non-response. It can also occur at other stages in research, such as while interviewing, in the design of questions, or in the way data are analyzed and presented. Bias means that the research findings will not be representative of, or generalizable to, a wider population.
  • Case Study -- the collection and presentation of detailed information about a particular participant or small group, frequently including data derived from the subjects themselves.
  • Causal Hypothesis -- a statement hypothesizing that the independent variable affects the dependent variable in some way.
  • Causal Relationship -- the relationship established that shows that an independent variable, and nothing else, causes a change in a dependent variable. It also establishes how much of a change is shown in the dependent variable.
  • Causality -- the relation between cause and effect.
  • Central Tendency -- any way of describing or characterizing typical, average, or common values in some distribution.
  • Chi-square Analysis -- a common non-parametric statistical test which compares an expected proportion or ratio to an actual proportion or ratio.
  • Claim -- a statement, similar to a hypothesis, which is made in response to the research question and that is affirmed with evidence based on research.
  • Classification -- ordering of related phenomena into categories, groups, or systems according to characteristics or attributes.
  • Cluster Analysis -- a method of statistical analysis where data that share a common trait are grouped together. The data is collected in a way that allows the data collector to group data according to certain characteristics.
  • Cohort Analysis -- group by group analytic treatment of individuals having a statistical factor in common to each group. Group members share a particular characteristic [e.g., born in a given year] or a common experience [e.g., entering a college at a given time].
  • Confidentiality -- a research condition in which no one except the researcher(s) knows the identities of the participants in a study. It refers to the treatment of information that a participant has disclosed to the researcher in a relationship of trust and with the expectation that it will not be revealed to others in ways that violate the original consent agreement, unless permission is granted by the participant.
  • Confirmability Objectivity -- the findings of the study could be confirmed by another person conducting the same study.
  • Construct -- refers to any of the following: something that exists theoretically but is not directly observable; a concept developed [constructed] for describing relations among phenomena or for other research purposes; or, a theoretical definition in which concepts are defined in terms of other concepts. For example, intelligence cannot be directly observed or measured; it is a construct.
  • Construct Validity -- seeks an agreement between a theoretical concept and a specific measuring device, such as observation.
  • Constructivism -- the idea that reality is socially constructed. It is the view that reality cannot be understood outside of the way humans interact and that the idea that knowledge is constructed, not discovered. Constructivists believe that learning is more active and self-directed than either behaviorism or cognitive theory would postulate.
  • Content Analysis -- the systematic, objective, and quantitative description of the manifest or latent content of print or nonprint communications.
  • Context Sensitivity -- awareness by a qualitative researcher of factors such as values and beliefs that influence cultural behaviors.
  • Control Group -- the group in an experimental design that receives either no treatment or a different treatment from the experimental group. This group can thus be compared to the experimental group.
  • Controlled Experiment -- an experimental design with two or more randomly selected groups [an experimental group and control group] in which the researcher controls or introduces the independent variable and measures the dependent variable at least two times [pre- and post-test measurements].
  • Correlation -- a common statistical analysis, usually abbreviated as r, that measures the degree of relationship between pairs of interval variables in a sample. The range of correlation is from -1.00 to zero to +1.00. Also, a non-cause and effect relationship between two variables.
  • Covariate -- a product of the correlation of two related variables times their standard deviations. Used in true experiments to measure the difference of treatment between them.
  • Credibility -- a researcher's ability to demonstrate that the object of a study is accurately identified and described based on the way in which the study was conducted.
  • Critical Theory -- an evaluative approach to social science research, associated with Germany's neo-Marxist “Frankfurt School,” that aims to criticize as well as analyze society, opposing the political orthodoxy of modern communism. Its goal is to promote human emancipatory forces and to expose ideas and systems that impede them.
  • Data -- factual information [as measurements or statistics] used as a basis for reasoning, discussion, or calculation.
  • Data Mining -- the process of analyzing data from different perspectives and summarizing it into useful information, often to discover patterns and/or systematic relationships among variables.
  • Data Quality -- this is the degree to which the collected data [results of measurement or observation] meet the standards of quality to be considered valid [trustworthy] and  reliable [dependable].
  • Deductive -- a form of reasoning in which conclusions are formulated about particulars from general or universal premises.
  • Dependability -- being able to account for changes in the design of the study and the changing conditions surrounding what was studied.
  • Dependent Variable -- a variable that varies due, at least in part, to the impact of the independent variable. In other words, its value “depends” on the value of the independent variable. For example, in the variables “gender” and “academic major,” academic major is the dependent variable, meaning that your major cannot determine whether you are male or female, but your gender might indirectly lead you to favor one major over another.
  • Deviation -- the distance between the mean and a particular data point in a given distribution.
  • Discourse Community -- a community of scholars and researchers in a given field who respond to and communicate to each other through published articles in the community's journals and presentations at conventions. All members of the discourse community adhere to certain conventions for the presentation of their theories and research.
  • Discrete Variable -- a variable that is measured solely in whole units, such as, gender and number of siblings.
  • Distribution -- the range of values of a particular variable.
  • Effect Size -- the amount of change in a dependent variable that can be attributed to manipulations of the independent variable. A large effect size exists when the value of the dependent variable is strongly influenced by the independent variable. It is the mean difference on a variable between experimental and control groups divided by the standard deviation on that variable of the pooled groups or of the control group alone.
  • Emancipatory Research -- research is conducted on and with people from marginalized groups or communities. It is led by a researcher or research team who is either an indigenous or external insider; is interpreted within intellectual frameworks of that group; and, is conducted largely for the purpose of empowering members of that community and improving services for them. It also engages members of the community as co-constructors or validators of knowledge.
  • Empirical Research -- the process of developing systematized knowledge gained from observations that are formulated to support insights and generalizations about the phenomena being researched.
  • Epistemology -- concerns knowledge construction; asks what constitutes knowledge and how knowledge is validated.
  • Ethnography -- method to study groups and/or cultures over a period of time. The goal of this type of research is to comprehend the particular group/culture through immersion into the culture or group. Research is completed through various methods but, since the researcher is immersed within the group for an extended period of time, more detailed information is usually collected during the research.
  • Expectancy Effect -- any unconscious or conscious cues that convey to the participant in a study how the researcher wants them to respond. Expecting someone to behave in a particular way has been shown to promote the expected behavior. Expectancy effects can be minimized by using standardized interactions with subjects, automated data-gathering methods, and double blind protocols.
  • External Validity -- the extent to which the results of a study are generalizable or transferable.
  • Factor Analysis -- a statistical test that explores relationships among data. The test explores which variables in a data set are most related to each other. In a carefully constructed survey, for example, factor analysis can yield information on patterns of responses, not simply data on a single response. Larger tendencies may then be interpreted, indicating behavior trends rather than simply responses to specific questions.
  • Field Studies -- academic or other investigative studies undertaken in a natural setting, rather than in laboratories, classrooms, or other structured environments.
  • Focus Groups -- small, roundtable discussion groups charged with examining specific topics or problems, including possible options or solutions. Focus groups usually consist of 4-12 participants, guided by moderators to keep the discussion flowing and to collect and report the results.
  • Framework -- the structure and support that may be used as both the launching point and the on-going guidelines for investigating a research problem.
  • Generalizability -- the extent to which research findings and conclusions conducted on a specific study to groups or situations can be applied to the population at large.
  • Grey Literature -- research produced by organizations outside of commercial and academic publishing that publish materials, such as, working papers, research reports, and briefing papers.
  • Grounded Theory -- practice of developing other theories that emerge from observing a group. Theories are grounded in the group's observable experiences, but researchers add their own insight into why those experiences exist.
  • Group Behavior -- behaviors of a group as a whole, as well as the behavior of an individual as influenced by his or her membership in a group.
  • Hypothesis -- a tentative explanation based on theory to predict a causal relationship between variables.
  • Independent Variable -- the conditions of an experiment that are systematically manipulated by the researcher. A variable that is not impacted by the dependent variable, and that itself impacts the dependent variable. In the earlier example of "gender" and "academic major," (see Dependent Variable) gender is the independent variable.
  • Individualism -- a theory or policy having primary regard for the liberty, rights, or independent actions of individuals.
  • Inductive -- a form of reasoning in which a generalized conclusion is formulated from particular instances.
  • Inductive Analysis -- a form of analysis based on inductive reasoning; a researcher using inductive analysis starts with answers, but formulates questions throughout the research process.
  • Insiderness -- a concept in qualitative research that refers to the degree to which a researcher has access to and an understanding of persons, places, or things within a group or community based on being a member of that group or community.
  • Internal Consistency -- the extent to which all questions or items assess the same characteristic, skill, or quality.
  • Internal Validity -- the rigor with which the study was conducted [e.g., the study's design, the care taken to conduct measurements, and decisions concerning what was and was not measured]. It is also the extent to which the designers of a study have taken into account alternative explanations for any causal relationships they explore. In studies that do not explore causal relationships, only the first of these definitions should be considered when assessing internal validity.
