Phenotyping chronic respiratory diseases with airways obstruction.

Given the high prevalence of asthma-chronic obstructive pulmonary disease overlap (ACO) in Vietnam, there is an urgent need to establish a simplified strategy for categorising patients as either having asthma or chronic obstructive pulmonary disease (COPD). This classification would streamline the application of treatment recommendations outlined by the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD).Patients with obstructive lung function were classified as having COPD, asthma, or ACO based on GINA/GOLD guidelines. We hypothesised that ACO-like asthma (ACO-A) would present with positive skin prick tests (SPTs) or early onset of symptoms without a history of tuberculosis (TB), while those with ACO-like COPD (ACO-B) would exhibit negative SPTs and late onset of symptoms and/or a history of TB.Among 235 patients, the prevalence of asthma, ACO-A, ACO-B, and COPD was respectively 21%, 22%, 17%, and 40%. Allergic history, rhinitis, and childhood asthma were associated with ACO-A, while high cumulative smoking was correlated with ACO-B. Socio-economic and demographic parameters, medical history, clinical features, smoking habits, lung function, and para-clinical investigations significantly differed between "all asthma" (i.e., individuals with asthma combined with ACO-A) and "all COPD" (i.e., individuals with COPD combined with ACO-B).Based on SPTs, history of TB, and onset age, ACO patients may be defined as people with asthma or COPD..

Differential efficacy of medical therapies for ulcerative colitis according to disease extent: patient-level analysis from multiple randomized controlled trials.

Background: Disease extent in Ulcerative Colitis (UC) has prognostic implications for disease course. It is unclear whether the efficacy of medical therapies for moderate to severely active UC vary according to disease extent at enrollment. Methods: We analyzed patient level data from 11 Phase 2 and 3 clinical trials of advanced therapies in patients with moderate-to-severe UC to assess modifications of advanced therapy effects by disease extent. Primary outcome was clinical response and secondary outcomes were clinical remission, endoscopic response/remission and endoscopic improvement, and Mayo clinic subscore for both induction and maintenance studies. Binary and continuous outcomes were analyzed using the modified Poisson regression model and the mixed-effects model, respectively, adjusting for age, sex, disease duration, concomitant steroid use and prior anti-TNF use. Effect modifications with binary outcomes were quantified by ratios of risk ratio for left-sided to that for extensive colitis while effect modifications with the Mayo subscores were quantified by differences of the differences between mean scores of the left-sided and extensive colitis. Results were presented with point estimates and 95% confidence intervals as well as p-values. Findings: Eleven clinical trials enrolling 5450 UC patients (infliximab = 2, adalimumab = 2, golimumab = 2, vedolizumab = 2, tofacitinib = 3) were included. In induction trials, there was evidence to suggest effect modification by disease extent for clinical response with tofacitinib (the ratio of RRs 0.67, 95% CI [0.45, 0.99], p = 0.049) and clinical remission with infliximab (ratio of RRs 0.33, 95% CI [0.13, 0.85], p = 0.020) favoring patients with extensive colitis. There was no evidence to suggest effect modification for endoscopic improvement and clinical outcomes. There was evidence to suggest effect modification by disease extent for clinical remission with tofacitinib (ratio of RRs 0.44, 95% CI [0.22, 0.89], p = 0.020) favoring patients with extensive colitis. For symptom subscores from the Mayo Clinic score, tofacitinib was associated with a greater reduction in both stool frequency (difference of differences 0.37, 95% CI [0.08, 0.65], p = 0.012) and rectal bleeding scores (difference of differences 0.25, 95% CI [0.03, 0.47], p = 0.026) in patients with extensive colitis compared to left sided. Interpretation: These findings underscore the possibility of differential efficacy of medical therapies according to disease distribution. These results warrant further exploration in forthcoming trials to better inform treatment strategies and consideration of disease distribution as a baseline stratification factor in clinical trials. Funding: This study did not receive any financial support.

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.

Endoscopic and Histological Placebo Rates in Crohn's Disease Clinical Trials: A Systematic Review and Meta-analysis.

BACKGROUND: Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials. METHODS: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated. RESULTS: In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes. CONCLUSIONS: Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.

