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BackgroundReliable and field-applicable diagnosis of schistosome infections in non-human animals is important for surveillance, control, and verification of interruption of human schistosomiasis transmission. This study aimed to summarize uses of available diagnostic techniques through a systematic review and meta-analysis.Methodology and principal findingsWe systematically searched the literature and reports comparing two or more diagnostic tests in non-human animals for schistosome infection. Out of 4,909 articles and reports screened, 19 met our inclusion criteria, four of which were considered in the meta-analysis. A total of 14 techniques (parasitologic, immunologic, and molecular) and nine types of non-human animals were involved in the studies. Notably, four studies compared parasitologic tests (miracidium hatching test (MHT), Kato-Katz (KK), the Danish Bilharziasis Laboratory technique (DBL), and formalin-ethyl acetate sedimentation-digestion (FEA-SD)) with quantitative polymerase chain reaction (qPCR), and sensitivity estimates (using qPCR as the reference) were extracted and included in the meta-analyses, showing significant heterogeneity across studies and animal hosts. The pooled estimate of sensitivity was 0.21 (95% confidence interval (CI): 0.03-0.48) with FEA-SD showing highest sensitivity (0.89, 95% CI: 0.65-1.00).Conclusions/significanceOur findings suggest that the parasitologic technique FEA-SD and the molecular technique qPCR are the most promising techniques for schistosome diagnosis in non-human animal hosts. Future studies are needed for validation and standardization of the techniques for real-world field applications.

Physicians practicing evidence-based medicine need to be able to appraise a new study and determine whether the results warrant sufficient certainty to the level that they can be applied to patient care. Without such appraisal, misleading results can be incorporated into patient care, which can lead to inefficient, costly, and possibly harmful care. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach offers a modern framework that can be applied to evaluate the trustworthiness of evidence. In this guide, we present a simplified approach based on GRADE; in which we call on readers of the medical literature to pay attention to six domains before making an overall judgment about the trustworthiness of results and before applying the evidence to patient care.

Background: Targeting epidermal growth factor receptors (EGFR) is an innovative approach to managing non-small cell lung cancer (NSCLC) which harbors EGFR mutation. However, the efficacy of these agents like erlotinib in patients without the mutation is not known. Methods: This systematic review included Phase III randomized clinical trials that compared single agent erlotinib to other management options in the setting of NSCLC with reported outcome data on patients with EGFR wild type (EGFRWT) tumors. Outcome data include overall survival (OS), progression free survival (PFS) and response rate (RR). Random effects meta-analysis was used to pool outcomes across studies. Results: Three studies met the inclusion criteria. These studies included a total of 2044 patients with outcome data on 674 patients with EGFRWT tumors (33%). Meta-analysis revealed a statistically significant improvement in OS with erlotinib (hazard ratio of 0.780; 95% confidence interval: 0.654-0.930, P = 0.006). Data were not available to perform PFS or RR analysis. The quality of this evidence is considered to be moderate to high. Conclusion: Our study revealed a significant benefit of erlotinib in patient with EGFRWT tumors compared with other approaches. These findings add another therapeutic option to patients generally considered difficult to treat.

Abstract Background Reference intervals, which define an interval in which a specific proportion of measurements from a healthy population are expected to fall, are commonly used in medical practice. Synthesizing information from multiple studies through meta-analysis can provide a more precise and representative reference interval than one derived from a single study. However, the current approaches for estimating the reference interval from a meta-analysis mainly rely on aggregate data and require parametric distributional assumptions that cannot always be checked. Methods With the availability of individual participant data (IPD), non-parametric methods can be used to estimate reference intervals without any distributional assumptions. Furthermore, patient-level covariates can be introduced to estimate personalized reference intervals that may be more applicable to specific patients. This paper introduces quantile regression as a method to estimate the reference interval from an IPD meta-analysis under the fixed effects model. Results We compared several non-parametric bootstrap methods through simulation studies to account for within-study correlation. Under fixed effects model, we recommend keeping the studies fixed and only randomly sampling subjects with replacement within each study. Conclusion We proposed to use the quantile regression in the IPD meta-analysis to estimate the reference interval. Based on the simulation results, we identify an optimal bootstrap strategy for estimating the uncertainty of the estimated reference interval. An example of liver stiffness measurements, a clinically important diagnostic test without explicitly established reference range in children, is provided to demonstrate the use of quantile regression in estimating both overall and subject-specific reference intervals.

