Prognostic Biomarkers in Kidney Transplantation: A Systematic Review and Critical Appraisal.

SIGNIFICANCE STATEMENT: Why are there so few biomarkers accepted by health authorities and implemented in clinical practice, despite the high and growing number of biomaker studies in medical research ? In this meta-epidemiological study, including 804 studies that were critically appraised by expert reviewers, the authors have identified all prognostic kidney transplant biomarkers and showed overall suboptimal study designs, methods, results, interpretation, reproducible research standards, and transparency. The authors also demonstrated for the first time that the limited number of studies challenged the added value of their candidate biomarkers against standard-of-care routine patient monitoring parameters. Most biomarker studies tended to be single-center, retrospective studies with a small number of patients and clinical events. Less than 5% of the studies performed an external validation. The authors also showed the poor transparency reporting and identified a data beautification phenomenon. These findings suggest that there is much wasted research effort in transplant biomarker medical research and highlight the need to produce more rigorous studies so that more biomarkers may be validated and successfully implemented in clinical practice. BACKGROUND: Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology, and reporting might contribute to this phenomenon. METHODS: We formed a consortium of experts in systematic reviews, nephrologists, methodologists, and epidemiologists. A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between January 1, 2005, and November 12, 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. RESULTS: A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood ( n =821, 71.8%), intragraft ( n =169, 14.8%), or urine ( n =81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (interquartile range [IQR], 23.8-35.5) between 2005 and 2012 and 57.5 (IQR, 53.3-59.8) between 2013 and 2022 ( P < 0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR, 96-629) with a median follow-up post-transplant of 4.8 years (IQR, 3.0-6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors, while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker, despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. CONCLUSIONS: Biomarker studies in kidney transplantation lack validation, rigorous design and methodology, accurate interpretation, and transparency. Higher standards are needed in biomarker research to prove the clinical utility and support clinical use.

Comparative Efficacy of Advanced Therapies for Achieving Endoscopic Outcomes in Crohn's Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND & AIMS: We conducted a network meta-analysis to compare the efficacy of advanced therapies for achieving endoscopic outcomes in patients with moderate-to-severely active Crohn's disease. METHODS: MEDLINE, Embase, and Cochrane CENTRAL databases were searched from inception to August 2, 2023 to identify phase II and III randomized controlled trials (RCTs) in adults (≥18 years) with moderate-to-severe Crohn's disease treated with tumor necrosis factor (TNF) antagonists, etrolizumab, vedolizumab, anti-interleukin (IL)12/23p40, anti-IL23p19, or Janus kinase-1 (JAK1) inhibitors, compared with placebo/active comparator, for induction and/or maintenance of remission and reported endoscopic outcomes. Primary outcome was endoscopic response after induction therapy, and endoscopic remission after maintenance therapy. We performed a random-effects network meta-analysis using a frequentist approach, and estimated relative risk (RRs), 95% confidence interval (CI) values, and P score for ranking agents. We used GRADE to ascertain certainty of evidence. RESULTS: A total of 20 RCTs (19 placebo-controlled and 1 head-to-head trial; 5592 patients) were included out of which 12 RCTs reported endoscopic outcomes for the induction phase, 5 reported for the maintenance phase, and 3 reported for both induction and maintenance phases. JAK1 inhibitors (RR, 3·49 [95% CI, 1·48-8·26]) and anti-IL23p19 (RR, 2·30 [95% CI, 1·02-5·18]) agents were more efficacious than etrolizumab (moderate certainty of evidence), and JAK1 inhibitors (RR, 2·34 [95% CI, 1·14-4·80]) were more efficacious than anti-IL12/23p40 agents for inducing endoscopic response (moderate certainty of evidence). JAK1 inhibitors and anti-IL23p19 ranked highest for induction of endoscopic response. There was paucity of RCTs of TNF antagonists reporting endoscopic outcomes with induction therapy. On network meta-analysis of 6 RCTs, all agents except vedolizumab (RR, 1.89 [95% CI, 0.61-5.92]) were effective in maintaining endoscopic remission compared with placebo. TNF antagonists, IL12/23p40, and JAK1 inhibitors were ranked highest. CONCLUSIONS: On network meta-analysis, JAK1 inhibitors and anti-IL23p19 agents may be the most effective among non-TNF-targeting advanced therapies for inducing endoscopic response. Future head-to-head trials will further inform positioning of different therapies for the management of Crohn's disease.