  • Life History -- a record of an event/events in a respondent's life told [written down, but increasingly audio or video recorded] by the respondent from his/her own perspective in his/her own words. A life history is different from a "research story" in that it covers a longer time span, perhaps a complete life, or a significant period in a life.
  • Margin of Error -- the permittable or acceptable deviation from the target or a specific value. The allowance for slight error or miscalculation or changing circumstances in a study.
  • Measurement -- process of obtaining a numerical description of the extent to which persons, organizations, or things possess specified characteristics.
  • Meta-Analysis -- an analysis combining the results of several studies that address a set of related hypotheses.
  • Methodology -- a theory or analysis of how research does and should proceed.
  • Methods -- systematic approaches to the conduct of an operation or process. It includes steps of procedure, application of techniques, systems of reasoning or analysis, and the modes of inquiry employed by a discipline.
  • Mixed-Methods -- a research approach that uses two or more methods from both the quantitative and qualitative research categories. It is also referred to as blended methods, combined methods, or methodological triangulation.
  • Modeling -- the creation of a physical or computer analogy to understand a particular phenomenon. Modeling helps in estimating the relative magnitude of various factors involved in a phenomenon. A successful model can be shown to account for unexpected behavior that has been observed, to predict certain behaviors, which can then be tested experimentally, and to demonstrate that a given theory cannot account for certain phenomenon.
  • Models -- representations of objects, principles, processes, or ideas often used for imitation or emulation.
  • Naturalistic Observation -- observation of behaviors and events in natural settings without experimental manipulation or other forms of interference.
  • Norm -- the norm in statistics is the average or usual performance. For example, students usually complete their high school graduation requirements when they are 18 years old. Even though some students graduate when they are younger or older, the norm is that any given student will graduate when he or she is 18 years old.
  • Null Hypothesis -- the proposition, to be tested statistically, that the experimental intervention has "no effect," meaning that the treatment and control groups will not differ as a result of the intervention. Investigators usually hope that the data will demonstrate some effect from the intervention, thus allowing the investigator to reject the null hypothesis.
  • Ontology -- a discipline of philosophy that explores the science of what is, the kinds and structures of objects, properties, events, processes, and relations in every area of reality.
  • Panel Study -- a longitudinal study in which a group of individuals is interviewed at intervals over a period of time.
  • Participant -- individuals whose physiological and/or behavioral characteristics and responses are the object of study in a research project.
  • Peer-Review -- the process in which the author of a book, article, or other type of publication submits his or her work to experts in the field for critical evaluation, usually prior to publication. This is standard procedure in publishing scholarly research.
  • Phenomenology -- a qualitative research approach concerned with understanding certain group behaviors from that group's point of view.
  • Philosophy -- critical examination of the grounds for fundamental beliefs and analysis of the basic concepts, doctrines, or practices that express such beliefs.
  • Phonology -- the study of the ways in which speech sounds form systems and patterns in language.
  • Policy -- governing principles that serve as guidelines or rules for decision making and action in a given area.
  • Policy Analysis -- systematic study of the nature, rationale, cost, impact, effectiveness, implications, etc., of existing or alternative policies, using the theories and methodologies of relevant social science disciplines.
  • Population -- the target group under investigation. The population is the entire set under consideration. Samples are drawn from populations.
  • Position Papers -- statements of official or organizational viewpoints, often recommending a particular course of action or response to a situation.
  • Positivism -- a doctrine in the philosophy of science, positivism argues that science can only deal with observable entities known directly to experience. The positivist aims to construct general laws, or theories, which express relationships between phenomena. Observation and experiment is used to show whether the phenomena fit the theory.
  • Predictive Measurement -- use of tests, inventories, or other measures to determine or estimate future events, conditions, outcomes, or trends.
  • Principal Investigator -- the scientist or scholar with primary responsibility for the design and conduct of a research project.
  • Probability -- the chance that a phenomenon will occur randomly. As a statistical measure, it is shown as p [the "p" factor].
  • Questionnaire -- structured sets of questions on specified subjects that are used to gather information, attitudes, or opinions.
  • Random Sampling -- a process used in research to draw a sample of a population strictly by chance, yielding no discernible pattern beyond chance. Random sampling can be accomplished by first numbering the population, then selecting the sample according to a table of random numbers or using a random-number computer generator. The sample is said to be random because there is no regular or discernible pattern or order. Random sample selection is used under the assumption that sufficiently large samples assigned randomly will exhibit a distribution comparable to that of the population from which the sample is drawn. The random assignment of participants increases the probability that differences observed between participant groups are the result of the experimental intervention.
  • Reliability -- the degree to which a measure yields consistent results. If the measuring instrument [e.g., survey] is reliable, then administering it to similar groups would yield similar results. Reliability is a prerequisite for validity. An unreliable indicator cannot produce trustworthy results.
  • Representative Sample -- sample in which the participants closely match the characteristics of the population, and thus, all segments of the population are represented in the sample. A representative sample allows results to be generalized from the sample to the population.
  • Rigor -- degree to which research methods are scrupulously and meticulously carried out in order to recognize important influences occurring in an experimental study.
  • Sample -- the population researched in a particular study. Usually, attempts are made to select a "sample population" that is considered representative of groups of people to whom results will be generalized or transferred. In studies that use inferential statistics to analyze results or which are designed to be generalizable, sample size is critical, generally the larger the number in the sample, the higher the likelihood of a representative distribution of the population.
  • Sampling Error -- the degree to which the results from the sample deviate from those that would be obtained from the entire population, because of random error in the selection of respondent and the corresponding reduction in reliability.
  • Saturation -- a situation in which data analysis begins to reveal repetition and redundancy and when new data tend to confirm existing findings rather than expand upon them.
  • Semantics -- the relationship between symbols and meaning in a linguistic system. Also, the cuing system that connects what is written in the text to what is stored in the reader's prior knowledge.
  • Social Theories -- theories about the structure, organization, and functioning of human societies.
  • Sociolinguistics -- the study of language in society and, more specifically, the study of language varieties, their functions, and their speakers.
  • Standard Deviation -- a measure of variation that indicates the typical distance between the scores of a distribution and the mean; it is determined by taking the square root of the average of the squared deviations in a given distribution. It can be used to indicate the proportion of data within certain ranges of scale values when the distribution conforms closely to the normal curve.
  • Statistical Analysis -- application of statistical processes and theory to the compilation, presentation, discussion, and interpretation of numerical data.
  • Statistical Bias -- characteristics of an experimental or sampling design, or the mathematical treatment of data, that systematically affects the results of a study so as to produce incorrect, unjustified, or inappropriate inferences or conclusions.
  • Statistical Significance -- the probability that the difference between the outcomes of the control and experimental group are great enough that it is unlikely due solely to chance. The probability that the null hypothesis can be rejected at a predetermined significance level [0.05 or 0.01].
  • Statistical Tests -- researchers use statistical tests to make quantitative decisions about whether a study's data indicate a significant effect from the intervention and allow the researcher to reject the null hypothesis. That is, statistical tests show whether the differences between the outcomes of the control and experimental groups are great enough to be statistically significant. If differences are found to be statistically significant, it means that the probability [likelihood] that these differences occurred solely due to chance is relatively low. Most researchers agree that a significance value of .05 or less [i.e., there is a 95% probability that the differences are real] sufficiently determines significance.
  • Subcultures -- ethnic, regional, economic, or social groups exhibiting characteristic patterns of behavior sufficient to distinguish them from the larger society to which they belong.
  • Testing -- the act of gathering and processing information about individuals' ability, skill, understanding, or knowledge under controlled conditions.
  • Theory -- a general explanation about a specific behavior or set of events that is based on known principles and serves to organize related events in a meaningful way. A theory is not as specific as a hypothesis.
  • Treatment -- the stimulus given to a dependent variable.
  • Trend Samples -- method of sampling different groups of people at different points in time from the same population.
  • Triangulation -- a multi-method or pluralistic approach, using different methods in order to focus on the research topic from different viewpoints and to produce a multi-faceted set of data. Also used to check the validity of findings from any one method.
  • Unit of Analysis -- the basic observable entity or phenomenon being analyzed by a study and for which data are collected in the form of variables.
  • Validity -- the degree to which a study accurately reflects or assesses the specific concept that the researcher is attempting to measure. A method can be reliable, consistently measuring the same thing, but not valid.
  • Variable -- any characteristic or trait that can vary from one person to another [race, gender, academic major] or for one person over time [age, political beliefs].
  • Weighted Scores -- scores in which the components are modified by different multipliers to reflect their relative importance.
  • White Paper -- an authoritative report that often states the position or philosophy about a social, political, or other subject, or a general explanation of an architecture, framework, or product technology written by a group of researchers. A white paper seeks to contain unbiased information and analysis regarding a business or policy problem that the researchers may be facing.