Characteristics of Interventional Trials for Patients Living With Intestinal Stoma Registered in ClinicalTrials.gov With a Focus on Inflammatory Bowel Disease.

BACKGROUND: This systematic review was performed to characterize the landscape of research conducted in patients with intestinal stoma (IS) and highlight unmet needs for clinical research in Crohn's disease (CD) and IS. METHODS: We searched ClinicalTrials.gov from inception to May 25, 2022, to identify clinical trials assessing interventions in patients with an IS, as well as those with an IS and CD. Studies were grouped according to type of intervention. We excluded observational studies with no treatment arm. RESULTS: A total of 253 studies were included in the final analysis. Most studies investigated devices (n = 122 [48.2%]), or surgical procedures (n = 63 [24.9%]), followed by behavioral interventions (n = 30 [11.8%]), drugs (n = 20 [7.9%]), dietary interventions (n = 2 [0.8%]), skin care products (n = 2 0.8%]), and others (n = 14 [5.5%]). A total of 50.9% (n = 129) of studies had completed recruitment, enrolling 11 116 participants. Only 6 studies (surgery: n = 3; physiological studies: n = 2; drugs: n = 1) exclusively included patients with inflammatory bowel disease (IBD), and 16 studies commented that patients with IBD were excluded in their eligibility criteria. No study assessed efficacy of drugs in patients with CD and IS. Approximately one-quarter of studies (n = 65 of 253) included quality of life as an outcome measure. CONCLUSION: There is a paucity of research in IBD patients with IS, with the majority focusing on devices and surgical procedures. There have been no drug trials evaluating efficacy in patients with CD and IS. There is an urgent need to identify barriers to enrollment and develop eligibility and outcome measures that enable the inclusion of patients with CD with stoma into clinical trials.

We analyzed registered trials for patients with intestinal stoma with special focus on Crohn's disease patients to explore research and unmet needs. Our results indicate a scarcity of studies in this area with most studies limited to surgical procedures and devices.

Harnessing the Near-Peer Effect in Anatomy Education.

Benefits of near-peer teaching are well-documented, but its time requirements can be prohibitive. We integrated the near-peer effect into a clinical anatomy course with weekly student-developed handouts vetted by faculty to provide an element of near-peer teaching without the burden of extra time.

Long Washout Periods Between Biologics for Inflammatory Bowel Disease Clinical Trials Are Unnecessary: A Canadian Retrospective Cohort Study.

INTRODUCTION: To assess the safety of early vs late biologic switch in patients with inflammatory bowel disease. METHODS: In this retrospective study, we included patients with inflammatory bowel disease who underwent biologic switch between January 2014 and July 2022 at a tertiary center. The primary outcome was any infection by 6 months. RESULTS: There was no statistically significant difference between patients who had early biologic switch (≤30 days, n = 51) and late switch (>30 days, n = 77) in either infectious or noninfectious adverse events by 6 and 12 months. DISCUSSION: Early biologic switch is safe. A prolonged washout period between 2 biologics is unnecessary.

Invasive Mold Infections in Children: Navigating Troubled Waters with a Broken Compass.

Incidence of invasive mold infections in children, while rare, is increasing as the population of high-risk patients expands, including premature infants, pediatric patients undergoing treatment for hematological malignancies, or recipients of allogeneic hematologic stem cell transplants. The infectious agents, including Aspergillus spp., Mucorales, and other molds, are especially difficult to treat and have serious morbidity and high mortality. Clinicians must maintain a high index of suspicion for invasive mold infections in at-risk patients. Diagnosis of invasive mold infections is complicated by difficulties isolating pathogens on culture, but progress is being made in immunological and molecular diagnostic technologies. Treatment in children is challenging; no randomized controlled trials exist. There is a growing body of data on treatment, specifically on safer antifungal agents, including indications for treatment, spectrum of coverage, pharmacokinetics for different ages, and pharmacodynamic targets associated with therapeutic success. However, pediatricians must often extrapolate from adult data. In this review, we aim to harmonize the existing body of literature on invasive mold infections in children, covering epidemiology, clinical presentations, diagnostic methods, and principles of management.

Improving rowing performance by adjusting oar blade size and angle.