Comparative Speed of Early Symptomatic Remission With Advanced Therapies for Moderate-to-Severe Ulcerative Colitis: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Rapidity of symptom resolution informs treatment choice in patients with moderate-severe ulcerative colitis (UC). We conducted a systematic review and network meta-analysis comparing early symptomatic remission with approved therapies. METHODS: Through a systematic literature review to December 31, 2022, we identified randomized trials in adult outpatients with moderate-severe UC treated with approved therapies (tumor necrosis factor α antagonists, vedolizumab, ustekinumab, janus kinase inhibitors, or ozanimod), compared with each other or placebo, reporting rates of symptomatic remission (based on partial Mayo score, with resolution of rectal bleeding and near-normalization of stool frequency) at weeks 2, 4, and/or 6. We performed random-effects network meta-analysis using a frequentist approach and estimated relative risk (RR) and 95% confidence interval values. RESULTS: On network meta-analysis, upadacitinib was more effective than all agents in achieving symptomatic remission at weeks 2 (range of RR, 2.85-6.27), 4 (range of RR, 1.78-2.37), and 6 (range of RR, 1.84-2.79). Tumor necrosis factor α antagonists and filgotinib, but not ustekinumab and vedolizumab, were more effective than ozanimod in achieving symptomatic remission at week 2, but not at weeks 4 and 6. With approximately 10% placebo-treated patients achieving symptomatic remission at 2 weeks, we estimated 68%, 22%, 23.7%, 23.9%, 22.2%, 18.4%, 15.7%, and 10.9% of upadacitinib-, filgotinib-, infliximab-, adalimumab-, golimumab-, ustekinumab-, vedolizumab-, and ozanimod-treated patients would achieve early symptomatic remission, ustekinumab and vedolizumab achieving rapid remission only in biologic-naïve patients. DISCUSSION: In a systematic review and network meta-analysis, upadacitinib was most effective in achieving early symptomatic remission, whereas ozanimod was relatively slower acting.

How to Critically Appraise and Interpret Systematic Reviews and Meta-Analyses of Diagnostic Accuracy: A User Guide.

Systematic reviews of diagnostic accuracy studies can provide the best available evidence to inform decisions regarding the use of a diagnostic test. In this guide, the authors provide a practical approach for clinicians to appraise diagnostic accuracy systematic reviews and apply their results to patient care. The first step is to identify an appropriate systematic review with a research question matching the clinical scenario. The user should evaluate the rigor of the review methods to evaluate its credibility (Did the review use clearly defined eligibility criteria, a comprehensive search strategy, structured data collection, risk of bias and applicability appraisal, and appropriate meta-analysis methods?). If the review is credible, the next step is to decide whether the diagnostic performance is adequate for clinical use (Do sensitivity and specificity estimates exceed the threshold that makes them useful in clinical practice? Are these estimates sufficiently precise? Is variability in the estimates of diagnostic accuracy across studies explained?). Diagnostic accuracy systematic reviews that are judged to be credible and provide diagnostic accuracy estimates with sufficient certainty and relevance are the most useful to inform patient care. This review discusses comparative, noncomparative, and emerging approaches to systematic reviews of diagnostic accuracy using a clinical scenario and examples based on recent publications.

A qualitative evidence synthesis of patient perspectives on migraine treatment features and outcomes.

OBJECTIVES: We aimed to identify migraine treatment features preferred by patients and treatment outcomes most valued by patients. BACKGROUND: The values and preferences of people living with migraine are critical for both the choice of acute therapy and management approach of migraine. METHODS: We conducted a qualitative evidence synthesis. Two reviewers independently selected studies, appraised methodological quality, and undertook a framework synthesis. We developed summary of findings tables following the approach of Grading of Recommendations, Assessment, Development and Evaluations Confidence in the Evidence from Reviews of Qualitative Research to assess confidence in the findings. RESULTS: Of 1691 candidate references, we included 19 studies (21 publications) involving 459 patients. The studies mostly recruited White women from North America (11 studies) and Europe (8 studies). We identified eight themes encompassing features preferred by patients in a migraine treatment process. Themes described a treatment process that included shared decision-making, a tailored approach, trust in health-care professionals, sharing of knowledge and diversity of treatment options, a holistic approach that does not just address the headache, ease of communication especially for complex treatments, a non-undermining approach, and reciprocity with mutual respect between patient and provider. In terms of the treatment itself, seven themes emerged including patients' preferences for nonpharmacologic treatment, high effectiveness, rapidity of action, long-lasting effect, lower cost and more accessibility, self-management/self-delivery option that increases autonomy, and a mixed preference for abortive versus prophylactic treatments. The treatment outcomes that have high value to patients included maintaining or improving function; avoiding side effects, potential for addiction to medications, and pain reoccurrence; and avoiding non-headache symptoms such as nausea, vomiting, and sensitivity to light or sounds. CONCLUSION: Patient values and preferences were individually constructed, varied widely, and could be at odds with conventional medical perspectives and evidence of treatment effects. Considering the availability of numerous treatments for acute migraine, it is necessary that decision-making incorporates patient values and preferences identified in qualitative research. The findings of this qualitative synthesis can be used to facilitate an individually tailored approach, strengthen the patient-health-care system relationship, and guide choices and decisions in the context of a clinical encounter or a clinical practice guideline.