Objective: To evaluate the heterogeneity in treatment effect in posttraumatic stress disorder (PTSD) trials. Patients and Methods: We downloaded data from a publicly available repository that captured PTSD trials published from January 1988 through February 2023. We applied restricted maximum-likelihood random-effect meta-analyses and meta-regression to explore potential moderators of treatment effect including methodologic study features (risk of bias domains and control group response rate), characteristics of the population, and intervention features following the theme, intensity, and platform framework. Results: We included 199 PTSD trials that reported the outcomes of diagnosis resolution (122 trials, 8437 patients) and clinically meaningful improvement (133 trials, 9895 patients). Multiple treatments demonstrated effectiveness but with significant heterogeneity. Statistically significant moderators included risk of bias domains of randomization sequence and outcome measurement, control group response rate reflecting severity of PTSD in the enrolled population, and whether the psychotherapeutic approach was trauma focused (P values

Objective To determine if the efficacy of biologics differ based on magnetic resonance imaging (MRI) and C‐reactive protein (CRP) findings. Methods We compared four subgroups (MRI+/CRP+, MRI+/CRP−, MRI−/CRP+, MRI−/CRP−) from randomized controlled trials (RCTs). A comprehensive database search was performed to include axial spondylarthritis (axSpA; both radiographic axSpA [r‐axSpA] and nonradiographic axSpA [nr‐axSpA]) RCTs with treatment efficacy reported by different MRI and CRP subgroups. Study‐specific disease activity scores (at 12‐16 weeks) were pooled using a random‐effects model and compared between the four subgroups. Results Five trials (all nr‐axSpA) were included: three with tumor necrosis factor inhibitors (TNFi, N = 729) and two with interleukin‐17 inhibitors (IL‐17i, N = 794). TNFi and IL‐17i showed efficacy based on the Assessment of Spondyloarthritis International Society 40 (ASAS40) and Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50) in all MRI and CRP subgroups, except the CRP−/MRI− subgroup, which had a single study with only 39 patients. There was no statistically significant difference between the four subgroups in terms of patients achieving ASAS40 (P = 0.60, I2 = 0%) or BASDAI50 (P = 0.27, I2 = 23.9%). The number needed to treat was three for the CRP+/MRI+ and CRP+/MRI− subgroups and six for the CRP−/MRI+ and CRP−/MRI− subgroups. All trials had a low risk of bias. Between‐study heterogeneity was low to moderate. Sensitivity analyses comparing TNFi or IL‐17i versus placebo similarly showed no difference between subgroups in terms of ASAS40 (TNFi, P = 0.57; IL‐17i, P = 0.28) and BASDAI50 (TNFi, P = 0.37; IL‐17i, P = 0.18). Conclusion In this systematic review, there was no statistically significant difference between the four subgroups in terms of efficacy based on ASAS40 or BASDAI50.

Objective: To systematically review contemporary prediction models for hospital mortality developed or validated in general medical patients. Methods: We screened articles in five databases, from January 1, 2010, through April 7, 2022, and the bibliography of articles selected for final inclusion. We assessed the quality for risk of bias and applicability using the Prediction Model Risk of Bias Assessment Tool (PROBAST) and extracted data using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist. Two investigators independently screened each article, assessed quality, and extracted data. Results: From 20,424 unique articles, we identified 15 models in 8 studies across 10 countries. The studies included 280,793 general medical patients and 19,923 hospital deaths. Models included 7 early warning scores, 2 comorbidities indices, and 6 combination models. Ten models were studied in all general medical patients (general models) and 7 in general medical patients with infection (infection models). Of the 15 models, 13 were developed using logistic or Poisson regression and 2 using machine learning methods. Also, 4 of 15 models reported on handling of missing values. None of the infection models had high discrimination, whereas 4 of 10 general models had high discrimination (area under curve >0.8). Only 1 model appropriately assessed calibration. All models had high risk of bias; 4 of 10 general models and 5 of 7 infection models had low concern for applicability for general medical patients. Conclusion: Mortality prediction models for general medical patients were sparse and differed in quality, applicability, and discrimination. These models require hospital-level validation and/or recalibration in general medical patients to guide mortality reduction interventions.

Acting on the renin–angiotensin–aldosterone system, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are mechanisms of some of the most prescribed medications in the world. In addition to their routine use for the treatment of hypertension, such agents have gained attention for their influence on the angiotensin receptor pathway in fibrotic skin disorders, including scars and keloids. To evaluate the current level of evidence supporting the use of these agents, a systematic review related to ACE-Is/ARBs and cutaneous scarring was conducted. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from database inception through January 26, 2022. Two independent reviewers identified eligible studies for inclusion and extracted data. Data were insufficient for meta-analysis and are presented narratively. Of 461 citations identified, seven studies were included (199 patients). The studies included two randomized clinical trials, one comparative observation study, and four case reports. All the included studies reported statistically significant improvement in cutaneous scarring in patients using ACE-Is/ARBs compared with that in those treated with placebo/control using various outcome measures such as scar size and scar scales. However, much of the literature on this subject to date is limited by study design.