The principal aim of the work presented here is to investigate and demonstrate that a forward tilted rowing blade would result in a more efficient and effective motion of the blade through the water that would result in a higher boat speed when an equal input power is provided. A 1:5 scaled rowing boat is used to determine the performance of rowing blades with different sizes and blade angles. This is used to validate the results of a previous study where the optimal blade angle of 15 ∘ with respect to the oar shaft was determined ( 1). The input power and speed of the rowing boat can be compared between original and modified oar blades. Measurements in a towing tank demonstrate that a modified rowing blade result in faster rowing by 0.4% at the same input power. Maintaining the same stroke rate, the improvement of the blade efficiency is compensated by using a 4-6% increased blade area to yield the same input power.

Patients With Crohn's Disease and Permanent Ileostomy Are Universally Excluded From Clinical Trials: A Systematic Review.

INTRODUCTION: We performed a systematic review to investigate whether patients with Crohn's disease (CD) and permanent ileostomy (PI) have been included in clinical trials evaluating biologics and small molecules. METHODS: MEDLINE, Embase and Cochrane library (CENTRAL) data bases were searched from inception to May 16, 2022 for placebo controlled induction and/or maintenance randomized controlled trials assessing biologics and oral small molecules in adult patients with active CD. RESULTS: Of the 81 induction and maintenance trials assessing biologics and oral small molecules in CD, none permitted the enrollment of patients with PI. Patients with CD and PI have been universally excluded from pharmaceutical trials of biologics and small molecules to date. DISCUSSION: There is an urgent need to identify barriers to enrollment and develop eligibility and outcome measures enabling the inclusion of patients with CD and PI into clinical trials.

Ampicillin and Gentamicin Treatment for Early Onset Neonatal Sepsis: When One Size Does Not Fit All.

Based on in vitro susceptibilities and the concern for emergence of resistance and long-term safety, ampicillin plus gentamicin remains the recommended antibiotic regimen for early onset neonatal sepsis. Our objective was to identify potential limitations of this regimen based on clinical and pathogen characteristics while minimizing risks associated with prolonged antibiotic exposure. We identified 43 gram-negative pathogens in 42 patients. Escherichia coli (E coli) occurred in 50% and Streptococcus agalactiae in 23.8% of patient. Ampicillin resistance was common, particularly in E coli (85.7%). Mortality was 23.8%, all due to E coli. We found that E coli is the most frequent pathogen and has a high mortality particularly in neonates < 1500 g; mortality is high with the current dosing strategy when E coli is resistant to ampicillin even when sensitive to gentamicin; resistance to gentamicin remains low but seems to be increasing while resistance to third-generation cephalosporins remains very low.

[Should we interfere with the interleukin-6 receptor during COVID-19: What do we know?] / Inhibiteurs du récepteur de l'IL-6 dans le traitement de la COVID-19 : que savons-nous ?

COVID-19 is a viral infection with predominant respiratory tropism. In its most severe forms, the initial viral aggression leads to acute respiratory failure due to damage secondary to an exacerbated inflammatory response provoked by the activation of innate, followed by adaptive immunity. The inflammatory response may entail respiratory distress syndrome, if not multivisceral failure and death. IL-6 receptor inhibitors (Tocilizumab and Sarilumab) have been proposed as treatments. Numerous studies have provided new information, which remains heterogeneous and difficult to interpret. This review is aimed at clarifying the potential role of IL-6 receptor inhibitors in severe forms of COVID-19.

Invasive meningococcal disease in Malaysia, Philippines, Thailand, and Vietnam: An Asia-Pacific expert group perspective on current epidemiology and vaccination policies.

Invasive meningococcal disease (IMD) imposes a significant burden on the global community due to its high case fatality rate (4-20%) and the risk of long-term sequelae for one in five survivors. An expert group meeting was held to discuss the epidemiology of IMD and immunization policies in Malaysia, Philippines, Thailand, and Vietnam. Most of these countries do not include meningococcal immunization in their routine vaccination programs, except for high-risk groups such as immunocompromised people and pilgrims. It is difficult to estimate the epidemiology of IMD in the highly diverse Asia-Pacific region, but available evidence indicate serogroup B is increasingly dominant. Disease surveillance systems differ by country. IMD is not a notifiable disease in some of them. Without an adequate surveillance system in the region, the risk and the burden of IMD might well be underestimated. With the availability of new combined meningococcal vaccines and the World Health Organization roadmap to defeat bacterial meningitis by 2030, a better understanding of the epidemiology of IMD in the Asia-Pacific region is needed.