A Bayesian model for combining standardized mean differences and odds ratios in the same meta-analysis.

In meta-analysis practice, researchers frequently face studies that report the same outcome differently, such as a continuous variable (e.g., scores for rating depression) or a binary variable (e.g., counts of patients with depression dichotomized by certain latent and unreported depression scores). For combining these two types of studies in the same analysis, a simple conversion method has been widely used to handle standardized mean differences (SMDs) and odds ratios (ORs). This conventional method uses a linear function connecting the SMD and log OR; it assumes logistic distributions for (latent) continuous measures. However, the normality assumption is more commonly used for continuous measures, and the conventional method may be inaccurate when effect sizes are large or cutoff values for dichotomizing binary events are extreme (leading to rare events). This article proposes a Bayesian hierarchical model to synthesize SMDs and ORs without using the conventional conversion method. This model assumes exact likelihoods for continuous and binary outcome measures, which account for full uncertainties in the synthesized results. We performed simulation studies to compare the performance of the conventional and Bayesian methods in various settings. The Bayesian method generally produced less biased results with smaller mean squared errors and higher coverage probabilities than the conventional method in most cases. Nevertheless, this superior performance depended on the normality assumption for continuous measures; the Bayesian method could lead to nonignorable biases for non-normal data. In addition, we used two case studies to illustrate the proposed Bayesian method in real-world settings.

Society for Vascular Surgery clinical practice guidelines for management of extracranial cerebrovascular disease.

Management of carotid bifurcation stenosis in stroke prevention has been the subject of extensive investigations, including multiple randomized controlled trials. The proper treatment of patients with carotid bifurcation disease is of major interest to vascular surgeons and other vascular specialists. In 2011, the Society for Vascular Surgery published guidelines for the treatment of carotid artery disease. At the time, several randomized trials, comparing carotid endarterectomy (CEA) and carotid artery stenting (CAS), were reported. Since the 2011 guidelines, several studies and a few systematic reviews comparing CEA and CAS have been reported, and the role of medical management has been reemphasized. In the present publication, we have updated and expanded on the 2011 guidelines with specific emphasis on five areas: (1) is CEA recommended over maximal medical therapy for low-risk patients; (2) is CEA recommended over transfemoral CAS for low surgical risk patients with symptomatic carotid artery stenosis of >50%; (3) the timing of carotid intervention for patients presenting with acute stroke; (4) screening for carotid artery stenosis in asymptomatic patients; and (5) the optimal sequence of intervention for patients with combined carotid and coronary artery disease. A separate implementation document will address other important clinical issues in extracranial cerebrovascular disease. Recommendations are made using the GRADE (grades of recommendation assessment, development, and evaluation) approach, as was used for other Society for Vascular Surgery guidelines. The committee recommends CEA as the first-line treatment for symptomatic low-risk surgical patients with stenosis of 50% to 99% and asymptomatic patients with stenosis of 70% to 99%. The perioperative risk of stroke and death in asymptomatic patients must be <3% to ensure benefit for the patient. In patients with recent stable stroke (modified Rankin scale score, 0-2), carotid revascularization is considered appropriate for symptomatic patients with >50% stenosis and should be performed as soon as the patient is neurologically stable after 48 hours but definitely <14 days after symptom onset. In the general population, screening for clinically asymptomatic carotid artery stenosis in patients without cerebrovascular symptoms or significant risk factors for carotid artery disease is not recommended. In selected asymptomatic patients with an increased risk of carotid stenosis, we suggest screening for clinically asymptomatic carotid artery stenosis as long as the patients would potentially be fit for and willing to consider carotid intervention if significant stenosis is discovered. For patients with symptomatic carotid stenosis of 50% to 99%, who require both CEA and coronary artery bypass grafting, we suggest CEA before, or concomitant with, coronary artery bypass grafting to potentially reduce the risk of stroke and stroke/death. The sequencing of the intervention depends on the clinical presentation and institutional experience.

