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Integrative Medicine Research Jun 2021Dyspepsia represents a symptom domain rather than a diagnostic condition and covers a wide range of complex, underlying pathophysiologies that are not well understood.... (Review)
Review
BACKGROUND
Dyspepsia represents a symptom domain rather than a diagnostic condition and covers a wide range of complex, underlying pathophysiologies that are not well understood. The review explores comparative effectiveness interventions for the treatment of symptomatic dyspepsia along a pragmatic-explanatory continuum. The aim is to identify relevant design characteristics applicable to future upper gastrointestinal comparative effectiveness research employing integrative medicine.
METHODS
Medline, CINAHL, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and WHO Clinical Trials were systematically searched until January 2019. Included articles were original research with two or more comparative intervention arms for the primary outcome; relief of symptomatic dyspepsia. Evaluation of the studies was conducted using the pragmatic-explanatory continuum indicator summary (PRECIS-2) tool.
RESULTS
Thirty-six articles were included in the review. A total of 68 Patient Reported Outcome Measurements (PROMs), utilizing 50 different formats were deployed across the studies. The appraisal process revealed eligibility, flexibility in adherence, flexibility in delivery and organization domains further aligned towards an explanatory design.
CONCLUSION
This review identified three design characteristics relevant for future comparative effectiveness research for the treatment of upper gastrointestinal disorders in a community setting. Extensive exclusion eligibility criteria limited the generalization of comparative effectiveness study results by removing sub-groups of the target populations more at risk of dyspeptic symptoms. The requirement for entry endoscopy was found to be common and not always pragmatically justifiable. Development of validated PROMs appropriate for a generic application to upper gastrointestinal disorders would be advantageous for future comparative effectiveness research within integrative medicine.
PubMed: 34258220
DOI: 10.1016/j.imr.2020.100663 -
Inflammopharmacology Aug 2021This paper aims to summarize through meta-analyses the overall vaccine effectiveness of the BNT162b2 mRNA vaccine from observational studies. A systematic literature... (Meta-Analysis)
Meta-Analysis
This paper aims to summarize through meta-analyses the overall vaccine effectiveness of the BNT162b2 mRNA vaccine from observational studies. A systematic literature search with no language restriction was performed in electronic databases to identify eligible observational studies which reported the adjusted effectiveness of the BNT162b2 mRNA vaccine to prevent RT-PCR confirmed COVID-19. Meta-analyses with the random-effects model were used to calculate the pooled hazard ratio (HR) and pooled incidence rate ratio (IRR) at 95% confidence intervals, and the vaccine effectiveness was indicated as (pooled HR - 1)/HR or (pooled IRR - 1)/IRR. Nineteen studies were included for this meta-analysis. The meta-analysis revealed significant protective effect against RT-PCR confirmed COVID-19 ≥ 14 days after the first dose, with vaccine effectiveness of 53% (95% confidence interval 32-68%), and ≥ 7 days after the second dose, with vaccine effectiveness of 95% (95% confidence interval: 96-97%). Despite its effectiveness, reporting vaccine safety data by relevant stakeholders should be encouraged as BNT162b2 mRNA is a new vaccine that has not gained full approval. There have been limited data about vaccine effectiveness among immunocompromised patients; thus, the vaccine should be used cautiously in this patient population.
Topics: BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Humans; Observational Studies as Topic; Pragmatic Clinical Trials as Topic; Treatment Outcome
PubMed: 34241782
DOI: 10.1007/s10787-021-00839-2 -
JAMA Network Open Jun 2021Randomized clinical trials (RCTs) provide the highest level of evidence to evaluate 2 or more surgical interventions. Surgical RCTs, however, face unique challenges in...
IMPORTANCE
Randomized clinical trials (RCTs) provide the highest level of evidence to evaluate 2 or more surgical interventions. Surgical RCTs, however, face unique challenges in design and implementation.
OBJECTIVE
To evaluate the design, conduct, and reporting of contemporary surgical RCTs.