A robust experimental and computational analysis framework at multiple resolutions, modalities and coverages.

The ability to study cancer-immune cell communication across the whole tumor section without tissue dissociation is needed, especially for cancer immunotherapy development, which requires understanding of molecular mechanisms and discovery of more druggable targets. In this work, we assembled and evaluated an integrated experimental framework and analytical process to enable genome-wide scale discovery of ligand-receptors potentially used for cellular crosstalks, followed by targeted validation. We assessed the complementarity of four different technologies: single-cell RNA sequencing and Spatial transcriptomic (measuring over >20,000 genes), RNA In Situ Hybridization (RNAscope, measuring 4-12 genes) and Opal Polaris multiplex protein staining (4-9 proteins). To utilize the multimodal data, we implemented existing methods and also developed STRISH (Spatial TRanscriptomic In Situ Hybridization), a computational method that can automatically scan across the whole tissue section for local expression of gene (e.g. RNAscope data) and/or protein markers (e.g. Polaris data) to recapitulate an interaction landscape across the whole tissue. We evaluated the approach to discover and validate cell-cell interaction in situ through in-depth analysis of two types of cancer, basal cell carcinoma and squamous cell carcinoma, which account for over 70% of cancer cases. We showed that inference of cell-cell interactions using scRNA-seq data can misdetect or detect false positive interactions. Spatial transcriptomics still suffers from misdetecting lowly expressed ligand-receptor interactions, but reduces false discovery. RNAscope and Polaris are sensitive methods for defining the location of potential ligand receptor interactions, and the STRISH program can determine the probability that local gene co-expression reflects true cell-cell interaction. We expect that the approach described here will be widely applied to discover and validate ligand receptor interaction in different types of solid cancer tumors.

Preferential reporting of significant p-values in radiology journal abstracts.

AIM: To assess the prevalence of publication bias in the radiology literature, data-mining techniques were used to extract p-values in abstracts published in key radiology journals over the past 20 years. MATERIALS AND METHODS: A total of 34,699 abstracts published in Radiology, Investigative Radiology, European Radiology, American Journal of Roentgenology, and American Journal of Neuroradiology published between January 2000 and December 2019 were included in the analysis. Automated text mining using regular expressions was used to mine abstracts for p-values. RESULTS: The text mining algorithm detected 43,489 p-values, the majority (82.4%) of which were reported as "significant", i.e., p<0.05. There has also been an increased propensity to report more p-values over time. The distribution of p-values showed a step change at the conventional significance threshold of 0.05. The odds ratio of a "significant" p-value being reported in the abstract compared to the full text was calculated to be 2.52 (95% confidence interval 1.78-3.58; p<0.001). Taken together, these results provide strong evidence for selective reporting of significant p-values in abstracts. CONCLUSION: Statistically significant p-values are preferentially reported in radiology journal abstracts.

GoFundMe as a Medical Plan: Ecological Study of Crowdfunding Insulin Success.