Comparison of Biliary Drainage Techniques for Malignant Biliary Obstruction: A Systematic Review and Network Meta-analysis.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic biliary drainage, and endoscopic ultrasound (EUS)-guided biliary drainage are all established techniques for drainage of malignant biliary obstruction. This network meta-analysis (NMA) was aimed at comparing all 3 modalities to each other. MATERIALS AND METHODS: Multiple databases were searched from inception to October 2019 to identify relevant studies. All the patients were eligible to receive any one of the 3 interventions. Data extraction and risk of bias assessment was performed using standardized tools. Outcomes of interest were technical success, clinical success, adverse events, and reintervention. Direct meta-analyses were performed using the random-effects model. NMA was conducted using a multivariate, consistency model with random-effects meta-regression. The GRADE approach was followed to rate the certainty of evidence. RESULTS: The final analysis included 17 studies with 1566 patients. Direct meta-analysis suggested that EUS-guided biliary drainage had a lower reintervention rate than ERCP. NMA did not show statistically significant differences to favor any one intervention with certainty across all the outcomes. The overall certainty of evidence was found to be low to very low for all the outcomes. CONCLUSIONS: The available evidence did not favor any intervention for drainage of malignant biliary obstruction across all the outcomes assessed. ERCP with or without EUS should be considered first to allow simultaneous tissue acquisition and biliary drainage.

Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature.

OBJECTIVE: To describe the presentation and outcomes of patients with adrenal ganglioneuromas (AGNs). DESIGN: Single-centre retrospective cohort study (1 January 1995 to 31 December 2019) and systematic review of literature (1 January 1980 to 19 November 2019). PATIENTS: Diagnosed with histologically confirmed AGN. MEASUREMENTS: Baseline clinical, imaging and biochemical characteristics, recurrence rates and mortality. Subgroup analysis was performed on tumours with histologic elements of ganglioneuroma and pheochromocytoma (ie composite tumours). RESULTS: The cohort study included 45 patients with AGN, 20 (44%) of which had composite tumours. Compared to pure AGN, patients with composite tumour were older (median age, 62.5 vs. 35 years, p < .001), had smaller tumours (median size, 3.9 vs. 5.7 cm, p = .016) and were discovered incidentally less frequently (65% vs. 84%, p = .009). No recurrences or ganglioneuroma-specific mortality occurred during follow-up (range, 0-266 months). The systematic review included 14 additional studies and 421 patients. The mean age of diagnosis was 39 years, and 47% were women. AGNs were discovered incidentally in 72% of patients, were predominantly unilateral (99%) and had a mean diameter of 5.8 cm and an unenhanced computed tomography (CT) attenuation of -118 to 49 Hounsfield units (HU). On imaging, 69% of AGNs were homogenous, 41% demonstrated calcifications, and 40% were lobulated. CONCLUSIONS: AGNs are rare benign tumours that present with variable imaging features including large size, unenhanced CT attenuation >20 HU, calcifications and lobulated shape. Imaging characteristics can assist in establishing a diagnosis and avoiding an unnecessary adrenalectomy. The association of pheochromocytomas with AGNs is frequent. Diagnosis should include biochemical testing.

A systematic review of adherence to physical activity interventions in individuals with type 2 diabetes.

Lifestyle interventions are pivotal for successful management of type 2 diabetes (T2D), however, the proportion of people with T2D adhering to physical activity advice has not been thoroughly studied. The purpose of this systematic review was to summarise the evidence on adherence to exercise or physical activity components in lifestyle interventions in those with T2D. We searched MEDLINE EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus on 12 November 2019. Eligible studies enrolled adults with T2D and reported the proportion of adherence to lifestyle interventions as a primary or secondary outcome. We included 11 studies (nine randomised controlled trials (RCTs) enrolling 1717 patients and two nonrandomised studies enrolling 62 patients). Only one of the studies had low risk of bias. The proportion of participants adhering to physical activity varied from 32% to 100% with a median of 58%. Adherence was higher in interventions using supervised training and lowest in interventions using remote coaching and the adherence rate in observational studies was higher compared to RCTs (92% vs. 55%; p < 0.01). Study duration, risk of bias, or participants' sex, were not associated with adherence to physical activity. The proportion of those with T2D adhering to physical activity interventions for T2D varies widely and most of the included studies had a high risk of bias. These findings have important implications for planning and power analysis of future trials and when counselling patients about lifestyle interventions including physical activity or exercise components.

