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Brain, Behavior, and Immunity Mar 2022COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome.
OBJECTIVE
To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome.
DATA SOURCES
Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists.
STUDY SELECTION
Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected.
DATA EXTRACTION & SYNTHESIS
Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model.
MAIN OUTCOMES & MEASURES
The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome.
RESULTS
The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals.
CONCLUSIONS & RELEVANCE
A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.
STUDY REGISTRATION
PROSPERO (CRD42021256965).
Topics: COVID-19; COVID-19 Testing; Cognitive Dysfunction; Fatigue; Humans; SARS-CoV-2; Post-Acute COVID-19 Syndrome
PubMed: 34973396
DOI: 10.1016/j.bbi.2021.12.020 -
International Journal of Environmental... Apr 2022Increasing numbers of individuals suffer from post-acute COVID-19 syndrome (PACS), which manifests with persistent symptoms, the most prevalent being dyspnea, fatigue,... (Review)
Review
Increasing numbers of individuals suffer from post-acute COVID-19 syndrome (PACS), which manifests with persistent symptoms, the most prevalent being dyspnea, fatigue, and musculoskeletal, cognitive, and/or mental health impairments. This systematic review investigated the effectiveness of rehabilitation interventions for individuals with PACS. We searched the MEDLINE, Embase, Cochrane Register of Controlled Trials, CINHAL, Scopus, Prospero, and PEDro databases and the International Clinical Trials Registry Platform for randomized controlled trials (RCTs) up to November 2021. We screened 516 citations for eligibility, i.e., trials that included individuals with PACS exposed to exercise-based rehabilitation interventions. Five RCTs were included, accounting for 512 participants (aged 49.2-69.4 years, 65% males). Based on the revised Cochrane risk-of-bias tool (RoB 2.0), two RCTs had "low risk of bias", and three were in the "some concerns" category. Three RCTs compared experimental rehabilitation interventions with no or minimal rehabilitation, while two compared two active rehabilitation interventions. Rehabilitation seemed to improve dyspnea, anxiety, and kinesiophobia. Results on pulmonary function were inconsistent, while improvements were detected in muscle strength, walking capacity, sit-to-stand performance, and quality of life. Pending further studies based on qualitatively sound designs, these first findings seem to advocate for rehabilitation interventions to lessen disability due to PACS.
Topics: COVID-19; Dyspnea; Exercise Therapy; Female; Humans; Male; Quality of Life; Post-Acute COVID-19 Syndrome
PubMed: 35564579
DOI: 10.3390/ijerph19095185 -
JAMA Sep 2018Burnout is a self-reported job-related syndrome increasingly recognized as a critical factor affecting physicians and their patients. An accurate estimate of burnout... (Review)
Review
IMPORTANCE
Burnout is a self-reported job-related syndrome increasingly recognized as a critical factor affecting physicians and their patients. An accurate estimate of burnout prevalence among physicians would have important health policy implications, but the overall prevalence is unknown.
OBJECTIVE
To characterize the methods used to assess burnout and provide an estimate of the prevalence of physician burnout.
DATA SOURCES AND STUDY SELECTION
Systematic search of EMBASE, ERIC, MEDLINE/PubMed, psycARTICLES, and psycINFO for studies on the prevalence of burnout in practicing physicians (ie, excluding physicians in training) published before June 1, 2018.
DATA EXTRACTION AND SYNTHESIS
Burnout prevalence and study characteristics were extracted independently by 3 investigators. Although meta-analytic pooling was planned, variation in study designs and burnout ascertainment methods, as well as statistical heterogeneity, made quantitative pooling inappropriate. Therefore, studies were summarized descriptively and assessed qualitatively.
MAIN OUTCOMES AND MEASURES
Point or period prevalence of burnout assessed by questionnaire.
RESULTS
Burnout prevalence data were extracted from 182 studies involving 109 628 individuals in 45 countries published between 1991 and 2018. In all, 85.7% (156/182) of studies used a version of the Maslach Burnout Inventory (MBI) to assess burnout. Studies variably reported prevalence estimates of overall burnout or burnout subcomponents: 67.0% (122/182) on overall burnout, 72.0% (131/182) on emotional exhaustion, 68.1% (124/182) on depersonalization, and 63.2% (115/182) on low personal accomplishment. Studies used at least 142 unique definitions for meeting overall burnout or burnout subscale criteria, indicating substantial disagreement in the literature on what constituted burnout. Studies variably defined burnout based on predefined cutoff scores or sample quantiles and used markedly different cutoff definitions. Among studies using instruments based on the MBI, there were at least 47 distinct definitions of overall burnout prevalence and 29, 26, and 26 definitions of emotional exhaustion, depersonalization, and low personal accomplishment prevalence, respectively. Overall burnout prevalence ranged from 0% to 80.5%. Emotional exhaustion, depersonalization, and low personal accomplishment prevalence ranged from 0% to 86.2%, 0% to 89.9%, and 0% to 87.1%, respectively. Because of inconsistencies in definitions of and assessment methods for burnout across studies, associations between burnout and sex, age, geography, time, specialty, and depressive symptoms could not be reliably determined.