BACKGROUND: Individuals in need of medical care turn to crowdfunding websites to engage a "crowd" or group for financial support. In the last decade, access to insulin has decreased considerably for several reasons, including the rising cost of insulin, increasing popularity of high-deductible insurance plans, and increasing insurance premiums. Many people with diabetes are forced to ration or go without insulin, and they turn to crowdfunding websites to seek financial donations to purchase insulin needed to reduce health risks and mortality, and sustain quality of life. OBJECTIVE: This study aimed to explore crowdfunding campaign requests to purchase insulin in the United States. METHODS: In this retrospective, quantitative, and qualitative study, we coded the text of GoFundMe online crowdfunding campaigns and viral measures (shares, hearts, and comments) from February 25 to April 15, 2019. We described campaigns (N=205) and explored the factors associated with campaign success using correlations and qualitative thematic analysis. RESULTS: The majority of campaigns were initiated by middle-aged adults (age 26-64 years; 77/205, 37.6%), those with type 1 diabetes (94/205, 45.9%), and those needing funds owing to insurance coverage issues (125/205, 61.0%). The factors associated with campaign success included requests for ≤US $500 (P=.007) and higher viral measures (shares, P=.007; hearts, P<.001; comments, P=.002). The following 4 themes emerged from the campaign text: (1) desire for self-management and survival, (2) diabetes management untenable given insulin access, (3) aftermath of insulin unaffordability, and (4) privacy issues with crowdfunding. Campaign comments were both supportive (tangible, informational, and emotional) and unsupportive (questioned the need for the campaign and deemed crowdfunding inappropriate). CONCLUSIONS: Despite crowdfunding websites being used to support the purchase of insulin, campaigns raised only a fraction of the money requested. Therefore, GoFundMe campaigns are not a reliable solution to obtain funds for insulin in the United States. Applying quantitative and qualitative methods is adequate to analyze online crowdfunding for costs of medications such as insulin. However, it is critical for people with diabetes to use resources other than online crowdfunding to access and obtain insulin owing to low success rates. Clinicians should routinely assess difficulty accessing or affording insulin, and federal health care policies should support lowering the cost of insulin.

Pharmacological Interventions for the Prevention and Treatment of Immune Checkpoint Inhibitor-Associated Enterocolitis: A Systematic Review.

BACKGROUND: Patients treated with immune checkpoint inhibitors (ICIs) may develop ICI-associated enterocolitis, for which there is no approved treatment. AIMS: We aimed to systematically review the efficacy and safety of medical interventions for the prevention and treatment of ICI-associated enterocolitis. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials (RCTs), cohort and case-control studies, and case series/reports, evaluating interventions (including corticosteroids, biologics, aminosalicylates, immunosuppressants, and fecal transplantation) for ICI-associated enterocolitis. Clinical, endoscopic, and histologic efficacy endpoints were evaluated. The Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to assess overall quality of evidence. RESULTS: A total of 160 studies (n = 1514) were included (one RCT, 3 retrospective cohort studies, 156 case reports/case series). Very low quality evidence from one RCT suggests budesonide is not effective for prevention of ICI-associated enterocolitis in ipilimumab-treated patients (relative risk 0.93 [95% confidence interval 0.56, 1.56]). Very low quality evidence suggests that corticosteroids, infliximab, and vedolizumab may be effective for treatment of ICI-associated enterocolitis by inducing clinical response and remission. No validated indices for measuring disease activity were used. Biologic treatment was used in 42% (641/1528) of patients, as reported in 97 studies. ICIs were discontinued in 65% (457/702) of patients, as reported in 63 studies. CONCLUSIONS: Current treatment recommendations for ICI-associated enterocolitis are based on very low quality evidence, primarily from case reports and case series. Large-scale prospective cohort studies and RCTs are needed to develop prophylactic and therapeutic treatments to minimize interruption or discontinuation of oncological therapies.

The Relationship Between Endoscopic and Clinical Recurrence in Postoperative Crohn's Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: We aimed to quantify the magnitude of the association between endoscopic recurrence and clinical recurrence [symptom relapse] in patients with postoperative Crohn's disease. METHODS: Databases were searched to October 2, 2020, for randomised controlled trials [RCTs] and cohort studies of adult patients with Crohn's disease with ileocolonic resection and anastomosis. Summary effect estimates for the association between clinical recurrence and endoscopic recurrence were quantified by risk ratios [RR] and 95% confidence intervals [95% CI]. Mixed-effects meta-regression evaluated the role of confounders. Spearman correlation coefficients were calculated to assess the relationship between these outcomes as endpoints in RCTs. An exploratory mixed-effects meta-regression model with the logit of the rate of clinical recurrence as the outcome and the rate of endoscopic recurrence as a predictor was also evaluated. RESULTS: In all, 37 studies [N = 4053] were included. For eight RCTs with available data, the RR for clinical recurrence for patients who experienced endoscopic recurrence was 10.77 [95% CI 4.08 to 28.40; GRADE moderate certainty evidence]; the corresponding estimate from 11 cohort studies was 21.33 [95% CI 9.55 to 47.66; GRADE low certainty evidence]. A single cohort study showed a linear relationship between Rutgeerts score and clinical recurrence risk. There was a strong correlation between endoscopic recurrence and clinical recurrence treatment effect estimates as trial outcomes [weighted Spearman correlation coefficient 0.51]. CONCLUSIONS: The associations between endoscopic recurrence and subsequent clinical recurrence lend support to the choice of endoscopic recurrence to monitor postoperative disease activity and as a primary endpoint in clinical trials of postoperative Crohn's disease.