Elliot, Mark, Fairweather, Ian, Olsen, Wendy Kay, and Pampaka, Maria. A Dictionary of Social Research Methods. Oxford, UK: Oxford University Press, 2016; Free Social Science Dictionary. [2008]. Glossary. Institutional Review Board. Colorado College; Glossary of Key Terms. Writing@CSU. Colorado State University; Glossary A-Z.; Glossary of Research Terms. Research Mindedness Virtual Learning Resource. Centre for Human Servive Technology. University of Southampton; Miller, Robert L. and Brewer, John D. The A-Z of Social Research: A Dictionary of Key Social Science Research Concepts London: SAGE, 2003; Jupp, Victor. The SAGE Dictionary of Social and Cultural Research Methods . London: Sage, 2006.

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Grace Under Pressure: a mixed methods impact assessment of a verbatim theatre intervention to improve healthcare workplace culture

  • Claire Hooker 1 ,
  • Aspasia Karageorge 2 ,
  • Karen M. Scott 3 , 4 ,
  • Renee Lim 4 &
  • Louise Nash 2 , 5  

BMC Health Services Research volume  24 , Article number:  474 ( 2024 ) Cite this article

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Healthcare workplace mistreatment has been documented globally. Poor workplace behaviour, ranging from incivility to bullying and harassment, is common in healthcare, and contributes significantly to adverse events in healthcare, poor mental health among healthcare workers, and to attrition in the healthcare workforce, particularly in junior years. Poor workplace behaviour is often normalised, and is difficult to address. Verbatim theatre, a form of research informed theatre in which plays are created from informants’ exact words only, is particularly suited to facilitating workplace culture change by raising awareness about issues that are difficult to discuss. The objective of this study was to assess the impact of the verbatim theatre play ‘Grace Under Pressure’ on workplace culture in NSW hospitals.

The intervention was conducted in 13 hospitals from 8 Local Health Districts (LHDs) in NSW, Australia, in October and November 2019, with aggregated impact across all sites measured by a bespoke survey (‘Pam McLean Centre (PMC) survey’) at the conclusion of the intervention. This study was conducted in 3 Local Health Districts (one urban, one regional, one remote), with data collection conducted in November–December 2019 and December 2020. The study design was a mixed methods assessment of the play’s impact using (1) validated baseline measures of psychosocial risk, analysed descriptively, (2) overall findings from the PMC survey above, analysed descriptively, (3) interviews conducted within a month of the intervention, analysed thematically and (4) interviews conducted one year later, analysed thematically.

Half (51.5%) of the respondents ( n  = 149) to the baseline survey had scores indicating high risk of job strain and depressive symptoms. Of 478 respondents to the PMC survey (response rate 57%), 93% found the play important, 92% recommended others see the play, 89% considered that it stimulated thinking about workplace behaviour, and 85% that it made discussing these issues easier. Thematic analysis of interviews within one month ( n  = 21) showed that the play raised awareness about poor workplace behaviour and motivated behaviour change. Interviews conducted one year later ( n  = 6) attributed improved workplace culture to the intervention due to improved awareness, discussion and capacity to respond to challenging issues.


Verbatim theatre is effective in raising awareness about difficult workplace behaviour in ways that motivate behaviour change, and hence can be effective in catalysing real improvements in healthcare workplace culture. Creative approaches are recommended for addressing similarly complex challenges in healthcare workforce retention.

Peer Review reports

Healthcare workforce shortages and retention of workers are urgent issues, particularly in the wake of the Covid-19 pandemic [ 1 ]. One significant contributor to attrition among healthcare staff is experiencing poor workplace behaviour from colleagues, which ranges from incivility (offensive, intimidating, or insulting behaviours) to bullying and harassment [ 19 ]. Poor healthcare workplace behaviour has been documented globally [ 2 , 3 ], and affects both medicine and nursing at varying rates; for example, recent reviews identified average prevalence among nurses at 26% and 66.9% (see [ 2 , 4 , 5 ]). Junior staff, women and minorities are more likely to be victims [ 6 , 7 ]. ‘Teaching by humiliation’ and other forms of mistreatment are experienced or witnessed by a majority of medical and nursing students [ 4 , 8 , 9 , 10 , 11 ].

Poor healthcare workplace behaviour can cause extensive harm in victims, including long lasting burnout, psychological distress, intentions to quit the profession, reduced clinical ability, reduced capacity to learn and reduced career progression [ 6 , 12 ]. Such behaviour can impact on the quality of care and patient safety as a result of impaired concentration, inhibited communication and delays or errors in care [ 5 , 13 ]. Positively, there is evidence suggesting that the converse is true, and that improvements in healthcare workplace culture will mitigate burnout [ 14 ] and improve cost-effectiveness and patient outcomes [ 6 ].

Although poor healthcare workplace behaviour is now widely researched, there have been few signs of improvement [ 4 , 7 , 15 , 16 ]. Often, the problem has not even been disclosed, either to colleagues or managers. Healthcare workplace behaviour often includes attacks on the victim’s professional identity. Feelings of shame [ 17 ] (common in victims of abuse) have often rendered the issue a ‘silent epidemic’ [ 18 ]. Institutional policies have often had little impact, in part because victims fear that a complaint may negatively impact their career prospects [ 19 ]. A cycle in which juniors internalise such behaviours during training and eventually reproduce them, is in place [ 7 , 20 ].

The creative arts have affordances particularly suited to intervene in poor workplace culture and halt self-perpetuating cycles. ‘Verbatim’ theatre is a form of ‘documentary’ or research-informed theatre. Verbatim theatre plays must be composed using only the exact words of real informants (usually provided in interview), who have lived experience of an issue of interest. Verbatim theatre was explicitly devised to raise awareness of discomfiting issues, especially the experiences of stigmatised social groups, from sex workers to refugees to sufferers of alopecia or those recovering from stroke. Verbatim theatre has been particularly valued for disrupting ‘social laryngitis’, that is, the perception that an issue is ‘unspeakable’ due to shame, stigma, fear or disempowered circumstances [ 21 , 22 , 23 ] – something that victims of bullying and harassment in healthcare work often experience [ 5 , 19 ]. Multiple ‘active ingredients’ [ 24 ], including fidelity to real experience, providing witness to distress, capacity to represent complexity, and humour, mean that verbatim theatre works can generate experiential and moral learning [ 25 , 26 ].

Rationale: assessing the impact of a creative intervention

Teaching by humiliation, poor workplace culture and bullying and harassment are unfortunately prevalent in the Australian healthcare industry [ 27 , 28 , 29 ] and produce high rates of burnout and mental ill health among the Australian healthcare workforce [ 30 ].

The verbatim theatre play Grace Under Pressure (Williams and Dwyer, 2017) was created in 2017 from interviews with 30 doctors and nurses across all career stages (including students) and representing a range of healthcare roles [ 31 ], to explore training and workplace challenges in healthcare. Topics represented in the play included burnout, excessive workloads, poor work/life balance, inappropriate levels of responsibility, poor workplace behaviour ranging from incivility to bullying, sexual harassment and sexism, interprofessional hierarchy, accidents and suicide. The play also portrayed humour, collegiality, joy at work, and care. Grace Under Pressure was well reviewed during its mainstage debut in Sydney, Australia, and was subsequently adapted by the Pam McLean Centre (PMC) and performed in a range of healthcare workplace and educational settings, as well as achieving a national mainstage tour in 2020 and 2021. In 2019, NSW Health, the Health Ministry in the state of New South Wales, supported the play as a healthcare workplace culture intervention, consisting of a performance followed by workshops in multiple hospitals across NSW.

Our aim was to assess the impact of this intervention. Our research questions were: (1) Did the play raise awareness about poor healthcare workplace behaviour? (2) Did the play create intentions to improve healthcare workplace culture? (3) Did the play contribute to generating actual improvements in healthcare workplace culture?

Intervention and research settings

The Grace Under Pressure play and workshop (‘the intervention’) was offered by PMC; NSW Health; and theatre company Alternative Facts. The intervention was conducted in November 2019 in 13 hospitals (4 metropolitan hospitals, 7 mid sized regional hospitals and 2 remote hospitals), located in 8 Local Health Districts (LHDs) across NSW, where there are 15 LHDs in total. All hospitals and LHDs who received the intervention responded to one component of impact research, a bespoke survey issued by PMC. Our additional impact research (baseline measures and qualitative interviews) was focused in 3 LHDs that typify health service contexts across the state. LHD #1 is a busy metropolitan LHD; the intervention was conducted in two hospitals. LHD #2 is a regional LHD and held the intervention in one hospital. LHD #3 is a remote LHD; the intervention was conducted in two hospitals. That is, our research assessed impacts of performances in 5 hospitals located in 3 LHDs.

Study design

This research employed an exploratory mixed-methods design comprising four stages, as shown in Fig.  1 .

figure 1

Research stages, times and methods

Variations and COVID-19 disruption

Local resource constraints and communications systems led to each LHD undertaking recruitment differently, including prioritising invitations to doctors and medical students at some sites. This resulted in an unclear total of invitations to participate in the intervention and in the research, and lower research participation in LHD#3. Post-play workshop content (delivered by PMC) was tailored to each LHD, and generally involved discussions of issues raised by the play. Due to disruption by COVID-19, only LHD #2 completed Stage 4.

Research activities

Stage 1 (pre intervention baseline).