Prior Choices of Between-Study Heterogeneity in Contemporary Bayesian Network Meta-analyses: an Empirical Study.

BACKGROUND: Network meta-analysis (NMA) is a popular tool to compare multiple treatments in medical research. It is frequently implemented via Bayesian methods. The prior choice of between-study heterogeneity is critical in Bayesian NMAs. This study evaluates the impact of different priors for heterogeneity on NMA results. METHODS: We identified all NMAs with binary outcomes published in The BMJ, JAMA, and The Lancet during 2010-2018, and extracted information about their prior choices for heterogeneity. Our primary analyses focused on those with publicly available full data. We re-analyzed the NMAs using 3 commonly-used non-informative priors and empirical informative log-normal priors. We obtained the posterior median odds ratios and 95% credible intervals of all comparisons, assessed the correlation among different priors, and used Bland-Altman plots to evaluate their agreement. The kappa statistic was also used to evaluate the agreement among these priors regarding statistical significance. RESULTS: Among the selected Bayesian NMAs, 52.3% did not specify the prior choice for heterogeneity, and 84.1% did not provide rationales. We re-analyzed 19 NMAs with full data available, involving 894 studies, 173 treatments, and 395,429 patients. The correlation among posterior median (log) odds ratios using different priors were generally very strong for NMAs with over 20 studies. The informative priors produced substantially narrower credible intervals than non-informative priors, especially for NMAs with few studies. Bland-Altman plots and kappa statistics indicated strong overall agreement, but this was not always the case for a specific NMA. CONCLUSIONS: Priors should be routinely reported in Bayesian NMAs. Sensitivity analyses are recommended to examine the impact of priors, especially for NMAs with relatively small sample sizes. Informative priors may produce substantially narrower credible intervals for such NMAs.

Risk Factors for Delirium in Older Adults in the Emergency Department: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to identify risk factors for delirium in geriatric patients in the emergency department and to identify emergency department (ED)-based modifiable risk factors for developing delirium during hospitalization. We searched evidence based medicine reviews, EMBASE, MEDLINE, Scopus, and Web of Science for observational studies from the time of their inception to July 2020. We included studies that evaluated potential risk factors for either prevalent or incident delirium among older adults (age ≥ 60 years) presenting to the ED. When appropriate, we meta-analyzed estimates for risk factors using a random-effects model. The certainty of evidence was evaluated using the grading of recommendations assessment, development and evaluation approach. The study's protocol was registered in PROSPERO (CDR42020175261). A total of 4,513 citations were reviewed, and 34 studies met the criteria for inclusion: 27 evaluating risk factors for ED delirium (13,412 patients) and 7 evaluating ED-based risk factors for developing delirium during hospitalization (2,238 patients). The prevalence of ED delirium ranged from 7% to 35%. Four factors had strong associations with ED delirium and were graded as high-certainty evidence, including nursing home residence (4 studies; odds ratio [OR], 3.45; 95% confidence interval [CI], 2.17 to 5.48), cognitive impairment (7 studies; OR, 4.46; 95% CI, 3.38 to 5.89), hearing impairment (3 studies, OR, 2.57; 95% CI, 1.03 to 6.41), and a history of stroke (3 studies; OR, 3.20; 95% CI, 1.17 to 8.75). The rate of developing delirium during hospitalization ranged from 11% to 27%. A length of stay of more than 10 hours in ED was associated with a higher risk of delirium (1 study; OR, 2.23; 95% CI, 1.13 to 4.41). One study reported that severe pain, rather than the use of opioids, was associated with the development of delirium. These findings can be used to prioritize delirium screening in the ED and develop novel ED delirium risk scores or prevention interventions.

Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis.

Importance: Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy. Objective: To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults. Data Sources: Multiple databases from database inception to February 24, 2021. Study Selection: Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks. Data Extraction and Synthesis: Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small. Main Outcomes and Measures: The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Findings: Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham. Conclusions and Relevance: There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

First- and Second-Line Pharmacotherapies for Patients With Moderate to Severely Active Ulcerative Colitis: An Updated Network Meta-Analysis.