Systematic Review and Meta-Analysis: Clinical, Endoscopic, Histological and Safety Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

BACKGROUND AND AIMS: Quantifying placebo rates and the factors influencing them are essential to inform trial design. We provide a contemporary summary of clinical, endoscopic, histological and safety placebo rates in induction and maintenance clinical trials of ulcerative colitis, and identify factors influencing them. METHODS: MEDLINE, EMBASE and the Cochrane library were searched from April 2014 to April 2020, updating a prior meta-analysis that searched from inception to April 2014. We included placebo-controlled trials of aminosalicylates, corticosteroids, immunosuppressives, small-molecules and biologics in adults with ulcerative colitis. Placebo rates were pooled using random-effects and mixed-effects meta-regression models to assess the associated study-level. RESULTS: In 119 trials [92 induction, 27 maintenance] clinical, endoscopic and histological remission placebo rates for induction trials were 11% (95% confidence interval [CI] 9-13%), 19% [95% CI 15-23%] and 15% [95% CI 11-19%], respectively; for maintenance trials, clinical and endoscopic placebo remission rates were 18% [95% CI 12-25%] and 20% [95% CI 15-25%], respectively. Higher endoscopic subscore and a higher rate of exposure to prior biologic therapy at enrolment were associated with lower clinical and endoscopic placebo remission rates. Absence of central reading was associated with an increase in placebo endoscopic response and remission rates. More follow-up visits and increasing trial duration were associated with higher clinical placebo rates. CONCLUSIONS: Placebo rates in ulcerative colitis trials vary according to the endpoint assessed, whether it is for assessment of response or remission, and whether the trial is designed for induction or maintenance. These contemporary rates across different endpoints and drug classes will help to inform trial design.

Disease Activity Indices for Pouchitis: A Systematic Review.

BACKGROUND: Several indices exist to measure pouchitis disease activity; however, none are fully validated. As an initial step toward creating a validated instrument, we identified pouchitis disease activity indices, examined their operating properties, and assessed their value as outcome measures in clinical trials. METHODS: Electronic databases were searched to identify randomized controlled trials including indices that evaluated clinical, endoscopic, or histologic pouchitis disease activity. A second search identified studies that assessed the operating properties of pouchitis indices. RESULTS: Eighteen randomized controlled trials utilizing 4 composite pouchitis disease activity indices were identified. The Pouchitis Disease Activity Index (PDAI) was most commonly used (12 of 18; 66.7%) to define both trial eligibility (8 of 12; 66.7%), and outcome measures (12 of 12; 100%). In a separate search, 21 studies evaluated the operating properties of 3 pouchitis indices; 90.5% (19 of 21) evaluated validity, of which 42.1% (8 of 19) evaluated the construct validity of the PDAI. Criterion validity (73.7%; 14 of 19) was evaluated through correlation of the PDAI with fecal calprotectin (FCP; r = 0.188 to 0.71), fecal lactoferrin (r = 0.570 to 0.582), and C-reactive protein (CRP; r = 0.584). Two studies assessed correlation of the modified PDAI (mPDAI) with FCP (r = 0.476 and r = 0.565, respectively). Fair to moderate inter-rater reliability of the PDAI (k = 0.440) and mPDAI (k = 0.389) was reported in a single study. Responsiveness of the PDAI pre-antibiotic and postantibiotic treatment was partially evaluated in a single study of 12 patients. CONCLUSIONS: Development and validation of a specific pouchitis disease activity index is needed given that existing instruments are not valid, reliable, or responsive.