EVIDENCE REVIEW
A literature search performed in the 2 journals with the highest impact factor in general medicine as well as 6 key surgical specialties was conducted to identify RCTs published between 2008 and 2020. All RCTs describing a surgical intervention in both experimental and control arms were included. The quality of included data was assessed by establishing an a priori protocol containing all the details to extract. Trial characteristics, fragility index, risk of bias (Cochrane Risk of Bias 2 Tool), pragmatism (Pragmatic Explanatory Continuum Indicator Summary 2 [PRECIS-2]), and reporting bias were assessed.
FINDINGS
A total of 388 trials were identified. Of them, 242 (62.4%) were registered; discrepancies with the published protocol were identified in 81 (33.5%). Most trials used superiority design (329 [84.8%]), and intention-to-treat as primary analysis (221 [56.9%]) and were designed to detect a large treatment effect (50.0%; interquartile range [IQR], 24.7%-63.3%). Only 123 trials (31.7%) used major clinical events as the primary outcome. Most trials (303 [78.1%]) did not control for surgeon experience; only 17 trials (4.4%) assessed the quality of the intervention. The median sample size was 122 patients (IQR, 70-245 patients). The median follow-up was 24 months (IQR, 12.0-32.0 months). Most trials (211 [54.4%]) had some concern of bias and 91 (23.5%) had high risk of bias. The mean (SD) PRECIS-2 score was 3.52 (0.65) and increased significantly over the study period. Most trials (212 [54.6%]) reported a neutral result; reporting bias was identified in 109 of 211 (51.7%). The median fragility index was 3.0 (IQR, 1.0-6.0). Multiplicity was detected in 175 trials (45.1%), and only 35 (20.0%) adjusted for multiple comparisons.
CONCLUSIONS AND RELEVANCE
In this systematic review, the size of contemporary surgical trials was small and the focus was on minor clinical events. Trial registration remained suboptimal and discrepancies with the published protocol and reporting bias were frequent. Few trials controlled for surgeon experience or assessed the quality of the intervention.
Topics: General Surgery; Humans; Randomized Controlled Trials as Topic; Time Factors
PubMed: 34190996
DOI: 10.1001/jamanetworkopen.2021.14494 -
The Cochrane Database of Systematic... Jun 2021Globally, children under 15 years represent approximately 12% of new tuberculosis cases, but 16% of the estimated 1.4 million deaths. This higher share of mortality... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Globally, children under 15 years represent approximately 12% of new tuberculosis cases, but 16% of the estimated 1.4 million deaths. This higher share of mortality highlights the urgent need to develop strategies to improve case detection in this age group and identify children without tuberculosis disease who should be considered for tuberculosis preventive treatment. One such strategy is systematic screening for tuberculosis in high-risk groups.
OBJECTIVES
To estimate the sensitivity and specificity of the presence of one or more tuberculosis symptoms, or symptom combinations; chest radiography (CXR); Xpert MTB/RIF; Xpert Ultra; and combinations of these as screening tests for detecting active pulmonary childhood tuberculosis in the following groups. - Tuberculosis contacts, including household contacts, school contacts, and other close contacts of a person with infectious tuberculosis. - Children living with HIV. - Children with pneumonia. - Other risk groups (e.g. children with a history of previous tuberculosis, malnourished children). - Children in the general population in high tuberculosis burden settings.
SEARCH METHODS
We searched six databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, on 14 February 2020 without language restrictions and contacted researchers in the field.
SELECTION CRITERIA
Cross-sectional and cohort studies where at least 75% of children were aged under 15 years. Studies were eligible if conducted for screening rather than diagnosing tuberculosis. Reference standards were microbiological (MRS) and composite reference standard (CRS), which may incorporate symptoms and CXR.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed study quality using QUADAS-2. We consolidated symptom screens across included studies into groups that used similar combinations of symptoms as follows: one or more of cough, fever, or poor weight gain and one or more of cough, fever, or decreased playfulness. For combination of symptoms, a positive screen was the presence of one or more than one symptom. We used a bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs) and performed analyses separately by reference standard. We assessed certainty of evidence using GRADE.