Objective: To summarize the available evidence about the perioperative management of patients who are receiving long-term antiplatelet therapy and require elective surgery/procedures. Methods: This systematic review supports the development of the American College of Chest Physicians guideline on the perioperative management of antiplatelet therapy. A literature search of MEDLINE, EMBASE, Scopus and Cochrane databases was conducted from each database’s inception to July 16, 2020. Meta-analyses were conducted when possible. Results: In patients receiving long-term antiplatelet therapy and undergoing elective noncardiac surgery, the available evidence did not show a significant difference in major bleeding between a shorter vs longer antiplatelet interruption, with low certainty of evidence (COE). Compared with patients who received placebo perioperatively, aspirin continuation was associated with increased risk of major bleeding (relative risk [RR], 1.31; 95% CI, 1.15-1.50; high COE) and lower risk of major thromboembolism (RR, 0.74; 95% CI, 0.58-0.94; moderate COE). During antiplatelet interruption, bridging with low-molecular-weight heparin was associated with increased risk of major bleeding compared with no bridging (RR, 1.86; 95% CI, 1.24-2.79; very low COE). Continuation of antiplatelets during minor dental and ophthalmologic procedures was not associated with a statistically significant difference in the risk of major bleeding (very low COE). Conclusion: This systematic review summarizes the current evidence about the perioperative management of antiplatelet therapy and highlights the urgent need for further research, particularly with the increasing prevalence of patients taking 1 or more antiplatelet agents.

Introduction Acute stroke patients presenting with large vessel occlusion secondary to intracranial atherosclerosis (ICAS‐LVO) may require rescue therapy (RT) in addition to mechanical thrombectomy (MT) to achieve and maintain successful recanalization. We performed a systematic review and meta‐analysis of comparative studies that reported outcomes of RT in ICAS‐LVO patients to evaluate its safety and efficacy. Methods Databases searched include PubMed, CINAHL Complete, and Scopus from database date of inception through August 17, 2021. We included comparative studies that reported the outcomes of ICAS‐LVO RT compared to outcomes of ICAS‐LVO patients who did not undergo RT or to those presenting with embolic LVO patients (non‐ICAS LVO). Meta‐analysis using the random effects model was used to combine estimates reporting odds ratios (OR) and 95% confidence intervals (CI). Results Total of 9 nonrandomized studies were included: 5 studies in ICAS‐LVO RT vs. ICAS‐LVO non‐RT analysis and 5 ICAS‐LVO RT vs. non‐ICAS LVO analysis. Rescue treatments included intra‐arterial antiplatelets, angioplasty, stenting or combination of treatments. Compared to non‐RT ICAS LVO, RT was associated with increased favorable 90‐day outcome (OR 3.19, 95% CI 1.91‐5.32, I2 14%) and decreased 90‐day mortality (OR 0.35, 95% CI 0.16‐0.76, I2 21%) (Figure 1). In the analysis of ICAS LVO vs embolic LVO, the incidence of favorable 90‐day outcome and 90‐day mortality did not differ between the ICAS‐LVO RT and non‐ICAS LVO (OR 0.97, 95% CI 0.58‐1.64, I2 50%) and (OR 1.22, 95% CI 0.90‐1.66, I2 0%), respectively. Conclusions Rescue treatment is associated with better outcomes in ICAS‐LVO patients. The outcomes of ICAS‐LVO patients who receive RT may be comparable to embolic LVO patients (non‐ICAS LVO).

Objective: To measure well-being at a community level using a valid instrument. Patients and Methods: Written surveys were mailed to a random sample of residents in Olmsted County, Minnesota, in 2015 and 2019 including the 5-item World Health Organization Well-being Index (0-100; for which 100 is the best imaginable well-being or quality of life). Multivariable hierarchical regression was used to evaluate the association between well-being and demographic characteristics, comorbid conditions, and environmental factors. Results: The survey was returned by 1232 of 4000 individuals (response rate, 30.80%). The average well-being score was 70.02. Impaired well-being was identified in 223/1187 individuals (18.79%). Adjusted regression models showed that impaired well-being was independently associated with household poverty, financial stress, reduced access to medical or mental health care, ever having depression diagnosed, living in an unsafe community, or being socially isolated. Conclusion: One in 5 people in a county in the US Midwest have impaired well-being. Well-being was associated with several modifiable factors. Data provide a rationale for policies that align transportation and housing and create opportunities for community members to connect and interact in a safe environment.

Abstract Regenerative, cell‐based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta‐analysis summarized the effect of cell‐based interventions in DKD animal models and treatment‐related factors modifying outcomes. Electronic databases were searched for original investigations applying cell‐based therapy in diabetic animals with kidney endpoints (January 1998‐May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random‐effects models. Subgroup analyses tested treatment‐related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non‐MSC (15%), and cell‐derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell‐based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial‐mesenchymal‐transition, oxidative stress). Preconditioning, xenotransplantation, and disease‐source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell‐based interventions in diabetic animals improved kidney function and reduced injury with treatment‐related factors modifying these effects. These findings may aid in development of optimal repair strategies through selective use of cells/products, tissue sources, and dose administrations to allow for successful adaptation of this novel therapeutic in human DKD.