BACKGROUND & AIMS: We compared the efficacy and safety of different first-line (biologic-naïve) and second-line (prior exposure to tumor necrosis factor [TNF] antagonists) agents for treatment of moderate to severely active ulcerative colitis in a systematic review and network meta-analysis. METHODS: We searched publication databases through September 30, 2019, for randomized trials of adults with moderate to severe ulcerative colitis treated with TNF antagonists, vedolizumab, tofacitinib, or ustekinumab, as first-line or second-line agents, compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of remission and endoscopic improvement; safety outcomes were serious adverse events and infections. We performed a fixed-effects network meta-analysis using the frequentist approach, and calculated odds ratios (ORs) and 95% CI values. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Overall quality of evidence was rated using GRADE (Grading of Recommendations, Assessment, Development and Evaluation). RESULTS: In biologic-naïve patients, infliximab was ranked highest for induction of clinical remission (OR vs placebo, 4.07; 95% CI, 2.67-6.21; SUCRA, 0.95) and endoscopic improvement (SUCRA, 0.95) (moderate confidence in estimates [CE]). In patients with prior exposure to TNF antagonists, ustekinumab (SUCRA, 0.87) and tofacitinib (SUCRA, 0.87) were ranked highest for induction of clinical remission and were superior to vedolizumab (ustekinumab vs vedolizumab: OR, 5.99; 95% CI, 1.13-31.76 and tofacitinib vs vedolizumab: OR, 6.18; 95% CI, 1.003-8.00; moderate CE) and adalimumab (ustekinumab vs adalimumab: OR, 10.71; 95% CI, 2.01-57.20 and tofacitinib vs adalimumab: OR, 11.05; 95% CI, 1.79-68.41; moderate CE). Vedolizumab had the lowest risk of infections (SUCRA, 0.81), followed by ustekinumab (SUCRA, 0.63) in maintenance trials. CONCLUSIONS: In a systematic review and network meta-analysis, we found infliximab to be ranked highest in biologic-naïve patients, and ustekinumab and tofacitinib were ranked highest in patients with prior exposure to TNF antagonists, for induction of remission and endoscopic improvement in patients with moderate to severe ulcerative colitis. More trials of direct comparisons are needed to inform clinical decision making with greater confidence.

Comparison of Therapies for Primary Prevention of Esophageal Variceal Bleeding: A Systematic Review and Network Meta-analysis.

We performed a systematic review with network meta-analysis (NMA) to compare the efficacy of different approaches in primary prevention of esophageal variceal bleeding and overall survival in patients with cirrhosis with large varices. Thirty-two randomized clinical trials (RCTs) with 3,362 adults with cirrhosis with large esophageal varices and no prior history of bleeding, with a minimum of 12 months of follow-up, were included. Nonselective beta-blockers (NSBB), isosorbide-mononitrate (ISMN), carvedilol, and variceal band ligation (VBL), alone or in combination, were compared with each other or placebo. Primary outcomes were reduction of all-cause mortality and prevention of esophageal variceal bleeding. Random-effects NMA was performed and summary estimates were expressed as odds ratio and 95% confidence intervals (OR; CI). Quality of evidence was critically appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. Moderate quality evidence supports NSBB monotherapy (0.70; 0.49-1.00) or in combination with VBL (0.49; 0.23-1.02) or ISMN (0.44; 0.21-0.93) for decreasing mortality in patients with cirrhosis with large esophageal varices and no prior history of bleeding. Moderate-quality evidence supports carvedilol (0.21; 0.08-0.56) and VBL monotherapy (0.33; 0.19-0.55) or in combination with NSBB (0.34; 0.14-0.86), and low-quality evidence supports NSBB monotherapy (0.64; 0.38-1.07) for primary prevention of variceal bleeding. VBL carries a higher risk of serious adverse events compared with NSBB. Conclusion: NSBB monotherapy may decrease all-cause mortality and the risk of first variceal bleeding in patients with cirrhosis with large esophageal varices. Additionally, NSBB carries a lower risk of serious complications compared with VBL. Therefore, NSBB may be the preferred initial approach for primary prophylaxis of esophageal variceal bleeding.

Eating, sleeping and sexual function disorders in women with polycystic ovary syndrome (PCOS): A systematic review and meta-analysis.