CONCLUSIONS AND RELEVANCE
In this systematic review, there was substantial variability in prevalence estimates of burnout among practicing physicians and marked variation in burnout definitions, assessment methods, and study quality. These findings preclude definitive conclusions about the prevalence of burnout and highlight the importance of developing a consensus definition of burnout and of standardizing measurement tools to assess the effects of chronic occupational stress on physicians.
Topics: Burnout, Professional; Compassion Fatigue; Depersonalization; Humans; Job Satisfaction; Physicians; Prevalence; Surveys and Questionnaires
PubMed: 30326495
DOI: 10.1001/jama.2018.12777 -
Infection Dec 2021To find out what is known from literature about Long COVID until January 30, 2021. (Review)
Review
PURPOSE
To find out what is known from literature about Long COVID until January 30, 2021.
METHODS
We undertook a four-step search with no language restriction. A preliminary search was made to identify the keywords. A search strategy of all electronic databases resulted in 66 eligible studies. A forward and backward search of the references and citations resulted in additional 54 publications. Non-English language articles were translated using Google Translate. We conducted our scoping review based on the PRISMA-ScR Checklist.
RESULTS
Of 120 papers, we found only one randomized clinical trial. Of the 67 original studies, 22 were cohort, and 28 were cross-sectional studies. Of the total 120 publications, 49.1% focused on signs and symptoms, 23.3% on management, and 10.8% on pathophysiology. Ten publications focused on imaging studies. The results are also presented extensively in a narrative synthesis in separated sections (nomenclature, diagnosis, pathophysiology, risk factors, signs/symptoms, management).
CONCLUSIONS
The controversies in its definition have impaired proper recognition and management. The predominant symptoms were: fatigue, breathlessness, arthralgia, sleep difficulties, and chest pain. Recent reports also point to the risk of long-term sequela with cutaneous, respiratory, cardiovascular, musculoskeletal, mental health, neurologic, and renal involvement in those who survive the acute phase of the illness.
Topics: COVID-19; Fatigue; Humans; Randomized Controlled Trials as Topic; SARS-CoV-2; Post-Acute COVID-19 Syndrome
PubMed: 34319569
DOI: 10.1007/s15010-021-01666-x -
PloS One 2017Burnout is a syndrome that results from chronic stress at work, with several consequences to workers' well-being and health. This systematic review aimed to summarize... (Review)
Review
Burnout is a syndrome that results from chronic stress at work, with several consequences to workers' well-being and health. This systematic review aimed to summarize the evidence of the physical, psychological and occupational consequences of job burnout in prospective studies. The PubMed, Science Direct, PsycInfo, SciELO, LILACS and Web of Science databases were searched without language or date restrictions. The Transparent Reporting of Systematic Reviews and Meta-Analyses guidelines were followed. Prospective studies that analyzed burnout as the exposure condition were included. Among the 993 articles initially identified, 61 fulfilled the inclusion criteria, and 36 were analyzed because they met three criteria that must be followed in prospective studies. Burnout was a significant predictor of the following physical consequences: hypercholesterolemia, type 2 diabetes, coronary heart disease, hospitalization due to cardiovascular disorder, musculoskeletal pain, changes in pain experiences, prolonged fatigue, headaches, gastrointestinal issues, respiratory problems, severe injuries and mortality below the age of 45 years. The psychological effects were insomnia, depressive symptoms, use of psychotropic and antidepressant medications, hospitalization for mental disorders and psychological ill-health symptoms. Job dissatisfaction, absenteeism, new disability pension, job demands, job resources and presenteeism were identified as professional outcomes. Conflicting findings were observed. In conclusion, several prospective and high-quality studies showed physical, psychological and occupational consequences of job burnout. The individual and social impacts of burnout highlight the need for preventive interventions and early identification of this health condition in the work environment.