Objective: To evaluate the magnitude of the association between risk factors and premature myocardial infarction (MI) (men aged 18-55 years; women aged 18-65 years). Patients and Methods: We searched MEDLINE and other databases from inception through April 30, 2020, as well as bibliography of articles selected for data extraction. We selected observational studies reporting the magnitude of the association of at least 1 risk factor (demographic characteristics, lifestyle factors, clinical risk factors, or biomarkers) with premature MI and a control group. Pooled risk estimates (random effects) from all studies unadjusted and adjusted for risk factors were reported as summary odds ratios (ORs) with 95% CIs. Results: From 35,320 articles of 12.7 million participants, we extracted data on 19 risk factors from 77 studies across 58 countries. Men had a higher risk of premature MI (OR, 2.39; 95% CI, 1.71 to 3.35) than did women. Family history of cardiac disease was associated with a higher risk of premature MI (OR, 2.67; 95% CI, 2.29 to 3.27). Major modifiable risk factors associated with higher risk were current smoking (OR, 4.34; 95% CI, 3.68 to 5.12 vs no/former), diabetes mellitus (OR, 3.54; 95% CI, 2.69 to 4.65), dyslipidemia (OR, 2.94; 95% CI, 1.76 to 4.91), and hypertension (OR, 2.85; 95% CI, 2.48 to 3.27). Higher body mass index carried higher risk (OR, 1.46; 95% CI, 1.24 to 1.71 for ≥25 kg/m2 vs

Abstract Objective Lidocaine is one of the most widely used local anesthetics with well-known pharmacological properties. The purpose of this systematic review is to investigate the effects of lidocaine on postoperative pain scores and recovery after cardiac surgery. Methods A comprehensive database search was conducted by a reference librarian for randomized clinical trials (RCT) from January 1, 1980 to September 1, 2019. Eligible study designs included randomized controlled trials of lidocaine for postoperative pain management in adults undergoing cardiac surgery. After removal of duplicates, 947 records were screened for eligibility and 3 RCTs met inclusion criteria. Results Sources of bias were identified in 2 of 3 RCTs. Lidocaine was administered intravenously, topically, and intrapleurally. Key findings included [1] 2% lidocaine placed topically on chest tube prior to intraoperative insertion was associated with significantly lower pain scores and lower cumulative doses of fentanyl; and [2] 2% lidocaine administered intrapleurally was associated with significantly lower pain scores and significant improvements in pulmonary mechanics. Lidocaine infusions were not associated with significant changes in pain scores or measures of recovery. No significant associations were observed between lidocaine and overall mortality, hospital length of stay or ICU length of stay. No data were reported for postoperative nausea and vomiting or arrhythmias. Conclusions Due to the favorable risk profile of topical lidocaine and the need for further advancements in the postoperative care of adults after cardiac surgery, topically administered lidocaine could be considered for incorporation into established postoperative recovery protocols.

Objective: To evaluate differences in thromboinflammatory biomarkers between patients with severe coronavirus disease 2019 (COVID-19) infection/death and mild infection. Patients and Methods: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, EBSCO, Web of Science, and CINAHL databases were searched for studies comparing thromboinflammatory biomarkers in COVID-19 among patients with severe COVID-19 disease or death (severe/nonsurvivors) and those with nonsevere disease or survivors (nonsevere/survivors) from January 1, 2020, through July 11, 2020. Inclusion criteria were (1) hospitalized patients 18 years or older comparing severe/nonsurvivors vs nonsevere/survivors and (2) biomarkers of inflammation and/or thrombosis. A random-effects model was used to estimate the weighted mean difference (WMD) between the 2 groups of COVID-19 severity. Results: We included 75 studies with 17,052 patients. The severe/nonsurvivor group was older, had a greater proportion of men, and had a higher prevalence of hypertension, diabetes, cardiac or cerebrovascular disease, chronic kidney disease, malignancy, and chronic obstructive pulmonary disease. Thromboinflammatory biomarkers were significantly higher in patients with severe disease, including D-dimer (WMD, 0.60; 95% CI, 0.49 to 0.71; I2=83.85%), fibrinogen (WMD, 0.42; 95% CI, 0.18 to 0.67; I2=61.88%; P 25%). Subanalysis based on disease severity, mortality, and geographic region of the studies revealed similar inferences. Conclusion: Thromboinflammatory biomarkers (D-dimer, fibrinogen, CRP, high-sensitivity CRP, ferritin, and interleukin 6) and marker of end-organ damage (high-sensitivity troponin I) are associated with increased severity and mortality in COVID-19 infection.