MAIN RESULTS
Nineteen studies assessed the following screens: one symptom (15 studies, 10,097 participants); combinations of symptoms (12 studies, 29,889 participants); CXR (10 studies, 7146 participants); and Xpert MTB/RIF (2 studies, 787 participants). Several studies assessed more than one screening test. No studies assessed Xpert Ultra. For 16 studies (84%), risk of bias for the reference standard domain was unclear owing to concern about incorporation bias. Across other quality domains, risk of bias was generally low. Symptom screen (verified by CRS) One or more of cough, fever, or poor weight gain in tuberculosis contacts (4 studies, tuberculosis prevalence 2% to 13%): pooled sensitivity was 89% (95% CI 52% to 98%; 113 participants; low-certainty evidence) and pooled specificity was 69% (95% CI 51% to 83%; 2582 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 339 would be screen-positive, of whom 294 (87%) would not have pulmonary tuberculosis (false positives); 661 would be screen-negative, of whom five (1%) would have pulmonary tuberculosis (false negatives). One or more of cough, fever, or decreased playfulness in children aged under five years, inpatient or outpatient (3 studies, tuberculosis prevalence 3% to 13%): sensitivity ranged from 64% to 76% (106 participants; moderate-certainty evidence) and specificity from 37% to 77% (2339 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 251 to 636 would be screen-positive, of whom 219 to 598 (87% to 94%) would not have pulmonary tuberculosis; 364 to 749 would be screen-negative, of whom 12 to 18 (2% to 3%) would have pulmonary tuberculosis. One or more of cough, fever, poor weight gain, or tuberculosis close contact (World Health Organization four-symptom screen) in children living with HIV, outpatient (2 studies, tuberculosis prevalence 3% and 8%): pooled sensitivity was 61% (95% CI 58% to 64%; 1219 screens; moderate-certainty evidence) and pooled specificity was 94% (95% CI 86% to 98%; 201,916 screens; low-certainty evidence). Of 1000 symptom screens where 50 of the screens are on children with pulmonary tuberculosis, 88 would be screen-positive, of which 57 (65%) would be on children who do not have pulmonary tuberculosis; 912 would be screen-negative, of which 19 (2%) would be on children who have pulmonary tuberculosis. CXR (verified by CRS) CXR with any abnormality in tuberculosis contacts (8 studies, tuberculosis prevalence 2% to 25%): pooled sensitivity was 87% (95% CI 75% to 93%; 232 participants; low-certainty evidence) and pooled specificity was 99% (95% CI 68% to 100%; 3281 participants; low-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 63 would be screen-positive, of whom 19 (30%) would not have pulmonary tuberculosis; 937 would be screen-negative, of whom 6 (1%) would have pulmonary tuberculosis. Xpert MTB/RIF (verified by MRS) Xpert MTB/RIF, inpatient or outpatient (2 studies, tuberculosis prevalence 1% and 4%): sensitivity was 43% and 100% (16 participants; very low-certainty evidence) and specificity was 99% and 100% (771 participants; moderate-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 31 to 69 would be Xpert MTB/RIF-positive, of whom 9 to 19 (28% to 29%) would not have pulmonary tuberculosis; 969 to 931 would be Xpert MTB/RIF-negative, of whom 0 to 28 (0% to 3%) would have tuberculosis. Studies often assessed more symptoms than those included in the index test and symptom definitions varied. These differences complicated data aggregation and may have influenced accuracy estimates. Both symptoms and CXR formed part of the CRS (incorporation bias), which may have led to overestimation of sensitivity and specificity.
AUTHORS' CONCLUSIONS
We found that in children who are tuberculosis contacts or living with HIV, screening tests using symptoms or CXR may be useful, but our review is limited by design issues with the index test and incorporation bias in the reference standard. For Xpert MTB/RIF, we found insufficient evidence regarding screening accuracy. Prospective evaluations of screening tests for tuberculosis in children will help clarify their use. In the meantime, screening strategies need to be pragmatic to address the persistent gaps in prevention and case detection that exist in resource-limited settings.
Topics: Adolescent; Bias; Child; Child Behavior; Child, Preschool; Cohort Studies; Confidence Intervals; Contact Tracing; Cough; Cross-Sectional Studies; False Negative Reactions; False Positive Reactions; Fever; HIV Infections; Humans; Mass Screening; Molecular Diagnostic Techniques; Radiography, Thoracic; Reference Standards; Sensitivity and Specificity; Symptom Assessment; Tuberculosis, Pulmonary; Weight Gain
PubMed: 34180536
DOI: 10.1002/14651858.CD013693.pub2 -
BMC Family Practice Jun 2021Learning health systems have been gaining traction over the past decade. The purpose of this study was to understand the spread of learning health systems in primary...