Stage 1 comprised the validated 4-item Psychosocial Safety Climate survey (PSC-4)14 [ 32 ] and the validated 9-item health practitioner wellbeing index [ 33 ]. A score >  = 3 in the Wellbeing Index places the respondent at greater risk for reporting a medical error and experiencing burnout, fatigue, suicidal ideation and/or lower quality of life [ 32 ]. In the Psychosocial Climate index, scores 41–37 indicate moderate, and scores <  = 37 indicate high, risk of job strain and symptoms of depression.

Stage 2 (close-of-intervention)

All intervention participants across all intervention sites (13 hospitals) were invited to complete the bespoke Pam McLean Centre (‘PMC’) survey (used to evaluate PMC activities), on paper, at close of intervention, while they were still in the room. This survey contained 16 items, comprising 1 consent item, 4 demographic items, 5 Likert-scale items measuring responses to the play, 5 Likert-scale items measuring experiences of workplace misconduct and personal resilience, and 5 free-text items that explored respondent perceptions of the play and of workplace culture. We report on the aggregated data set provided by PMC here using 3 categories, Strongly Agree/Agree, Neutral and Disagree/Strongly Disagree, to provide at-a-glance understanding of the outcomes without compromise of validity [ 34 , 35 ].

Stage 3 (post intervention)

All registered audience members at LHDs #1, #2 and #3 were invited by email or at the play, to participate in a semi-structured single or group interview within one month of the intervention (supplementary materials), with attendance at the play the only inclusion criterion applied. The interview guide was developed by the research team to address the research questions. All interviews were recorded and professionally transcribed.

Stage 4 (One year follow up)

Due to COVID-19 disruptions, only LHD #2 was able to participate in Stage 4. All LHD #2 interviewees from Stage 3 were invited to participate in a structured interview in December 2020 to explore the play’s impact at one year. The interview guide was adapted from that used in Stage 3. Interviews were recorded and professionally transcribed.

Human Research Ethics approval was granted by the University of Sydney Human Research Ethics Committee for the Phase I pre-intervention survey, and the interviews and focus groups. The Royal North Shore Hospital Human Research Ethics Committee granted Ethics approval for the PMC Survey.

Data analysis

Survey data was analysed using simple descriptive statistics.

Interview data was analysed thematically using NVivo. The team extracted relevant key words and concepts from immersive reading, after which AK and CH constructed latent themes [ 36 ] designed to answer our research questions. Extensive reflexive discussions were used to check and develop themes and sub themes.

Stage 1: Baseline measures of wellbeing

Psychosocial climate survey and wellbeing index.

There were 162 respondents to the survey across 3 LHDs. Females comprised 80% (128/162) of the sample. 50% (80/159) had staff reporting to them or under their supervision and 57% (90/159) reported they made decisions that impacted on the workings of the hospital. The respondent’s main role in their LHD was: clinician 52% (83/159), administrator 21% (33/159), educator 10% (16/159), student 2% (3/159) and other 15% (24/159). For clinicians (including students), this divided further into: allied health 26% (28/108); nursing 24% (26/108); medical practitioner 42% (45/108) and other 8% (9/108).

Sixty percent of respondents scored as being at high risk of burnout, mental illness, and reporting a medical error (Table  1 ).

Stage 2: close-of-intervention PMC Survey responses

A total of 852 people attended the play across all (13 hospital) sites in NSW. Four hundred and eighty eight (response rate 57%) responded to the PMC survey issued at the conclusion of post-play discussions or workshops. After demographic information was extracted, data for those who completed less than 75% of survey questions were excluded ( n  = 7), and descriptive statistics were used to analyse the remaining 478 responses (response rate of 55%).

The audience who attended the play was a heterogenous group of clinicians across medicine, nursing and allied health (and including dentistry, pharmacy), alongside staff with management, human resources, finance, administration, risk management, health informatics, community health and pastoral care roles (‘Other’ in Table  2 ).

The PMC Survey results showed that this heterogenous audience of healthcare staff valued the play highly (93%) (Table  3 ). An overwhelming majority indicated that they would recommend that colleagues, family, friends and members of the public saw the play (92%). They considered that the play stimulated their thinking about workplace behaviour (89%) and agreed that seeing the play made discussing these issues easier (85%).

Survey responses demonstrated that the play authentically represented real healthcare work experiences. Most participants had witnessed or experienced situations similar (66%, n  = 310) or somewhat similar (24%, n  = 112) to those in the play. Only 11% ( n  = 50) did not relate to play content. Respondents were unlikely to disclose experiences of poor workplace behaviour to supervisors or hospital management, but would disclose such experiences to peers (see Table  4 ).

Free-text responses to the question ‘What are three things that might make you consider leaving your job?’ also confirmed the negative impact of poor workplace culture, with the top 5 answers by frequency being; Lack of support/appreciation, Too much work, Bullying, Stress, and Change.

Stage 3: interviews (within 1 month after the play)

Six interviews (2 group (5 participants), 4 single) were conducted at LHD #1, 8 single interviews were conducted at LHD#2, and 3 single interviews were conducted at LHD #3 within 1 month after the performances. These 20 interviews included 16 females and 5 males; 3 junior doctors (Junior Medical Officer or Resident Medical Officer); 7 senior physicians; 6 nurses; 2 allied health; and 3 staff from Human Resources. Some held or had held leadership roles.

Respondents were emphatic that the play was highly valued as an important means of raising awareness of, insight into, and discussion about, healthcare workplace pressures, which they perceived as faithfully represented. Respondents commented on a range of changes they were motivated to undertake after seeing the play, and one year later, considered that the play had played a significant role in facilitating real changes in workplace culture.

One over-arching theme for each research question was constructed through latent thematic analysis. In Stage 3, these themes were ‘raising awareness’ and ‘intentions for change’. Each theme was constructed from inter-related sub themes which were derived inductively. These are briefly described below with illustrative examples.

Raising awareness

This theme was composed of seven sub themes: (1) ‘recognition’, in which respondents recognised their own experiences in the play; (2) ‘need for raising awareness’, in which respondents commented on the need for, and value of, making the play’s issues more widely known; (3) ‘raising awareness in managers’, in which respondents made claims about the importance of managers becoming more aware of the issues raised by the play; (4) ‘already aware’, in which respondents spoke of their knowledge and experience of the issues depicted (sometimes connected with the sub-theme ‘recognition’); (5) awareness of what is working, in which respondents identified models of positive workplace culture; (6) ‘gaining insight’, in which respondents recounted how the play increased their understanding of the phenomena portrayed in it; and (7) ‘recommending the play’, which captured comments from participants who considered seeing the play valuable, usually because of one or more of the other six sub themes. Brief examples of each sub theme are provided below.

Many respondents commented that the play accurately reflected their own experiences, for example:

So yeah I felt quite overwhelmed, I think part of it was just I could relate to quite a lot of the scenarios, both from a clinical perspective but also the sense of pressure about performance and being things to all people and all those things. (Manager, male).

The perception that the play authentically represented real experiences of workplace pressure and misconduct led respondents to comment on their perceptions of issues of burnout, bullying, harassment, incivility and mental ill health at work. Some talked about how important it is to increase awareness of the issues, including the detail of how they present in the workplace:

I think the more people that are aware of what goes on behind the scenes the—because that's really the only way to effect behavioural change; to not just—I guess not just say oh people get bullied and bad things happen. But just say this is the actual breakdown of what people are experiencing and it's not appropriate (Registered Medical Officer, male).

Others stated that they were already aware of these issues, either from their own experiences or from recent attention to such issues:

It wasn’t like a shock for me to hear this, because there’s been lots of literature on this and I attend the IHI [Institute for Healthcare Improvement] annual international conference every year. (Manager, male).

Relatedly, many respondents were quick to state that poor workplace behaviour is far from universal and to comment on examples of positive workplace culture:

I had two of them come back to me on the Monday saying that they feel quite protected where we are. … I think it may be a good thing to look at what’s working well in the teams that are functioning at that respectful level and so that we can model some of that. (Nurse Manager, male).

Some respondents emphasised that the need for awareness was highest in groups who are either more likely to be perpetrators (directly or indirectly), or who have most power to effect change:

I think it was quite I guess comforting to see that while I was finding it confronting that it's good for the top brass to be aware of this kind of stuff as well. (Registered Medical Officer, male).

Many respondents spoke at length of how the play increased their insight into the issues it raised:

I think as well we can probably mostly empathise with their situation that the vascular surgeon is having an insanely stressful experience and therefore snaps, I mean it’s normal for people to lash out when they’re that under pressure, and that’s never going to disappear, but there’s a difference between individual incidents of lashing out and a culture of hierarchy in grinding down the people below you. (Nurse, female).
I don’t think after seeing that play will change the way that I interact with especially my seniors … but I think it makes me hyperaware of how I am around other people, like I’ve always had a really huge issue with the way that doctors treat nurses …like being hyperaware of that hierarchical kind of development and not abiding by it, but then again not speaking up to my seniors it might be doing something different to what I think is wrong. (role not supplied, female).

As a result, most respondents stated that they would recommend that colleagues and friends and family should see the play:

I thought it would be helpful for my family to be able to watch this to give them some kind of experience of what it's like. (Human Resources, female) I’d love to get it out to more staff and encourage them to see it. I know that that’s not practical anymore …There’s no short movie, YouTube or anything on it is there? (Manager, female).