Objective: To assess the core knowledge of health indicators, federal health programs, and public health functions in practicing clinicians along with perceptions of their education and engagement with public health. Patients and Methods: A paper survey in booklet form was administered to attendees at 2 general medical conferences in May 2019. The survey was divided into 5 sections: knowledge of health systems and policy, knowledge of public health concepts and function, public health engagement, public health education, and demographics. Results: One hundred two surveys were received from 402 attendees (response rate, 24.3%). Most were male (56%), older than 50 years (51%), and physicians (86%). Respondents had a fairly good knowledge of federal health programs (77%) and public health functions (84%), but less than half had a personal interaction with public health in the past 2 years (45%) or were aware of how to work with public health organizations in their community (46%). Only a few respondents rated their public health training as good or excellent during their primary degree (7%) or graduate medical education (15%), and most (75%) were interested in learning more about public health and health policy. Conclusion: Respondents had generally good foundational knowledge of federal health programs and public health functions, although some gaps were identified. Inclusion of health policy and public health topics in continuing medical education would be well received by clinicians. To improve collaboration between public health and medicine, public health should personally engage clinicians more and explain how they can work together to improve population health.

Abstract Severe cases of COVID‐19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID‐19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo‐capillary barriers. The authors performed a systematic literature review and random‐effects meta‐analysis to determine the potential value of MSC therapy for treating COVID‐19‐infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2/FiO2 ratio, alveolo‐capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.

Data are conflicting regarding the optimal cutoffs of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) to predict short-term mortality in patients with sepsis. We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus) for English-language reports of studies evaluating adult patients with sepsis, severe sepsis, and septic shock with BNP/NT-proBNP levels and short-term mortality (intensive care unit, in-hospital, 28-day, or 30-day) published from January 1, 2000, to September 5, 2017. The average values in survivors and nonsurvivors were used to estimate the receiver operating characteristic curve (ROC) using a parametric regression model. Thirty-five observational studies (3508 patients) were included (median age, 51-75 years; 12%-74% males; cumulative mortality, 34.2%). A BNP of 622 pg/mL had the greatest discrimination for mortality (sensitivity, 0.695 [95% CI, 0.659-0.729]; specificity, 0.907 [95% CI, 0.810-1.003]; area under the ROC, 0.766 [95% CI, 0.734-0.797]). An NT-proBNP of 4000 pg/mL had the greatest discrimination for mortality (sensitivity, 0.728 [95% CI, 0.703-0.753]; specificity, 0.789 [95% CI, 0.710-0.867]; area under the ROC, 0.787 [95% CI, 0.766-0.809]). In prespecified subgroup analyses, identified BNP/NT-proBNP cutoffs had higher discrimination if specimens were obtained 24 hours or less after admission, in patients with severe sepsis/septic shock, in patients enrolled after 2010, and in studies performed in the United States and Europe. There was inconsistent adjustment for renal function. In this hypothesis-generating analysis, BNP and NT-proBNP cutoffs of 622 pg/mL and 4000 pg/mL optimally predicted short-term mortality in patients with sepsis. The applicability of these results is limited by the heterogeneity of included patient populations.

Slow deep breathing (SDB) may help patients with acute pain. The primary aim of this systematic review and meta-analysis is to investigate the effects of SDB on acute pain. Secondary aims include investigating the effects of SDB on acute pain-related physical and emotional functioning. An a priori protocol was registered and a database search was conducted by a reference librarian. Randomized controlled trials (RCT) were eligible for inclusion and exclusion criteria included studies of SDB for non-pain indications and studies that applied SDB as a component of an encompassing intervention. The risk or bias was assessed using the Cochrane Collaboration's revised tool for assessing risk of bias in randomized trials. Meta-analysis was conducted using the random effects model. A total of 11 968 studies were screened and seven RCTs met inclusion criteria; five were judged to have low risk of bias. Meta-analysis of post-intervention pain scores demonstrated that SDB was associated with significantly lower pain scores compared with a control group, but with high levels of heterogeneity. Subgroup analyzes demonstrated that trials of burn pain were associated with a larger reduction in pain which partially explains the heterogeneity. Very low certainty evidence suggests that SDB may reduce acute pain intensity. Further research is needed to identify patients who are candidates for SDB and determine the best approach to deliver this therapy.

Abstract: The American Society of Hematology (ASH) convened 5 guideline panels to develop clinical practice recommendations addressing 5 management areas of highest importance to individuals living with sickle cell disease: pain, cerebrovascular complications, pulmonary and kidney complications, transfusion, and hematopoietic stem cell transplant. Panels were multidisciplinary and consisted of patient representatives, content experts, and methodologists. The Mayo Clinic Evidence-Based Practice Center conducted systematic reviews based on a priori selected questions. In this exposition, we describe the process used by ASH, including the GRADE approach (Grades of Recommendations, Assessment, Development and Evaluation) for rating certainty of the evidence and the GRADE Evidence to Decision Framework. We also describe several unique challenges faced by the guideline panels and the specific innovations and solutions used to address them, including a curriculum to train patients to engage in guideline development, dealing with the opioid crisis, and working with indirect and noncomparative evidence.