PURPOSE: We aim to evaluate the association of PCOS with eating, sleeping and sexual function disorders. METHODS: A comprehensive search including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through 01 August 2018 was conducted for studies reporting the prevalence of any eating, sleep or sexual function disorders in patients with PCOS. Independent reviewers selected studies and extracted data. A random-effects model was utilized to generate pooled odds ratio (OR) and 95% confidence intervals (CI) for binary outcomes, and mean difference (MD) and 95% CI for continuous outcomes. RESULTS: We included 36 studies reporting on 349,529 patients. Compared to women without PCOS, women with PCOS were more likely to have bulimia nervosa (OR 1.37; %CI, 1.17 to 1.60), binge eating (OR 2.95; 95%CI, 1.61 to 5.42), or any eating disorder (OR 1.96; 95% CI 1.18 to 3.24); but not anorexia nervosa (OR 0.92; 95%CI, 0.78 to 1.10). Women with PCOS were more likely to have sleep disorders like hypersomnia (OR 4.39; %CI, 1.07 to 18.07) and obstructive sleep apnoea (OR 10.81; %CI, 2.39 to 48.83). Women with PCOS had lower sexual satisfaction as measured on a visual analogue scale (MD -29.67; 95% CI, -36.97 to -22.37), but no difference in Total Female Sexual Function Index (MD -0.06; 95% CI, -0.51 to 0.38). CONCLUSION: PCOS can be associated with an increased risk of eating and sleeping disorders as well as decreased sexual satisfaction. Screening for these disorders in women with PCOS may allow early intervention and improve quality of life.

Antifungal prophylaxis in lung transplant recipients: A systematic review and meta-analysis.

BACKGROUND: No consensus exists regarding optimal strategy for antifungal prophylaxis following lung transplant. OBJECTIVE: To review data regarding antifungal prophylaxis on the development of fungal infections. STUDY SELECTION/APPRAISAL: We searched MEDLINE, Embase, and Scopus for eligible articles through December 10, 2019. Observational or controlled trials published after January 1, 2001, that pertained to the prevention of fungal infections in adult lung recipients were reviewed independently by two reviewers for inclusion. METHODS: Of 1702 articles screened, 24 were included. Data were pooled using random effects model to evaluate for the primary outcome of fungal infection. Studies were stratified by prophylactic strategy, medication, and duration (short term < 6 months and long term ≥ 6 months). RESULTS: We found no difference in the odds of fungal infection with universal prophylaxis (49/101) compared to no prophylaxis (36/93) (OR 0.76, CI: 0.03-17.98; I2  = 93%) and preemptive therapy (25/195) compared to universal prophylaxis (35/222) (OR 0.91, CI: 0.06-13.80; I2  = 93%). The cumulative incidence of fungal infections within 12 months was not different with nebulized amphotericin (0.08, CI: 0.04-0.13; I2  = 87%) compared to systemic triazoles (0.07, CI: 0.03-0.11; I2  = 21%) (P = .65). Likewise, duration of prophylaxis did not impact the incidence of fungal infections (short term: 0.11, CI: 0.05-0.17; I2  = 89%; long term: 0.06, CI: 0.03-0.08; I2  = 51%; P = .39). CONCLUSIONS: We have insufficient evidence to support or exclude a benefit of antifungal prophylaxis.

External beam radiotherapy versus vaginal brachytherapy in patients with stage II endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: The choice of adjuvant treatment for women with stage II endometrial cancer is challenging, given the known increase in morbidity with external beam radiation compared with vaginal brachytherapy, and the lack of consensus on its benefits. We summarized the evidence on survival and recurrence for stage II endometrial cancer, defined as cervical stromal invasion, after adjuvant postoperative external beam radiotherapy and vaginal brachytherapy. METHODS: We searched the MEDLINE, EMBASE, CENTRAL, and Scopus databases from inception to January 2019 to identify studies that compared adjuvant postoperative external beam radiotherapy with or without vaginal brachytherapy and vaginal brachytherapy alone in stage II endometrial cancer. Our primary outcome was the locoregional recurrence rate, defined as recurrence in the pelvis or vagina. Secondary outcomes included the rate of recurrence at any site, distant recurrence rate, vaginal recurrence rate, pelvic recurrence rate, and 5 year overall survival. Study selection, assessment, and data abstraction were performed by an independent set of reviewers. Random effects models were used to synthesize quantitative data. RESULTS: We included 15 cohort studies reporting data on 1070 women. Most women with stage II endometrial cancer (848/1070, 79.3%) were treated with external beam radiotherapy with or without vaginal brachytherapy. Subgroup analysis was stratified by whether >90% of the women included underwent pelvic lymph node assessment (sampling or full dissection). Locoregional recurrence (pelvic and vaginal recurrence) was significantly reduced with external beam radiotherapy with or without vaginal brachytherapy compared with vaginal brachytherapy alone (14 studies (n=1057); odds ratio (OR) 0.33 (95% confidence interval (CI) 0.16 to 0.68); I2=5%) regardless of pelvic lymph node assessment. Most women (81.8%) who recurred locoregionally had a least one uterine risk factor (grade 3 tumor, myometrial invasion >50%, or lymphovascular invasion). There was no difference in overall survival with external beam radiotherapy with or without vaginal brachytherapy compared with vaginal brachytherapy alone (five studies (n=463); OR 0.78 (95% CI 0.34 to 1.80); I2=48%). CONCLUSIONS: External beam radiotherapy with or without vaginal brachytherapy decreased the locoregional recurrence threefold for stage II endometrial cancer, regardless of pelvic lymph node assessment. Most women who suffered recurrence locoregionally had a least one high risk factor. Vaginal brachytherapy alone may be sufficient therapy for node negative stage II endometrial cancer without uterine risk factors, while those with uterine risk factors should be considered for external beam radiotherapy with or without vaginal brachytherapy to improve locoregional control.