Topics: Burnout, Professional; Humans; Occupations; Prospective Studies
PubMed: 28977041
DOI: 10.1371/journal.pone.0185781 -
BMC Neurology Mar 2020Despite many benefits of the physical activity on physical and mental health of patients with Multiple Sclerosis (MS), the activity level in these patients is still very... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite many benefits of the physical activity on physical and mental health of patients with Multiple Sclerosis (MS), the activity level in these patients is still very limited, and they continue to suffer from impairment in functioning ability. The main aim of this study is thus to closely examine exercise's effect on fatigue of patients with MS worldwide, with particular interest on Iran based on a comprehensive systematic review and meta-analysis.
METHODS
The studies used in this systematic review were selected from the articles published from 1996 to 2019, in national and international databases including SID, Magiran, Iranmedex, Irandoc, Google Scholar, Cochrane, Embase, ScienceDirect, Scopus, PubMed and Web of Science (ISI). These databases were thoroughly searched, and the relevant ones were selected based on some plausible keywords to the aim of this study. Heterogeneity index between studies was determined using Cochran's test and I. Due to heterogeneity in studies, the random effects model was used to estimate standardized mean difference.
RESULTS
From the systematic review, a meta-analysis was performed on 31 articles which were fulfilled the inclusion criteria. The sample including of 714 subjects was selected from the intervention group, and almost the same sample size of 720 individuals were selected in the control group. Based on the results derived from this meta-analysis, the standardized mean difference between the intervention group before and after the intervention was respectively estimated to be 23.8 ± 6.2 and 16.9 ± 3.2, which indicates that the physical exercise reduces fatigue in patients with MS.
CONCLUSION
The results of this study extracted from a detailed meta-analysis reveal and confirm that physical exercise significantly reduces fatigue in patients with MS. As a results, a regular exercise program is strongly recommended to be part of a rehabilitation program for these patients.
Topics: Exercise; Exercise Therapy; Fatigue; Humans; Iran; Multiple Sclerosis
PubMed: 32169035
DOI: 10.1186/s12883-020-01654-y -
The Cochrane Database of Systematic... Nov 2014Improving upper limb function is a core element of stroke rehabilitation needed to maximise patient outcomes and reduce disability. Evidence about effects of individual... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Improving upper limb function is a core element of stroke rehabilitation needed to maximise patient outcomes and reduce disability. Evidence about effects of individual treatment techniques and modalities is synthesised within many reviews. For selection of effective rehabilitation treatment, the relative effectiveness of interventions must be known. However, a comprehensive overview of systematic reviews in this area is currently lacking.
OBJECTIVES
To carry out a Cochrane overview by synthesising systematic reviews of interventions provided to improve upper limb function after stroke.
SEARCH METHODS
We comprehensively searched the Cochrane Database of Systematic Reviews; the Database of Reviews of Effects; and PROSPERO (an international prospective register of systematic reviews) (June 2013). We also contacted review authors in an effort to identify further relevant reviews.
SELECTION CRITERIA
We included Cochrane and non-Cochrane reviews of randomised controlled trials (RCTs) of patients with stroke comparing upper limb interventions with no treatment, usual care or alternative treatments. Our primary outcome of interest was upper limb function; secondary outcomes included motor impairment and performance of activities of daily living. When we identified overlapping reviews, we systematically identified the most up-to-date and comprehensive review and excluded reviews that overlapped with this.
DATA COLLECTION AND ANALYSIS
Two overview authors independently applied the selection criteria, excluding reviews that were superseded by more up-to-date reviews including the same (or similar) studies. Two overview authors independently assessed the methodological quality of reviews (using a modified version of the AMSTAR tool) and extracted data. Quality of evidence within each comparison in each review was determined using objective criteria (based on numbers of participants, risk of bias, heterogeneity and review quality) to apply GRADE (Grades of Recommendation, Assessment, Development and Evaluation) levels of evidence. We resolved disagreements through discussion. We systematically tabulated the effects of interventions and used quality of evidence to determine implications for clinical practice and to make recommendations for future research.