Small relative effect sizes are common in observational studies of exposure in environmental and public health. However, such effects can still have considerable policy importance when the baseline rate of the health outcome is high, and many persons are exposed. Assessing the certainty of the evidence based on these effect sizes is challenging because they can be prone to residual confounding due to the non-randomized nature of the evidence. When applying GRADE, a precise relative risk >2.0 increases the certainty in an existing effect because residual confounding is unlikely to explain the association. GRADE also suggests rating up when opposing plausible residual confounding exists for other effect sizes. In this concept paper, we propose using the E-value, defined as the smallest effect size of a confounder that still can reduce an observed RR to the null value, and a reference confounder to assess the likelihood of residual confounding. We propose a 4-step approach. 1. Assess the association of interest for relevant exposure levels. 2. Calculate the E-value for this observed association. 3. Choose a reference confounder with sufficient strength and information and assess its effect on the observed association using the E-value. 4. Assess how likely it is that residual confounding will still bias the observed RR. We present three case studies and discuss the feasibility of the approach.

ABSTRACT: Background: Comparative effectiveness of 7 glucagon-like peptide 1 (GLP-1) agents on weight loss (WL) in obesity remains unknown. Methods: We performed a systematic review, network meta-analysis (NMA) utilizing the following data sources: MEDLINE, EMBASE, Scopus, Cochrane Central and clinical trial registries, from inception to March 2, 2021. The prespecified criteria for study inclusion were randomized clinical trials (RCTs) of ≥12 weeks’ duration. The data appraisal and extraction were performed by two investigators independently, using the published reports. The main outcomes and statistical methods were weight loss over placebo (WLOP) and adverse events (AEs) among GLP-1 agents using random-effects NMA (frequentist approach); relative ranking using surface under the cumulative ranking (SUCRA) method and certainty of evidence using grading of recommendations, assessment, development and evaluations (GRADE). Findings: 64 RCTs (from 2004 to 2021) included 27018 patients (median of age, 55.1 years old; 57.4% women; baseline weight 94.8kg and BMI 33.0kg/m2; trial duration 26 weeks). Direct meta-analysis showed significant WLOP with: -1.44kg (95% CI, -2.14 to -0.74) with dulaglutide ≥1.5 mg; -1.82kg (-2.42 to -1.23) with exenatide immediate release (IR); -2.20kg (-4.31 to -0.08) with exenatide extended release (ER); -3.20kg (-6.53 to 0.15) with efpeglenatide; -2.72kg (-3.35 to -2.09) with liraglutide ≤1.8mg; -4.49kg (-5.26 to -3.72) with liraglutide >1.8mg; -0.62kg (-1.22 to -0.02) with lixisenatide; -4.33kg (-5.71 to -3.00) with semaglutide SQ 1.8mg (SUCRAs 100, 86.1, 82.8 respectively). Highest SUCRAs for discontinuation due to AEs were with taspoglutide and liraglutide >1.8mg. Risk of bias was high or unclear for random sequence generation (29.7%), allocation concealment (26.6%), and incomplete outcome data (26.6%). Heterogeneity (I2 >50%) in WL and AEs reflected magnitude, not direction of effect.

Abstract Background Culinary interventions (cooking classes) have been used to improve the quality of dietary intake and change behavior. The aim of this systematic review is to investigate the effects of culinary interventions on dietary intake and behavioral and cardiometabolic outcomes. Methods We conducted a systematic review of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus for comparative studies that evaluated culinary interventions to a control group or baseline values. The intervention was defined as a cooking class regardless of its length or delivery approach. Studies included populations of children, healthy adults or adults with morbidities. The risk of bias was assessed using the Cochrane Risk of Bias tool and the Newcastle-Ottawa Scale. Outcomes were pooled using the random-effects model and descriptive statistics and depicted in an evidence map. Simple logistic regression was used to evaluate factors associated with intervention success. Results We included 30 studies (6 were randomized, 7381 patients, average follow up 25 weeks). Culinary interventions were not associated with a significant change in body mass index (− 0.07 kg/m2, 95% CI: -1.53, 1.40), systolic (− 5.31 mmHg, 95% CI: -34.2, 23.58) or diastolic blood pressure (− 3.1 mmHg, 95% CI: -23.82, 17.62) or LDL cholesterol (− 8.09 mg/dL, 95% CI: -84.43, 68.25). Culinary interventions were associated with improved attitudes, self-efficacy and healthy dietary intake in adults and children. We were unable to demonstrate whether the effect of a culinary intervention was modified by various characteristics of the intervention such as its delivery or intensity. Interventions with additional components such as education on nutrition, physical activity or gardening were particularly effective. Conclusions Culinary interventions were not associated with a significant change in cardiometabolic risk factors, but were associated with improved attitudes, self-efficacy and a healthier dietary intake in adults and children.