BACKGROUND
Learning health systems have been gaining traction over the past decade. The purpose of this study was to understand the spread of learning health systems in primary care, including where they have been implemented, how they are operating, and potential challenges and solutions.
METHODS
We completed a scoping review by systematically searching OVID Medline®, Embase®, IEEE Xplore®, and reviewing specific journals from 2007 to 2020. We also completed a Google search to identify gray literature.
RESULTS
We reviewed 1924 articles through our database search and 51 articles from other sources, from which we identified 21 unique learning health systems based on 62 data sources. Only one of these learning health systems was implemented exclusively in a primary care setting, where all others were integrated health systems or networks that also included other care settings. Eighteen of the 21 were in the United States. Examples of how these learning health systems were being used included real-time clinical surveillance, quality improvement initiatives, pragmatic trials at the point of care, and decision support. Many challenges and potential solutions were identified regarding data, sustainability, promoting a learning culture, prioritization processes, involvement of community, and balancing quality improvement versus research.
CONCLUSIONS
We identified 21 learning health systems, which all appear at an early stage of development, and only one was primary care only. We summarized and provided examples of integrated health systems and data networks that can be considered early models in the growing global movement to advance learning health systems in primary care.
Topics: Humans; Learning; Learning Health System; Primary Health Care; Quality Improvement
PubMed: 34162336
DOI: 10.1186/s12875-021-01483-z -
BMJ Global Health Jun 2021Routine health information system(s) (RHIS) facilitate the collection of health data at all levels of the health system allowing estimates of disease prevalence,...
BACKGROUND
Routine health information system(s) (RHIS) facilitate the collection of health data at all levels of the health system allowing estimates of disease prevalence, treatment and preventive intervention coverage, and risk factors to guide disease control strategies. This core health system pillar remains underdeveloped in many low-income and middle-income countries. Efforts to improve RHIS data coverage, quality and timeliness were launched over 10 years ago.
METHODS
A systematic review was performed across 12 databases and literature search engines for both peer-reviewed articles and grey literature reports on RHIS interventions. Studies were analysed in three stages: (1) categorisation of RHIS intervention components and processes; (2) comparison of intervention component effectiveness and (3) whether the post-intervention outcome improved above the WHO integrated disease surveillance response framework data quality standard of 80% or above.
RESULTS
5294 references were screened, resulting in 56 studies. Three key performance determinants-technical, organisational and behavioural-were proposed as critical to RHIS strengthening. Seventy-seven per cent [77%] of studies identified addressed all three determinants. The most frequently implemented intervention components were 'providing training' and 'using an electronic health management information systems'. Ninety-three per cent [93%] of pre-post or controlled trial studies showed improvements in one or more data quality outputs, but after applying a standard threshold of >80% post-intervention, this number reduced to 68%. There was an observed benefit of multi-component interventions that either conducted data quality training or that addressed improvement across multiple processes and determinants of RHIS.
CONCLUSION
Holistic data quality interventions that address multiple determinants should be continuously practised for strengthening RHIS. Studies with clearly defined and pragmatic outcomes are required for future RHIS improvement interventions. These should be accompanied by qualitative studies and cost analyses to understand which investments are needed to sustain high-quality RHIS in low-income and middle-income countries.
Topics: Delivery of Health Care; Developing Countries; Health Information Systems; Humans; Income; Poverty
PubMed: 34117009
DOI: 10.1136/bmjgh-2020-004223 -
BMC Public Health Jun 2021Youth suicide prevention in high-schools and universities is a public health priority. Our aim was to propose a research agenda to advance evidence-based suicide...
BACKGROUND
Youth suicide prevention in high-schools and universities is a public health priority. Our aim was to propose a research agenda to advance evidence-based suicide prevention in high-schools and universities by synthesizing and critically reviewing the research focus and methodologies used in existing intervention studies.