Intentions to change

We identified sub-themes in this theme: (1) ‘practical intentions for change’; (2) ‘scepticism about change’; (3) ‘management needing to change’; (4) ‘optimism about change’; and (5) ‘performing arts and change.’

A number of respondents stated that the play had prompted them to consider practical changes that they could implement immediately as individuals. These included addressing their own symptoms of burnout:

I think my health was only getting worse between seeing the play and now and it was clear that it was unsustainable and something needed to change, so that’s what prompted me to make a plan. (Allied Health, female).

Respondents also reported having increased awareness of others’ burnout; and addressing potential burnout in others by being more available to junior staff and colleagues and by offering to cover shifts where that would be helpful.

Saying is there anything outside of work or do you need to—do you need me to take an afterhours shift for you… in thinking not just oh I've finally got days off; just thinking how does this balance with other people and can I be a bit altruistic with supporting my colleagues. I think it was the main thing that I've done since seeing the play. (Registered Medical Officer, male).

The heightened awareness of the impacts of poor behaviour created by the play motivated some participants to try to prevent such behaviour in themselves:

I've said to the NUM [Nurse Unit Manager] if you see me being rude can you pull me up on it? Because that's the person I don't want to become … it's hard when you're exhausted to step up. (Junior Medical Officer, male).

Other practical intentions included being ‘hyperaware’ of the needs of others, and particularly being more mindful of gender issues specifically; and intentions to explicitly model zero tolerance for workplace misconduct by naming or confronting perpetrators.

Several participants commented on how the play increased the perspective taking that they considered necessary to achieve change:

For me, the thing that will make the biggest change is when we can help people to stand in the shoes of the person – every person in a matter and think about from their perspective for a moment. (Human Resources, female).

Some of the male participants commented that their sensitivity in relation to female colleagues had increased. The play also motivated one participant to directly confront poor behaviour:

After the play, well I had a feedback form that I hadn't filled in for my last term.. and I thought, you know what? I'm actually going to say who the people were that had these certain actions. Because I was like, you know what? We shouldn't have to put up with this. (Registrar, female).

This participant’s action, however, did not achieve a constructive outcome:

They read it and they laughed. … I said, you asked for feedback, I'm just going to write what I honestly saw and I was like okay, I get laughed at when I put that in to work. (Registrar, female).

This experience perhaps reflected the views of many respondents who were sceptical that culture change could occur. In part, this was because some perceived change to require support from high levels of management :

I think we have heard quite a lot from junior people that they do like the validation but they also say why are we in the audience, why aren’t our managers? They are the ones that should be here and yeah and where is the change going to come from. (Nurse Unit Manager, female).

However many respondents were optimistic about culture change , seeing that this was already occurring and might be additionally facilitated by the play:

I think one of the things we need to say about this project is that we started it with the idea that culture doesn’t change overnight. Culture changes because people start to have conversations about what is and isn’t acceptable to them and to draw new boundaries. And that’s exactly what we have in this room tonight. (Physician, female). I think the play is very graphic, and I think people feel very sad and emotional when they see the play. I think this is our burning platform if you go to change management. (Manager, male).

Stage 4: interviews (1 year after the play)

Six single interviews were conducted with senior staff with leadership in LHD#2 only (due to COVID disruption). Severe COVID-19 disruption at the time prevented greater participation. Latent thematic analysis was undertaken to answer our third research question, on interview data collected 1 year after the intervention. Analysis identified the theme ‘achieved change’.

Respondents spoke of many spontaneous ways in which their thinking and actions were influenced by the play, especially during interactions with colleagues, and reflected on how seeing the play had facilitated culture change at a local level. Three subthemes were identified: (1) ‘transformative learning’, (2) ‘looking through a new lens’, and (3) ‘increased understanding between groups’.

‘Transformative learning’ describes how recalling the play influenced workplace interactions. One staff member spoke of spontaneously recalling the play “when I’m dealing with workplace conflict”:

[The play is] regularly in my thinking and emotions about our work environment […] it comes up in conversations. (Human resources, female).

Increasing conversation about these issues after the performance and workshop improved staff capacity to address workplace behaviour incidents.

People want to debrief when things occurred, rather than things jumping into a full-blown investigation, having that opportunity to try and nip it in the bud before it turns into something more than what it may be initially. (Senior doctor, male).

‘Looking through a new lens’ refers to the experience of the play enabling enhanced perspective-taking. Participants spoke of how the different viewpoints of the play’s characters, increased the value of perspective taking generally:

Grace Under Pressure puts the different characters on stage in front of you … I think people can identify with themselves in those scenarios. Then there’s that potential to look again through another lens at maybe how I interact with those other roles around me. (Manager, male).

Further, the play translated to “more insights into what being in the shoes of a junior doctor might feel like, with that power imbalance that they experience with seniors’, and understandings such as that “I need to take an equal amount of care for my colleagues as I do for my patients”. (Senior doctor, male).

Relatedly, ‘increased understanding between groups’ refers specifically to a better understanding of the pressures other people face in their roles, and as a result, to improved capacity to reduce “ argy bargy” and increase dialogue between disciplines and within hierarchies. This not only increased civility, but produced practical improvements in patient safety, for example, including:

All the ancillary staff [get together] in their safety huddles in the morning because these staff are going to be participating in supporting the clinicians when they’re providing care, rolling people over and doing their pressure injury treatments. (Senior Manager, female).

Other concrete changes that had taken place 12 months after the play included establishing a local charter of organisational values; formally integrating these values into existing systems such as performance reviews; monthly recognition of team members living the values well; the creation of individual coaching programs; and establishing a Welfare Officer position. In addition, there had been an increase in complaints, which was interpreted positively:

We’ve actually seen a rise in complaints, which we attribute to increased confidence that there’s somewhere to take those complaints and have them managed. (Human Resources, female).

This mixed methods study assessed the impact of the verbatim theatre play Grace Under Pressure on an audience of healthcare staff in 5 hospitals across 3 Local Health Districts, one metropolitan, one regional and one remote. The play, followed by tailored workshops, formed an intervention to improve healthcare workplace culture, by (1) raising awareness (2) facilitating discussion of difficult workplace experiences, and (3) motivating those present to conceive of, and implement, actions to improve culture.

Pre-intervention surveys established that workplace culture needed improvement in the three LHDs where our study was conducted: the majority (60%) of participants were at risk of poor wellbeing (including burnout, fatigue, job strain or suicidal ideation). These results matches the results of two surveys routinely issued by the NSW State Government [ 37 ], which is the employer for all public healthcare staff. Employee engagement scores in the 2019 ‘People Matter’ survey found only 65% felt commitment and connection to workplaces. Wellbeing and training scores in the 2018 ‘Your training and wellbeing matters’ survey for junior doctors were very low, indicating high risk of mental illhealth and attrition, with LHD#1 returning the lowest training scores in the State. This confirmed that the intervention was provided in LHDs with considerable need.

Our study showed that Grace Under Pressure was very effective in achieving the aims of awareness raising, generating discussion, creation intentions to change and, in one site, facilitating positive change. The close-of-intervention PMC survey strikingly demonstrated the play’s value and impact on a heterogenous audience of healthcare staff: 89% related to the experiences represented in the play, 93% valued the play highly, 92% would recommend that friends, family and the public see it, 89% considered that the play provided insight into poor workplace behaviour and 85% that seeing it made discussing these issues easier.

Thematic analysis of 20 group and single interviews within a month after the play found that the play was very effective in raising awareness – indeed, ‘hyper-awareness’ – of challenging workplace culture issues. Viewing the play’s high fidelity [ 21 ] representation of healthcare workplace stressors provided audience members with new insights into how these issues occur and are experienced. The research team has found that video excerpts from the play (CREATE Centre YouTube channel, . See eg ) and used in health professions education, have also achieved such insights [ 38 ]. As a result, participants stated intentions to take practical actions to address these issues, including changing their own work habits, being more available to and supportive of their colleagues, and speaking out about poor behaviour. Six interviews conducted in one research site one year following the intervention found that actual improvements in healthcare workplace culture had occurred, and were ascribed in part to the influence of the play. These changes were considered to arise from increased understanding of other colleagues’ workplace pressures, and more capacity to constructively address difficult workplace behaviour.

This study provides evidence that creative interventions can be an effective means of improving healthcare workplace culture. Existing studies of healthcare workplace stressors have repeatedly emphasised that problems such as burnout and mental illhealth cannot be addressed only by treating affected individuals [ 39 ]. Instead, a combination of organisational and individual supports are needed to achieve real improvements [ 40 , 41 ]. Grace Under Pressure represented this. The intervention provided an opportunity for whole-of-workplace consideration of the interplay between structural (eg, rostering), cultural (eg teaching by humiliation) and individual (eg perpetrator/struggling employee) factors in difficult workplace experiences.