Abstract. Introduction:. The inconsistent use of standardized approaches for classifying postamputation pain (PAP) has been a barrier to establishing its prevalence. Objectives:. The primary objective of this systematic review and meta-analysis is to determine the prevalence of nontraumatic lower-extremity PAP using an established taxonomy. The secondary objective is to determine the prevalence of PAP subtypes, including phantom limb pain and residual limb pain (RLP). Methods:. An a priori protocol was registered, and a database search was conducted by a reference librarian. Randomized trials and uncontrolled studies were eligible for inclusion. The risk of bias was assessed using a tool developed for uncontrolled studies. A total of 2679 studies were screened, and 13 studies met inclusion criteria (n = 1063). Results:. The sources of risk of bias included selection bias and, to a lesser extent, whether the outcome was adequately ascertained. Two studies reported the prevalence of PAP and the pooled prevalence was 61% (95% confidence interval [CI], 33%–86%) with high heterogeneity (I2 = 93%). Thirteen studies reported the prevalence of phantom limb pain and the pooled prevalence was 53% (95% CI, 40%–66%) with high heterogeneity (I2 = 93%). Eight studies reported the prevalence of RLP and the pooled prevalence was 32% (95% CI 24%–41%) with high heterogeneity (I2 = 76%). Clinical subtypes of RLP were not reported. Conclusions:. The prevalence of PAP is high in patients with nontraumatic lower-extremity amputations. Ongoing research that uses a taxonomy for PAP is needed to fully delineate the prevalence of PAP subtypes.

Background: The Comprehensive Care for Joint Replacement program implemented by the Centers for Medicare and Medicaid Services did not incorporate risk adjustment for lower extremity joint replacement (LEJR). Lack of adjustment places hospitals at financial risk and creates incentives for adverse patient selection. Objective: To identify patient-level risk factors associated with health care utilization and costs of patients undergoing LEJR. Methods: A comprehensive search of research databases from January 1, 1990, through January 31, 2016, was conducted. The databases included Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and SCOPUS and is reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The search identified 2020 studies. Eligible studies focused on primary unilateral and bilateral LEJR. Independent reviewers determined study eligibility and extracted utilization and cost data. Results: Seventy-nine of 330 studies (24%) were included and were abstracted for analysis. Comorbidities, age, disease severity, and obesity were associated with increased costs. Increased number of comorbidities and age, presence of specific comorbidities, lower socioeconomic status, and female sex had evidence of increased length of stay. We found no significant association between indication for surgery and the likelihood of readmission. Conclusion: Developing a risk adjustment model for LEJR that incorporates clinical variables may serve to reduce the likelihood of adverse patient selection and enhance appropriate reimbursement aligned with procedural complexity.

Abstract Background Hypomethylating agents (HMA), azacitidine, and decitabine are frequently used in the management of myelodysplastic syndromes (MDS). However, there are no clinical trials that have directly compared these agents. We conducted a systematic review and indirectly compared the efficacy of azacitidine to decitabine in MDS. Methods We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) through June 28, 2018, without language or time restrictions. Studies were screened by two independent reviewers, and differences were resolved by consensus. The fixed effect model and adjusted indirect comparison methods were used to pool relative risks (RR) of major outcomes of interest (mortality, response rate, quality of life, hematologic improvement, hospitalization, leukemia transformation, transfusion independence). Results Only four trials met the eligibility criteria. Two trials compared azacitidine to the best supportive care (BSC) and included 549 patients, and the other two compared decitabine to BSC and included 403 patients. The risk of bias was unclear overall. Compared to BSC, azacitidine was significantly associated with lower mortality (RR = 0.83, 95% CI 0.74–0.94, I 2 = 89%) whereas decitabine did not significantly reduce mortality (RR = 0.88, 95% CI 0.77–1.00, I 2 = 53%). Both drugs were associated with higher partial and complete response compared to BSC. Indirect comparisons were not statistically significant for all the studied outcomes, except for complete response where azacitidine was less likely to induce complete response compared to decitabine (RR = 0.11, 95% CI = 0.01–0.86, very low-certainty evidence). Conclusions Azacitidine and decitabine are both associated with improved outcomes compared to BSC. The available indirect evidence comparing the two agents warrants very low certainty and cannot reliably confirm the superiority of either agent. Head-to-head trials are needed. In the meantime, the choice of agent should be driven by patient preferences, adverse effects, drug availability, and cost.