MAIN RESULTS
Our searches identified 1840 records, from which we included 40 completed reviews (19 Cochrane; 21 non-Cochrane), covering 18 individual interventions and dose and setting of interventions. The 40 reviews contain 503 studies (18,078 participants). We extracted pooled data from 31 reviews related to 127 comparisons. We judged the quality of evidence to be high for 1/127 comparisons (transcranial direct current stimulation (tDCS) demonstrating no benefit for outcomes of activities of daily living (ADLs)); moderate for 49/127 comparisons (covering seven individual interventions) and low or very low for 77/127 comparisons.Moderate-quality evidence showed a beneficial effect of constraint-induced movement therapy (CIMT), mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice, suggesting that these may be effective interventions; moderate-quality evidence also indicated that unilateral arm training may be more effective than bilateral arm training. Information was insufficient to reveal the relative effectiveness of different interventions.Moderate-quality evidence from subgroup analyses comparing greater and lesser doses of mental practice, repetitive task training and virtual reality demonstrates a beneficial effect for the group given the greater dose, although not for the group given the smaller dose; however tests for subgroup differences do not suggest a statistically significant difference between these groups. Future research related to dose is essential.Specific recommendations for future research are derived from current evidence. These recommendations include but are not limited to adequately powered, high-quality RCTs to confirm the benefit of CIMT, mental practice, mirror therapy, virtual reality and a relatively high dose of repetitive task practice; high-quality RCTs to explore the effects of repetitive transcranial magnetic stimulation (rTMS), tDCS, hands-on therapy, music therapy, pharmacological interventions and interventions for sensory impairment; and up-to-date reviews related to biofeedback, Bobath therapy, electrical stimulation, reach-to-grasp exercise, repetitive task training, strength training and stretching and positioning.
AUTHORS' CONCLUSIONS
Large numbers of overlapping reviews related to interventions to improve upper limb function following stroke have been identified, and this overview serves to signpost clinicians and policy makers toward relevant systematic reviews to support clinical decisions, providing one accessible, comprehensive document, which should support clinicians and policy makers in clinical decision making for stroke rehabilitation.Currently, no high-quality evidence can be found for any interventions that are currently used as part of routine practice, and evidence is insufficient to enable comparison of the relative effectiveness of interventions. Effective collaboration is urgently needed to support large, robust RCTs of interventions currently used routinely within clinical practice. Evidence related to dose of interventions is particularly needed, as this information has widespread clinical and research implications.
Topics: Activities of Daily Living; Exercise Movement Techniques; Exercise Therapy; Humans; Imagination; Recovery of Function; Review Literature as Topic; Robotics; Stroke Rehabilitation; Therapy, Computer-Assisted; Upper Extremity
PubMed: 25387001
DOI: 10.1002/14651858.CD010820.pub2 -
International Journal of Environmental... Jun 2016Compassion fatigue (CF) is stress resulting from exposure to a traumatized individual. CF has been described as the convergence of secondary traumatic stress (STS) and... (Review)
Review
Compassion fatigue (CF) is stress resulting from exposure to a traumatized individual. CF has been described as the convergence of secondary traumatic stress (STS) and cumulative burnout (BO), a state of physical and mental exhaustion caused by a depleted ability to cope with one's everyday environment. Professionals regularly exposed to the traumatic experiences of the people they service, such as healthcare, emergency and community service workers, are particularly susceptible to developing CF. This can impact standards of patient care, relationships with colleagues, or lead to more serious mental health conditions such as posttraumatic stress disorder (PTSD), anxiety or depression. A systematic review of the effectiveness of interventions to reduce CF in healthcare, emergency and community service workers was conducted. Thirteen relevant studies were identified, the majority of which were conducted on nurses (n = 10). Three included studies focused on community service workers (social workers, disability sector workers), while no studies targeting emergency service workers were identified. Seven studies reported a significant difference post-intervention in BO (n = 4) or STS (n = 3). This review revealed that evidence of the effectiveness of CF interventions in at-risk health and social care professions is relatively recent. Therefore, we recommend more research to determine how best to protect vulnerable workers at work to prevent not only CF, but also the health and economic consequences related to the ensuing, and more disabling, physical and mental health outcomes.
Topics: Adaptation, Psychological; Adult; Burnout, Professional; Community Health Workers; Compassion Fatigue; Emergency Responders; Female; Health Personnel; Humans; Male; Middle Aged; Occupational Diseases; Risk Factors; Stress Disorders, Post-Traumatic; Stress, Psychological
PubMed: 27338436
DOI: 10.3390/ijerph13060618 -
International Journal of Environmental... Nov 2021Sleep disorders, especially insomnia, are very common in different kinds of cancers, but their prevalence and incidence are not well-known. Disturbed sleep in cancer is... (Review)
Review
INTRODUCTION
Sleep disorders, especially insomnia, are very common in different kinds of cancers, but their prevalence and incidence are not well-known. Disturbed sleep in cancer is caused by different reasons and usually appears as a comorbid disorder to different somatic and psychiatric diagnoses, psychological disturbances and treatment methods. There can be many different predictors for sleep disturbances in these vulnerable groups, such as pre-existing sleep disorders, caused by the mental status in cancer or as side effect of the cancer treatment.