This study shows that Grace Under Pressure was a high impact, time efficient means to activate factors that have been shown to be effective in improving workplace culture. Such factors include: processes that increase staff kindness and compassion to their colleagues, that provide recognition of staff work and needs, that realign working practices to core organisational values [ 39 , 42 ], and that increase capacity to have constructive ‘courageous conversations’ [ 13 ]. Those who saw Grace Under Pressure were motivated to think of and undertake practical actions that showed kindness and compassion to colleagues, in part by recognising their colleagues’ personal and work needs. This is in keeping with studies showing that theatre works achieve desired social improvements through small individual actions [ 43 ]. A key achievement was that Grace Under Pressure prompted some audience members to take steps to prevent poor behaviour in themselves . This capacity to prevent poor behaviour in potential perpetrators was also found in earlier studies [ 31 , 44 ]. As a result, one year after the performance, participants described perceived real improvements in workplace culture. They ascribed this specifically to increased ability to conduct difficult conversations (which addressed poor workplace interactions at the time of occurrence), and to increased capacity to enact core organisational values.

This study has shown the importance of longitudinal impact assessment of such interventions. Further longitudinal studies are important to map the multiple pathways through which creative interventions impact healthcare workplaces, and assess the extent and duration of resulting change [ 45 ]. We note that it is well known that arts based health interventions achieve outcomes as a result of multiple ‘active ingredients’ [ 24 ], making it challenging to assess their impact. Future studies should include complexity in their study design, to capture the multiple and synergistic impacts of creative approaches [ 46 ].

In April 2023 PMC accepted yet another commission from local hospitals to perform Grace Under Pressure – in this case, specifically as a means of supporting healthcare workers experiencing a burnout crisis, due to the ongoing impact of COVID-19. Such continuing requests for the play, 6 years after its initial season and 2 years after a national mainstage tour, constitute very strong evidence for the play’s impact and value.


Resourcing constraints, which were uneven across LHDs, limited consistency in recruitment for Stage 1, impacted on sample sizes, and precluded much capacity to make comparisons across settings in this study. Covid-19 disruptions severely limited the participant recruitment at 1 year post intervention.

Summary of findings

This study found that the verbatim theatre play Grace Under Pressure was highly valued by its healthcare staff audiences because it made visible real workplace conditions and behaviour that contribute substantially to poor staff wellbeing, and provided validation of staff suffering as a result of them. The study found that the play achieved the aims of raising awareness about, and discussion of, poor workplace behaviour and workplace stressors, providing healthcare worker audiences with considerable insight into how burnout and mistreatment arise in healthcare work. The play was successful in motivating members of its audience to take small actions to mitigate these problems, and this resulted in real improvements in workplace culture in the one setting where longitudinal data could be collected despite COVID-19 disruption.


Verbatim theatre is a powerful tool in achieving real organisational change. It is likely that other creative arts based methodologies will similarly achieve significant impacts when used to address other complex, multi-faceted organisational challenges in healthcare delivery.

Availability of data and materials

The datasets generated and analysed during the current study are not publicly available due to human research ethics approval requirements to maintain confidentiality and privacy and due to intellectual property provisions at the Pam Maclean Centre. They are stored securely in accordance with human research ethics approval requirements and are available from the corresponding author upon reasonable request.


Local Health District, an administrative unit that delivers operational healthcare under the direction of the NSW Government Ministry for Health

New South Wales, a State in Australia

Pam McLean Centre, a healthcare communication centre that offers theatre and drama based resources to improve healthcare communication, and is affiliated with the University of Sydney

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This project was collaborative and involved a large number of clinical, academic and Local Health District colleagues, particularly Dr Brooke Short and Dr Mary-Ann Ryall (who were extensively involved in research design, data collection and data analysis), Prof Peter Hockey and Dr Caryl Barnes. Mr James Dalton contributed to the analysis of the PMC Survey data. We appreciate the detailed feedback from two unnamed reviewers which improved the manuscript’s clarity and rigour.

The Grace Under Pressure workplace culture intervention received funding from: NSW Health; Pam Maclean Centre; and participating Local Health Districts. In-kind contributions came from Alternative Facts, Inc.

This research, evaluating the intervention, received funding from: Western Sydney Local Health District; Central Coast Local Health District (CCLHD Caring for the Future Research grant scheme 2019); Western Region Training Hub. Note due to confidentiality concerns, this statement should appear in a publication as “This research, evaluating the intervention, received funding from participating Local Health Districts and the Western Region Training Hub”.

In-kind support for this research came from: Pam Maclean Centre (access to data and initial analysis of Pam Maclean Survey data), and the University of Sydney (researcher time contributions).

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Specialty of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia

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CH, LN, and KS contributed to the research design, data collection, and analysis of interviews used to create the play Grace Under Pressure, and provided iterative feedback on playscript and performance, informing the play itself. CH, LN, KS and RL contributed to the research design of this study. CH, LN, RL, AK and KS contributed to collection of survey data. CH, LN and KS collected qualitative data. All authors were involved in data analysis. CH led the writing of this manuscript with extensive contributions from AK, LN and KS. CH also led the revisions in response to reviewer comments. All authors read and approved the final manuscript.

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Correspondence to Claire Hooker .

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Ethics approval and consent to participate.

Human Research Ethics approval was granted by the Western Sydney Local Health District Research Ethics Committee for the Phase I pre-intervention survey, and the interviews and focus groups. Project title “Can the performing arts stimulate culture change in the health workplace?”.

Site specific approvals were then obtained from other Local Health Districts.

The Royal North Shore Hospital Human Research Ethics Committee granted Ethics approval for the PMC Survey.

The authors confirm that all methods were carried out in accordance with relevant guidelines and regulations. In accordance with Human Research Ethics approval, informed consent was obtained from all participants.

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Not Applicable. No individual person’s data is included in this manuscript in any form. All data included is deidentified. Consent for publication of deidentified data was obtained from all interview research participants at the time of data collection.

Competing interests

Dr Renee Lim is Director of Program Development at Pam McLean Centre (PMC). The Grace Under Pressure workplace culture intervention received funding from: NSW Health; Pam McLean Centre; and participating Local Health Districts. PMC provides transparent reporting on Centre programs and activities.

There are no other competing interests to declare for any of the authors.

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Structure peer review to make it more robust

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  • Mario Malički 0

Mario Malički is associate director of the Stanford Program on Research Rigor and Reproducibility (SPORR) and co-editor-in-chief of the Research Integrity and Peer Review journal.

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In February, I received two peer-review reports for a manuscript I’d submitted to a journal. One report contained 3 comments, the other 11. Apart from one point, all the feedback was different. It focused on expanding the discussion and some methodological details — there were no remarks about the study’s objectives, analyses or limitations.

My co-authors and I duly replied, working under two assumptions that are common in scholarly publishing: first, that anything the reviewers didn’t comment on they had found acceptable for publication; second, that they had the expertise to assess all aspects of our manuscript. But, as history has shown, those assumptions are not always accurate (see Lancet 396 , 1056; 2020 ). And through the cracks, inaccurate, sloppy and falsified research can slip.

As co-editor-in-chief of the journal Research Integrity and Peer Review (an open-access journal published by BMC, which is part of Springer Nature), I’m invested in ensuring that the scholarly peer-review system is as trustworthy as possible. And I think that to be robust, peer review needs to be more structured. By that, I mean that journals should provide reviewers with a transparent set of questions to answer that focus on methodological, analytical and interpretative aspects of a paper.

For example, editors might ask peer reviewers to consider whether the methods are described in sufficient detail to allow another researcher to reproduce the work, whether extra statistical analyses are needed, and whether the authors’ interpretation of the results is supported by the data and the study methods. Should a reviewer find anything unsatisfactory, they should provide constructive criticism to the authors. And if reviewers lack the expertise to assess any part of the manuscript, they should be asked to declare this.

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Anonymizing peer review makes the process more just

Other aspects of a study, such as novelty, potential impact, language and formatting, should be handled by editors, journal staff or even machines, reducing the workload for reviewers.

The list of questions reviewers will be asked should be published on the journal’s website, allowing authors to prepare their manuscripts with this process in mind. And, as others have argued before, review reports should be published in full. This would allow readers to judge for themselves how a paper was assessed, and would enable researchers to study peer-review practices.

To see how this works in practice, since 2022 I’ve been working with the publisher Elsevier on a pilot study of structured peer review in 23 of its journals, covering the health, life, physical and social sciences. The preliminary results indicate that, when guided by the same questions, reviewers made the same initial recommendation about whether to accept, revise or reject a paper 41% of the time, compared with 31% before these journals implemented structured peer review. Moreover, reviewers’ comments were in agreement about specific parts of a manuscript up to 72% of the time ( M. Malički and B. Mehmani Preprint at bioRxiv; 2024 ). In my opinion, reaching such agreement is important for science, which proceeds mainly through consensus.

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Stop the peer-review treadmill. I want to get off

I invite editors and publishers to follow in our footsteps and experiment with structured peer reviews. Anyone can trial our template questions (see ), or tailor them to suit specific fields or study types. For instance, mathematics journals might also ask whether referees agree with the logic or completeness of a proof. Some journals might ask reviewers if they have checked the raw data or the study code. Publications that employ editors who are less embedded in the research they handle than are academics might need to include questions about a paper’s novelty or impact.