Plain English summary With the growing movement to engage patients in research, questions are being asked about who is engaging patients and how they are being engaged. Internationally, research groups are supporting and funding patient-oriented research studies that engage patients in the identification of research priorities and the design, conduct and uptake of research. As we move forward, we need to know what meaningful patient engagement looks like, how it benefits research and clinical practice, and what are the barriers to patient engagement? We conducted a review of the published literature looking for trials that report engaging patients in the research. We included both randomized controlled trials and non-randomized comparative trials. We looked at these trials for important study characteristics, including how patients were engaged, to better understand the practices used in trials. Importantly, we also discuss the number of trials reporting patient engagement practices relative to all published trials. We found that very few trials report any patient engagement activities even though it is widely supported by many major funding organizations. The findings of our work will advance patient-oriented research by showing how patients can be engaged and by stressing that patient engagement practices need to be better reported. Abstract Background Patient-Oriented Research (POR) is research informed by patients and is centred on what is of importance to them. A fundamental component of POR is that patients are included as an integral part of the research process from conception to dissemination and implementation, and by extension, across the research continuum from basic research to pragmatic trials [J Comp Eff Res 2012, 1:181–94, JAMA 2012, 307:1587–8]. Since POR’s inception, questions have been raised as to how best to achieve this goal. We conducted a systematic review of randomized controlled trials and non-randomized comparative trials that report engaging patients in their research. Our main goal was to describe the characteristics of published trials engaging patients in research, and to identify the extent of patient engagement activities reported in these trials. Methods The MEDLINE®, EMBASE®, Cinahl, PsycINFO, Cochrane Methodology Registry, and Pubmed were searched from May 2011 to June 16th, 2016. Title, abstract and full text screening of all reports were conducted independently by two reviewers. Data were extracted from included trials by one reviewer and verified by a second. All trials that report patient engagement for the purposes of research were included. Results Of the 9490 citations retrieved, 2777 were reviewed at full text, of which 23 trials were included. Out of the 23 trials, 17 were randomized control trials, and six were non-randomized comparative trials. The majority of these trials (83%, 19/23) originated in the United States and United Kingdom. The trials engaged a range of 2-24 patients/ community representatives per study. Engagement of children and minorities occurred in 13% (3/23) and 26% (6/23) of trials; respectively. Engagement was identified in the development of the research question, the selection of study outcomes, and the dissemination and implementation of results. Conclusions The prevalence of patient engagement in patient-oriented interventional research is very poor with 23 trials reporting activities engaging patients. Research dedicated to determining the best practice for meaningful engagement is still needed, but adequate reporting measures also need to be defined.

Objectives: This systematic review evaluated the accuracy of triaxial and omnidirectional accelerometers for measuring physical activity and sedentary behavior in children. Design: Systematic review of the literature. Methods: We comprehensively searched several databases for studies published from January 1996 through June 2018 that reported diagnostic accuracy measures in children and adolescents (age 3-18 years) and compared accelerometers with energy expenditure using indirect calorimetry. Results: We included 11 studies that enrolled 570 participants. All studies used indirect calorimetry as the reference standard. Across the studies, median sensitivity ranged from 46% to 96% and median specificity ranged from 71% to 96%. Median area under the curve ranged from 69% to 98%. Conclusions: Accuracy measures were greatest when detecting sedentary behavior and lowest when detecting light physical activity. Accuracy was higher when the accelerometer was placed on the hip compared with the wrist. The current evidence suggests that triaxial and omnidirectional accelerometers are accurate in measuring sedentary behavior and physical activity levels in children.

Abstract Background Data abstraction, a critical systematic review step, is time-consuming and prone to errors. Current standards for approaches to data abstraction rest on a weak evidence base. We developed the Data Abstraction Assistant (DAA), a novel software application designed to facilitate the abstraction process by allowing users to (1) view study article PDFs juxtaposed to electronic data abstraction forms linked to a data abstraction system, (2) highlight (or “pin”) the location of the text in the PDF, and (3) copy relevant text from the PDF into the form. We describe the design of a randomized controlled trial (RCT) that compares the relative effectiveness of (A) DAA-facilitated single abstraction plus verification by a second person, (B) traditional (non-DAA-facilitated) single abstraction plus verification by a second person, and (C) traditional independent dual abstraction plus adjudication to ascertain the accuracy and efficiency of abstraction. Methods This is an online, randomized, three-arm, crossover trial. We will enroll 24 pairs of abstractors (i.e., sample size is 48 participants), each pair comprising one less and one more experienced abstractor. Pairs will be randomized to abstract data from six articles, two under each of the three approaches. Abstractors will complete pre-tested data abstraction forms using the Systematic Review Data Repository (SRDR), an online data abstraction system. The primary outcomes are (1) proportion of data items abstracted that constitute an error (compared with an answer key) and (2) total time taken to complete abstraction (by two abstractors in the pair, including verification and/or adjudication). Discussion The DAA trial uses a practical design to test a novel software application as a tool to help improve the accuracy and efficiency of the data abstraction process during systematic reviews. Findings from the DAA trial will provide much-needed evidence to strengthen current recommendations for data abstraction approaches. Trial registration The trial is registered at National Information Center on Health Services Research and Health Care Technology (NICHSR) under Registration # HSRP20152269: https://wwwcf.nlm.nih.gov/hsr_project/view_hsrproj_record.cfm?NLMUNIQUE_ID=20152269&SEARCH_FOR=Tianjing%20Li . All items from the World Health Organization Trial Registration Data Set are covered at various locations in this protocol. Protocol version and date: This is version 2.0 of the protocol, dated September 6, 2016. As needed, we will communicate any protocol amendments to the Institutional Review Boards (IRBs) of Johns Hopkins Bloomberg School of Public Health (JHBSPH) and Brown University. We also will make appropriate as-needed modifications to the NICHSR website in a timely fashion.