METHODS
A systematic literature review of 8073 studies was conducted on the topic of sleep and sleep disorders in cancer patients. The articles were identified though PubMed, PsycInfo and Web of Knowledge, and a total number of 89 publications were qualified for analysis.
RESULTS
The identified eighty-nine studies were analyzed on the topic of sleep and sleep disorders in cancer, twenty-six studies on sleep and fatigue in cancer and sixty-one studies on the topic of sleep disorders in cancer. The prevalence of sleep disturbences and/or sleep disorders in cancer was up to 95%.
DISCUSSION
Sleep disturbances and sleep disorders (such as insomnia, OSAS, narcolepsy and RLS; REM-SBD) in cancer patients can be associated with different conditions. Side effects of cancer treatment and cancer-related psychological dysfunctions can be instigated by sleep disturbances and sleep disorders in these patients, especially insomnia and OSAS are common. An evidence-based treatment is necessary for concomitant mental and/or physical states.
Topics: Humans; Narcolepsy; Neoplasms; Restless Legs Syndrome; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders
PubMed: 34770209
DOI: 10.3390/ijerph182111696 -
PLoS Medicine Apr 2022The importance of patient-reported outcome measurement in chronic kidney disease (CKD) populations has been established. However, there remains a lack of research that... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The importance of patient-reported outcome measurement in chronic kidney disease (CKD) populations has been established. However, there remains a lack of research that has synthesised data around CKD-specific symptom and health-related quality of life (HRQOL) burden globally, to inform focused measurement of the most relevant patient-important information in a way that minimises patient burden. The aim of this review was to synthesise symptom prevalence/severity and HRQOL data across the following CKD clinical groups globally: (1) stage 1-5 and not on renal replacement therapy (RRT), (2) receiving dialysis, or (3) in receipt of a kidney transplant.
METHODS AND FINDINGS
MEDLINE, PsycINFO, and CINAHL were searched for English-language cross-sectional/longitudinal studies reporting prevalence and/or severity of symptoms and/or HRQOL in CKD, published between January 2000 and September 2021, including adult patients with CKD, and measuring symptom prevalence/severity and/or HRQOL using a patient-reported outcome measure (PROM). Random effects meta-analyses were used to pool data, stratified by CKD group: not on RRT, receiving dialysis, or in receipt of a kidney transplant. Methodological quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data, and an exploration of publication bias performed. The search identified 1,529 studies, of which 449, with 199,147 participants from 62 countries, were included in the analysis. Studies used 67 different symptom and HRQOL outcome measures, which provided data on 68 reported symptoms. Random effects meta-analyses highlighted the considerable symptom and HRQOL burden associated with CKD, with fatigue particularly prevalent, both in patients not on RRT (14 studies, 4,139 participants: 70%, 95% CI 60%-79%) and those receiving dialysis (21 studies, 2,943 participants: 70%, 95% CI 64%-76%). A number of symptoms were significantly (p < 0.05 after adjustment for multiple testing) less prevalent and/or less severe within the post-transplantation population, which may suggest attribution to CKD (fatigue, depression, itching, poor mobility, poor sleep, and dry mouth). Quality of life was commonly lower in patients on dialysis (36-Item Short Form Health Survey [SF-36] Mental Component Summary [MCS] 45.7 [95% CI 45.5-45.8]; SF-36 Physical Component Summary [PCS] 35.5 [95% CI 35.3-35.6]; 91 studies, 32,105 participants for MCS and PCS) than in other CKD populations (patients not on RRT: SF-36 MCS 66.6 [95% CI 66.5-66.6], p = 0.002; PCS 66.3 [95% CI 66.2-66.4], p = 0.002; 39 studies, 24,600 participants; transplant: MCS 50.0 [95% CI 49.9-50.1], p = 0.002; PCS 48.0 [95% CI 47.9-48.1], p = 0.002; 39 studies, 9,664 participants). Limitations of the analysis are the relatively few studies contributing to symptom severity estimates and inconsistent use of PROMs (different measures and time points) across the included literature, which hindered interpretation.
CONCLUSIONS
The main findings highlight the considerable symptom and HRQOL burden associated with CKD. The synthesis provides a detailed overview of the symptom/HRQOL profile across clinical groups, which may support healthcare professionals when discussing, measuring, and managing the potential treatment burden associated with CKD.
PROTOCOL REGISTRATION
PROSPERO CRD42020164737.
Topics: Adult; Cross-Sectional Studies; Fatigue; Humans; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 35385471
DOI: 10.1371/journal.pmed.1003954