Scientists can also use these questions, either as a checklist when writing papers or when they are reviewing for journals that don’t apply structured peer review.

Some journals — including Proceedings of the National Academy of Sciences , the PLOS family of journals, F1000 journals and some Springer Nature journals — already have their own sets of structured questions for peer reviewers. But, in general, these journals do not disclose the questions they ask, and do not make their questions consistent. This means that core peer-review checks are still not standardized, and reviewers are tasked with different questions when working for different journals.

Some might argue that, because different journals have different thresholds for publication, they should adhere to different standards of quality control. I disagree. Not every study is groundbreaking, but scientists should view quality control of the scientific literature in the same way as quality control in other sectors: as a way to ensure that a product is safe for use by the public. People should be able to see what types of check were done, and when, before an aeroplane was approved as safe for flying. We should apply the same rigour to scientific research.

Ultimately, I hope for a future in which all journals use the same core set of questions for specific study types and make all of their review reports public. I fear that a lack of standard practice in this area is delaying the progress of science.

Nature 628 , 476 (2024)


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M.M. is co-editor-in-chief of the Research Integrity and Peer Review journal that publishes signed peer review reports alongside published articles. He is also the chair of the European Association of Science Editors Peer Review Committee.

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Pew Research Center has conducted many surveys about abortion over the years, providing a lens into Americans’ views on whether the procedure should be legal, among a host of other questions.

In a  Center survey  conducted nearly a year after the Supreme Court’s June 2022 decision that  ended the constitutional right to abortion , 62% of U.S. adults said the practice should be legal in all or most cases, while 36% said it should be illegal in all or most cases. Another survey conducted a few months before the decision showed that relatively few Americans take an absolutist view on the issue .

Find answers to common questions about abortion in America, based on data from the Centers for Disease Control and Prevention (CDC) and the Guttmacher Institute, which have tracked these patterns for several decades:

How many abortions are there in the U.S. each year?

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This compilation of data on abortion in the United States draws mainly from two sources: the Centers for Disease Control and Prevention (CDC) and the Guttmacher Institute, both of which have regularly compiled national abortion data for approximately half a century, and which collect their data in different ways.

The CDC data that is highlighted in this post comes from the agency’s “abortion surveillance” reports, which have been published annually since 1974 (and which have included data from 1969). Its figures from 1973 through 1996 include data from all 50 states, the District of Columbia and New York City – 52 “reporting areas” in all. Since 1997, the CDC’s totals have lacked data from some states (most notably California) for the years that those states did not report data to the agency. The four reporting areas that did not submit data to the CDC in 2021 – California, Maryland, New Hampshire and New Jersey – accounted for approximately 25% of all legal induced abortions in the U.S. in 2020, according to Guttmacher’s data. Most states, though,  do  have data in the reports, and the figures for the vast majority of them came from each state’s central health agency, while for some states, the figures came from hospitals and other medical facilities.

Discussion of CDC abortion data involving women’s state of residence, marital status, race, ethnicity, age, abortion history and the number of previous live births excludes the low share of abortions where that information was not supplied. Read the methodology for the CDC’s latest abortion surveillance report , which includes data from 2021, for more details. Previous reports can be found at  by entering “abortion surveillance” into the search box.

For the numbers of deaths caused by induced abortions in 1963 and 1965, this analysis looks at reports by the then-U.S. Department of Health, Education and Welfare, a precursor to the Department of Health and Human Services. In computing those figures, we excluded abortions listed in the report under the categories “spontaneous or unspecified” or as “other.” (“Spontaneous abortion” is another way of referring to miscarriages.)

Guttmacher data in this post comes from national surveys of abortion providers that Guttmacher has conducted 19 times since 1973. Guttmacher compiles its figures after contacting every known provider of abortions – clinics, hospitals and physicians’ offices – in the country. It uses questionnaires and health department data, and it provides estimates for abortion providers that don’t respond to its inquiries. (In 2020, the last year for which it has released data on the number of abortions in the U.S., it used estimates for 12% of abortions.) For most of the 2000s, Guttmacher has conducted these national surveys every three years, each time getting abortion data for the prior two years. For each interim year, Guttmacher has calculated estimates based on trends from its own figures and from other data.

The latest full summary of Guttmacher data came in the institute’s report titled “Abortion Incidence and Service Availability in the United States, 2020.” It includes figures for 2020 and 2019 and estimates for 2018. The report includes a methods section.

In addition, this post uses data from StatPearls, an online health care resource, on complications from abortion.

An exact answer is hard to come by. The CDC and the Guttmacher Institute have each tried to measure this for around half a century, but they use different methods and publish different figures.

The last year for which the CDC reported a yearly national total for abortions is 2021. It found there were 625,978 abortions in the District of Columbia and the 46 states with available data that year, up from 597,355 in those states and D.C. in 2020. The corresponding figure for 2019 was 607,720.

The last year for which Guttmacher reported a yearly national total was 2020. It said there were 930,160 abortions that year in all 50 states and the District of Columbia, compared with 916,460 in 2019.

  • How the CDC gets its data: It compiles figures that are voluntarily reported by states’ central health agencies, including separate figures for New York City and the District of Columbia. Its latest totals do not include figures from California, Maryland, New Hampshire or New Jersey, which did not report data to the CDC. ( Read the methodology from the latest CDC report .)
  • How Guttmacher gets its data: It compiles its figures after contacting every known abortion provider – clinics, hospitals and physicians’ offices – in the country. It uses questionnaires and health department data, then provides estimates for abortion providers that don’t respond. Guttmacher’s figures are higher than the CDC’s in part because they include data (and in some instances, estimates) from all 50 states. ( Read the institute’s latest full report and methodology .)

While the Guttmacher Institute supports abortion rights, its empirical data on abortions in the U.S. has been widely cited by  groups  and  publications  across the political spectrum, including by a  number of those  that  disagree with its positions .

These estimates from Guttmacher and the CDC are results of multiyear efforts to collect data on abortion across the U.S. Last year, Guttmacher also began publishing less precise estimates every few months , based on a much smaller sample of providers.

The figures reported by these organizations include only legal induced abortions conducted by clinics, hospitals or physicians’ offices, or those that make use of abortion pills dispensed from certified facilities such as clinics or physicians’ offices. They do not account for the use of abortion pills that were obtained  outside of clinical settings .

(Back to top)

A line chart showing the changing number of legal abortions in the U.S. since the 1970s.

The annual number of U.S. abortions rose for years after Roe v. Wade legalized the procedure in 1973, reaching its highest levels around the late 1980s and early 1990s, according to both the CDC and Guttmacher. Since then, abortions have generally decreased at what a CDC analysis called  “a slow yet steady pace.”

Guttmacher says the number of abortions occurring in the U.S. in 2020 was 40% lower than it was in 1991. According to the CDC, the number was 36% lower in 2021 than in 1991, looking just at the District of Columbia and the 46 states that reported both of those years.

(The corresponding line graph shows the long-term trend in the number of legal abortions reported by both organizations. To allow for consistent comparisons over time, the CDC figures in the chart have been adjusted to ensure that the same states are counted from one year to the next. Using that approach, the CDC figure for 2021 is 622,108 legal abortions.)

There have been occasional breaks in this long-term pattern of decline – during the middle of the first decade of the 2000s, and then again in the late 2010s. The CDC reported modest 1% and 2% increases in abortions in 2018 and 2019, and then, after a 2% decrease in 2020, a 5% increase in 2021. Guttmacher reported an 8% increase over the three-year period from 2017 to 2020.

As noted above, these figures do not include abortions that use pills obtained outside of clinical settings.

Guttmacher says that in 2020 there were 14.4 abortions in the U.S. per 1,000 women ages 15 to 44. Its data shows that the rate of abortions among women has generally been declining in the U.S. since 1981, when it reported there were 29.3 abortions per 1,000 women in that age range.

The CDC says that in 2021, there were 11.6 abortions in the U.S. per 1,000 women ages 15 to 44. (That figure excludes data from California, the District of Columbia, Maryland, New Hampshire and New Jersey.) Like Guttmacher’s data, the CDC’s figures also suggest a general decline in the abortion rate over time. In 1980, when the CDC reported on all 50 states and D.C., it said there were 25 abortions per 1,000 women ages 15 to 44.

That said, both Guttmacher and the CDC say there were slight increases in the rate of abortions during the late 2010s and early 2020s. Guttmacher says the abortion rate per 1,000 women ages 15 to 44 rose from 13.5 in 2017 to 14.4 in 2020. The CDC says it rose from 11.2 per 1,000 in 2017 to 11.4 in 2019, before falling back to 11.1 in 2020 and then rising again to 11.6 in 2021. (The CDC’s figures for those years exclude data from California, D.C., Maryland, New Hampshire and New Jersey.)

The CDC broadly divides abortions into two categories: surgical abortions and medication abortions, which involve pills. Since the Food and Drug Administration first approved abortion pills in 2000, their use has increased over time as a share of abortions nationally, according to both the CDC and Guttmacher.