Professionalism and inter-communication skills (ICS): a multi-site validity study assessing proficiency in core competencies and milestones in medical learners.

BACKGROUND: Interpersonal and Communication Skills (ICS) and Professionalism milestones are challenging to evaluate during medical training. Paucity in proficiency, direction and validity evidence of assessment tools of these milestones warrants further research. We validated the reliability of the previously-piloted Instrument for Communication skills and Professionalism Assessment (InCoPrA) in medical learners. METHODS: This validity approach was guided by the rigorous Kane's Framework. Faculty-raters and standardized patients (SPs) used their respective InCoPrA sub-component to assess distinctive domains pertinent to ICS and Professionalism through multiple expert-built simulated-scenarios comparable to usual care. Evaluations included; inter-rater reliability of the faculty total score; the correlation between the total score by the SPs; and the average of the total score by two-faculty members. Participants were surveyed regarding acceptability, realism, and applicability of this experience. RESULTS: Eighty trainees and 25 faculty-raters from five medical residency training sites participated. ICC of the total score between faculty-raters was generally moderate (ICC range 0.44-0.58). There was on average a moderate linear relationship between the SPs and faculty total scores (Pearson correlations range 0.23-0.44). Majority of participants ascertained receiving a meaningful, immediate, and comprehensive patient-faculty feedback. CONCLUSIONS: This work substantiated that InCoPrA was a reliable, standardized, evidence-based, and user-friendly assessment tool for ICS and Professionalism milestones. Validating InCoPrA showed generally-moderate agreeability and high acceptability. Using InCoPrA also promoted engaging all stakeholders in medical education and training-faculty, learners, and SPs-using simulation-media as pathway for comprehensive feedback of milestones growth.

Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-analysis.

BACKGROUND: The relationship between delayed gastric emptying and upper GI symptoms (UGI Sx) is controversial. OBJECTIVE: To assess association between gastric emptying and UGI Sx, independent of treatment. DESIGN: We performed a systematic review and meta-analysis of the literature from 2007 to 2017, review of references and additional papers identified by content expert. We included studies evaluating the association between gastric emptying and nausea, vomiting, early satiety/postprandial fullness, abdominal pain and bloating. Covariate analyses included optimal gastric emptying test method, gastric emptying type (breath test or scintigraphy) and patient category. Meta-regression compared the differences based on type of gastric emptying tests. RESULTS: Systematic review included 92 gastric emptying studies (26 breath test, 62 scintigraphy, 1 ultrasound and 3 wireless motility capsule); 25 of these studies provided quantitative data for meta-analysis (15 scintigraphy studies enrolling 4056 participants and 10 breath test studies enrolling 2231 participants). Meta-regression demonstrated a significant difference between optimal and suboptimal gastric emptying test methods when comparing delayed gastric emptying with nausea and vomiting. On evaluating studies using optimal gastric emptying test methodology, there were significant associations between gastric emptying and nausea (OR 1.6, 95% CI 1.4 to 1.8), vomiting (OR 2.0, 95% CI 1.6 to 2.7), abdominal pain (OR 1.5, 95% CI 1.0 to 2.2) and early satiety/fullness (OR 1.8, 95% CI 1.2 to 2.6) for patients with UGI Sx; gastric emptying and early satiety/fullness in patients with diabetes; gastric emptying and nausea in patients with gastroparesis. CONCLUSIONS: The systematic review and meta-analysis supports an association between optimally measured delayed gastric emptying and UGI Sx.