METHODS
Fourteen databases were systematically searched to identify studies which evaluate suicide prevention interventions delivered on high-school or university campuses, with before and after measures. Data from included studies (n = 43) were extracted to identify what, where, how and for whom interventions have been tested. Narrative synthesis was used to critically evaluate research focus and methodology. Study quality was assessed.
RESULTS
Research has focused primarily on selective interventions, with less attention on indicated and universal interventions. Most evidence comes from North America and high-income countries. The target of interventions has been: non-fatal suicidal behaviour; confidence and ability of staff/students to intervene in a suicidal crisis; suicide-related knowledge and attitudes; and suicide-related stigma. No studies included suicide deaths as an outcome, evaluated eco-systemic interventions, explored how context influences implementation, used multisite study designs, or focused explicitly on LGBTQ+ youth. Two studies evaluated digital interventions. Quality of the majority of studies was compromised by lack of methodological rigour, small samples, and moderate/high risk of bias. Interventions often assume the existence of an external well-functioning referral pathway, which may not be true in low-resource settings.
CONCLUSION
To advance evidence-based suicide prevention in educational settings we need to: conduct more high-quality clinical and pragmatic trials; promote research in low- and middle-income countries; test targeted interventions for vulnerable populations (like LGBTQ+ youth), evaluate interventions where death by suicide is the primary outcome; include translational studies and use implementation science to promote intervention uptake; evaluate the potential use of digital and eco-systemic interventions; and conduct multisite studies in diverse cultural settings.
Topics: Adolescent; Evidence-Based Practice; Humans; North America; Schools; Universities; Suicide Prevention
PubMed: 34112141
DOI: 10.1186/s12889-021-11124-w -
International Review of Psychiatry... May 2021Depression is a prevalent disorder and leading cause of disability in Latin America, where the mental health treatment gap is still above 50%. We sought to synthesise...
Depression is a prevalent disorder and leading cause of disability in Latin America, where the mental health treatment gap is still above 50%. We sought to synthesise and assess the quality of the evidence on the feasibility of mHealth-based interventions for depression in Latin America. We conducted a literature search of studies published in 2007 and after using four electronic databases. We included peer-reviewed articles, in English, Spanish or Portuguese, that evaluated interventions for depressive symptoms. Two authors independently extracted data using forms developed a priori. We assessed appropriateness of reporting utilising the CONSORT checklist for feasibility trials. Eight manuscripts were included for full data extraction. Appropriate reporting varied greatly. Most ( = 6, 75%) of studies were conducted in primary care settings and sought to deliver psychoeducation or behaviour change interventions for depressive symptoms. We found great heterogeneity in the assessment of feasibility. Two studies used comparator conditions. mHealth research for depression in Latin America is scarce. Included studies showed some feasibility despite methodological inconsistencies. Given the dire need for evidence-based mental health interventions in this region, governments and stakeholders must continue promoting and funding research tailored to cultural and population characteristics with subsequent pragmatic clinical trials.
Topics: Depression; Feasibility Studies; Humans; Latin America; Telemedicine
PubMed: 34102945
DOI: 10.1080/09540261.2021.1887822 -
The Journal of Hospital Infection Sep 2021Hospital-onset COVID-19 infections (HOCIs) are associated with excess morbidity and mortality in patients and healthcare workers. The aim of this review was to explore...
Hospital-onset COVID-19 infections (HOCIs) are associated with excess morbidity and mortality in patients and healthcare workers. The aim of this review was to explore and describe the current literature in HOCI surveillance. Medline, EMBASE, the Cochrane Database of Systematic Reviews, the Cochrane Register of Controlled Trials, and MedRxiv were searched up to 30 November 2020 using broad search criteria. Articles of HOCI surveillance systems were included. Data describing HOCI definitions, HOCI incidence, types of HOCI identification surveillance systems, and level of system implementation were extracted. A total of 292 citations were identified. Nine studies on HOCI surveillance were included. Six studies reported on the proportion of HOCI among hospitalized COVID-19 patients, which ranged from 0 to 15.2%. Six studies provided HOCI case definitions. Standardized national definitions provided by the UK and US governments were identified. Four studies included healthcare workers in the surveillance. One study articulated a multimodal strategy of infection prevention and control practices including HOCI surveillance. All identified HOCI surveillance systems were implemented at institutional level, with eight studies focusing on all hospital inpatients and one study focusing on patients in the emergency department. Multiple types of surveillance were identified. Four studies reported automated surveillance, of which one included real-time analysis, and one included genomic data. Overall, the study quality was limited by the observational nature with short follow-up periods. In conclusion, HOCI case definitions and surveillance methods were developed pragmatically. Whilst standardized case definitions and surveillance systems are ideal for integration with existing routine surveillance activities and adoption in different settings, we acknowledged the difficulties in establishing such standards in the short-term.