The majority of abortions in the U.S. now involve pills, according to both the CDC and Guttmacher. The CDC says 56% of U.S. abortions in 2021 involved pills, up from 53% in 2020 and 44% in 2019. Its figures for 2021 include the District of Columbia and 44 states that provided this data; its figures for 2020 include D.C. and 44 states (though not all of the same states as in 2021), and its figures for 2019 include D.C. and 45 states.

Guttmacher, which measures this every three years, says 53% of U.S. abortions involved pills in 2020, up from 39% in 2017.

Two pills commonly used together for medication abortions are mifepristone, which, taken first, blocks hormones that support a pregnancy, and misoprostol, which then causes the uterus to empty. According to the FDA, medication abortions are safe  until 10 weeks into pregnancy.

Surgical abortions conducted  during the first trimester  of pregnancy typically use a suction process, while the relatively few surgical abortions that occur  during the second trimester  of a pregnancy typically use a process called dilation and evacuation, according to the UCLA School of Medicine.

In 2020, there were 1,603 facilities in the U.S. that provided abortions,  according to Guttmacher . This included 807 clinics, 530 hospitals and 266 physicians’ offices.

A horizontal stacked bar chart showing the total number of abortion providers down since 1982.

While clinics make up half of the facilities that provide abortions, they are the sites where the vast majority (96%) of abortions are administered, either through procedures or the distribution of pills, according to Guttmacher’s 2020 data. (This includes 54% of abortions that are administered at specialized abortion clinics and 43% at nonspecialized clinics.) Hospitals made up 33% of the facilities that provided abortions in 2020 but accounted for only 3% of abortions that year, while just 1% of abortions were conducted by physicians’ offices.

Looking just at clinics – that is, the total number of specialized abortion clinics and nonspecialized clinics in the U.S. – Guttmacher found the total virtually unchanged between 2017 (808 clinics) and 2020 (807 clinics). However, there were regional differences. In the Midwest, the number of clinics that provide abortions increased by 11% during those years, and in the West by 6%. The number of clinics  decreased  during those years by 9% in the Northeast and 3% in the South.

The total number of abortion providers has declined dramatically since the 1980s. In 1982, according to Guttmacher, there were 2,908 facilities providing abortions in the U.S., including 789 clinics, 1,405 hospitals and 714 physicians’ offices.

The CDC does not track the number of abortion providers.

In the District of Columbia and the 46 states that provided abortion and residency information to the CDC in 2021, 10.9% of all abortions were performed on women known to live outside the state where the abortion occurred – slightly higher than the percentage in 2020 (9.7%). That year, D.C. and 46 states (though not the same ones as in 2021) reported abortion and residency data. (The total number of abortions used in these calculations included figures for women with both known and unknown residential status.)

The share of reported abortions performed on women outside their state of residence was much higher before the 1973 Roe decision that stopped states from banning abortion. In 1972, 41% of all abortions in D.C. and the 20 states that provided this information to the CDC that year were performed on women outside their state of residence. In 1973, the corresponding figure was 21% in the District of Columbia and the 41 states that provided this information, and in 1974 it was 11% in D.C. and the 43 states that provided data.

In the District of Columbia and the 46 states that reported age data to  the CDC in 2021, the majority of women who had abortions (57%) were in their 20s, while about three-in-ten (31%) were in their 30s. Teens ages 13 to 19 accounted for 8% of those who had abortions, while women ages 40 to 44 accounted for about 4%.

The vast majority of women who had abortions in 2021 were unmarried (87%), while married women accounted for 13%, according to  the CDC , which had data on this from 37 states.

A pie chart showing that, in 2021, majority of abortions were for women who had never had one before.

In the District of Columbia, New York City (but not the rest of New York) and the 31 states that reported racial and ethnic data on abortion to  the CDC , 42% of all women who had abortions in 2021 were non-Hispanic Black, while 30% were non-Hispanic White, 22% were Hispanic and 6% were of other races.

Looking at abortion rates among those ages 15 to 44, there were 28.6 abortions per 1,000 non-Hispanic Black women in 2021; 12.3 abortions per 1,000 Hispanic women; 6.4 abortions per 1,000 non-Hispanic White women; and 9.2 abortions per 1,000 women of other races, the  CDC reported  from those same 31 states, D.C. and New York City.

For 57% of U.S. women who had induced abortions in 2021, it was the first time they had ever had one,  according to the CDC.  For nearly a quarter (24%), it was their second abortion. For 11% of women who had an abortion that year, it was their third, and for 8% it was their fourth or more. These CDC figures include data from 41 states and New York City, but not the rest of New York.

A bar chart showing that most U.S. abortions in 2021 were for women who had previously given birth.

Nearly four-in-ten women who had abortions in 2021 (39%) had no previous live births at the time they had an abortion,  according to the CDC . Almost a quarter (24%) of women who had abortions in 2021 had one previous live birth, 20% had two previous live births, 10% had three, and 7% had four or more previous live births. These CDC figures include data from 41 states and New York City, but not the rest of New York.

The vast majority of abortions occur during the first trimester of a pregnancy. In 2021, 93% of abortions occurred during the first trimester – that is, at or before 13 weeks of gestation,  according to the CDC . An additional 6% occurred between 14 and 20 weeks of pregnancy, and about 1% were performed at 21 weeks or more of gestation. These CDC figures include data from 40 states and New York City, but not the rest of New York.

About 2% of all abortions in the U.S. involve some type of complication for the woman , according to an article in StatPearls, an online health care resource. “Most complications are considered minor such as pain, bleeding, infection and post-anesthesia complications,” according to the article.

The CDC calculates  case-fatality rates for women from induced abortions – that is, how many women die from abortion-related complications, for every 100,000 legal abortions that occur in the U.S .  The rate was lowest during the most recent period examined by the agency (2013 to 2020), when there were 0.45 deaths to women per 100,000 legal induced abortions. The case-fatality rate reported by the CDC was highest during the first period examined by the agency (1973 to 1977), when it was 2.09 deaths to women per 100,000 legal induced abortions. During the five-year periods in between, the figure ranged from 0.52 (from 1993 to 1997) to 0.78 (from 1978 to 1982).

The CDC calculates death rates by five-year and seven-year periods because of year-to-year fluctuation in the numbers and due to the relatively low number of women who die from legal induced abortions.

In 2020, the last year for which the CDC has information , six women in the U.S. died due to complications from induced abortions. Four women died in this way in 2019, two in 2018, and three in 2017. (These deaths all followed legal abortions.) Since 1990, the annual number of deaths among women due to legal induced abortion has ranged from two to 12.

The annual number of reported deaths from induced abortions (legal and illegal) tended to be higher in the 1980s, when it ranged from nine to 16, and from 1972 to 1979, when it ranged from 13 to 63. One driver of the decline was the drop in deaths from illegal abortions. There were 39 deaths from illegal abortions in 1972, the last full year before Roe v. Wade. The total fell to 19 in 1973 and to single digits or zero every year after that. (The number of deaths from legal abortions has also declined since then, though with some slight variation over time.)

The number of deaths from induced abortions was considerably higher in the 1960s than afterward. For instance, there were 119 deaths from induced abortions in  1963  and 99 in  1965 , according to reports by the then-U.S. Department of Health, Education and Welfare, a precursor to the Department of Health and Human Services. The CDC is a division of Health and Human Services.

Note: This is an update of a post originally published May 27, 2022, and first updated June 24, 2022.

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Support for legal abortion is widespread in many countries, especially in Europe

Nearly a year after roe’s demise, americans’ views of abortion access increasingly vary by where they live, by more than two-to-one, americans say medication abortion should be legal in their state, most latinos say democrats care about them and work hard for their vote, far fewer say so of gop, positive views of supreme court decline sharply following abortion ruling, most popular.

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6 Common Leadership Styles — and How to Decide Which to Use When

  • Rebecca Knight

common research article

Being a great leader means recognizing that different circumstances call for different approaches.

Research suggests that the most effective leaders adapt their style to different circumstances — be it a change in setting, a shift in organizational dynamics, or a turn in the business cycle. But what if you feel like you’re not equipped to take on a new and different leadership style — let alone more than one? In this article, the author outlines the six leadership styles Daniel Goleman first introduced in his 2000 HBR article, “Leadership That Gets Results,” and explains when to use each one. The good news is that personality is not destiny. Even if you’re naturally introverted or you tend to be driven by data and analysis rather than emotion, you can still learn how to adapt different leadership styles to organize, motivate, and direct your team.

Much has been written about common leadership styles and how to identify the right style for you, whether it’s transactional or transformational, bureaucratic or laissez-faire. But according to Daniel Goleman, a psychologist best known for his work on emotional intelligence, “Being a great leader means recognizing that different circumstances may call for different approaches.”

common research article

  • RK Rebecca Knight is a journalist who writes about all things related to the changing nature of careers and the workplace. Her essays and reported stories have been featured in The Boston Globe, Business Insider, The New York Times, BBC, and The Christian Science Monitor. She was shortlisted as a Reuters Institute Fellow at Oxford University in 2023. Earlier in her career, she spent a decade as an editor and reporter at the Financial Times in New York, London, and Boston.

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