Topics: Humans; COVID-19; Cross Infection; Hospitals; SARS-CoV-2
PubMed: 34098049
DOI: 10.1016/j.jhin.2021.05.016 -
PLoS Medicine May 2021Antiretroviral therapy (ART) initiation in the community and outside of a traditional health facility has the potential to improve linkage to ART, decongest health... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antiretroviral therapy (ART) initiation in the community and outside of a traditional health facility has the potential to improve linkage to ART, decongest health facilities, and minimize structural barriers to attending HIV services among people living with HIV (PLWH). We conducted a systematic review and meta-analysis to determine the effect of offering ART initiation in the community on HIV treatment outcomes.
METHODS AND FINDINGS
We searched databases between 1 January 2013 and 22 February 2021 to identify randomized controlled trials (RCTs) and observational studies that compared offering ART initiation in a community setting to offering ART initiation in a traditional health facility or alternative community setting. We assessed risk of bias, reporting of implementation outcomes, and real-world relevance and used Mantel-Haenszel methods to generate pooled risk ratios (RRs) and risk differences (RDs) with 95% confidence intervals. We evaluated heterogeneity qualitatively and quantitatively and used GRADE to evaluate overall evidence certainty. Searches yielded 4,035 records, resulting in 8 included studies-4 RCTs and 4 observational studies-conducted in Lesotho, South Africa, Nigeria, Uganda, Malawi, Tanzania, and Haiti-a total of 11,196 PLWH. Five studies were conducted in general HIV populations, 2 in key populations, and 1 in adolescents. Community ART initiation strategies included community-based HIV testing coupled with ART initiation at home or at community venues; 5 studies maintained ART refills in the community, and 4 provided refills at the health facility. All studies were pragmatic, but in most cases provided additional resources. Few studies reported on implementation outcomes. All studies showed higher ART uptake in community initiation arms compared to facility initiation and refill arms (standard of care) (RR 1.73, 95% CI 1.22 to 2.45; RD 30%, 95% CI 10% to 50%; 5 studies). Retention (RR 1.43, 95% CI 1.32 to 1.54; RD 19%, 95% CI 11% to 28%; 4 studies) and viral suppression (RR 1.31, 95% CI 1.15 to 1.49; RD 15%, 95% CI 10% to 21%; 3 studies) at 12 months were also higher in the community-based ART initiation arms. Improved uptake, retention, and viral suppression with community ART initiation were seen across population subgroups-including men, adolescents, and key populations. One study reported no difference in retention and viral suppression at 2 years. There were limited data on adherence and mortality. Social harms and adverse events appeared to be minimal and similar between community ART initiation and standard of care. One study compared ART refill strategies following community ART initiation (community versus facility refills) and found no difference in viral suppression (RD -7%, 95% CI -19% to 6%) or retention at 12 months (RD -12%, 95% CI -23% to 0.3%). This systematic review was limited by few studies for inclusion, poor-quality observational data, and short-term outcomes.
CONCLUSIONS
Based on data from a limited set of studies, community ART initiation appears to result in higher ART uptake, retention, and viral suppression at 1 year compared to facility-based ART initiation. Implementation on a wider scale necessitates broader exploration of costs, logistics, and acceptability by providers and PLWH to ensure that these effects are reproducible when delivered at scale, in different contexts, and over time.
Topics: Anti-HIV Agents; Community Participation; HIV; HIV Infections; Humans; Models, Theoretical
PubMed: 34048443
DOI: 10.1371/journal.pmed.1003646