An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials

Background & Aims: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. Methods: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. Results: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. Conclusions: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Manejo de residuos sólidos en el distrito de Chicche - provincia de Huancayo Departamento de Junín año 2016-2018

El presente Proyecto de Investigación Aplicada (PIA), identifica el problema que es la Inadecuada Gestión Integral de los Residuos Sólidos de la Municipalidad de Distrital de Chicche, a partir de ello se desarrolla un análisis comparativo entre la realidad actual de la generación y gestión de residuos sólidos en el Distrito de Chicche Provincia de Huancayo y la situación ideal que se plantea con la aplicación del presente Plan de Gestión. Para precisar dichos escenarios, se ha realizado el diagnóstico organizacional utilizando la metodología del análisis interno, identificando las brechas existentes a nivel institucional, enfatizado en los subsistemas razón de ser, tecnológico, estructural, psicosocial y de gestión; así como la metodología del análisis del entorno inmediato, intermedio y global de la Municipalidad Distrital de Chicche. Se ha formulado como Objetivo General del presente Trabajo de Investigación “Mejorar la Gestión Integral de Residuos Sólidos Municipales en el Distrito de Chicche -Provincia de Huancayo departamento de Junín del año 2016-2018”, y objetivos específicos como: a) Fomentar una cultura de conservación ambiental implementando estrategias de educación y sensibilización en temas de gestión ambiental y manejo adecuado de residuos sólidos. b) Fortalecer la gestión municipal a través del desarrollo de capacidades en temas de gestión ambiental. c) Fortalecer la institucionalidad municipal promoviendo la interacción institucional, las alianzas estratégicas y la convergencia de esfuerzos en la gestión de los residuos sólidos. Para lograr el objetivo general se propone el Producto: Programa para el manejo de residuos sólidos y los sub productos: a) Educación y Sensibilización Ambiental. b) Fortalecimiento de la gestión ambiental municipal. c) Fortalecimiento institucional, con estos sub producto se alcanzarán los objetivos específicos, tomando como referencia Planes de Gestión similares de otras localidades del país, así como de otros países de la región; así mismo, la consecución de dichos objetivos en los próximos años se verá reflejados en productos. Para la implementación del Plan de Gestión para el manejo de residuos sólidos se ha planteado metas a 3 años considerando los recursos humanos, logístico, financieros y tiempo. La importancia que tiene todo plan de gestión es el monitoreo para el cumplimiento de los objetivos a través de los productos, el monitoreo es constante y su medición se realiza con indicadores propuestos. Se ha analizado y demostrado la factibilidad de los productos elaborados para la ejecución del presente Plan de Gestión, para lo cual se ha desarrollado el método del Sistema de Análisis y Desarrollo de la Capacidad Institucional (SADCI) donde no se han identificado puntos críticos por lo que no se propone un plan de contingencia, también se desarrolló el método de Matriz de Alianzas y Conflictos: Tácticas, Objetivos y Recomendaciones (MACTOR), donde los actores no comprometen el plan de manejo de residuos sólidos y así mismo están de acuerdo con los objetivos propuestos a excepción de los ciudadanos que no están de acuerdo con el cobro por concepto de limpieza pública. Para revertir esta posición se plantea un plan de incidencia. Se ha desarrollado el análisis gerencial enriquecido con otros autores y experiencias, enfatizado a los objetivos propuestos y la pertinencia de los productos propuestos para lograrlos. Finalmente, alcanzamos las conclusiones y recomendaciones resaltando la importancia de la implementación del Plan de Manejo de los Residuos Sólidos por la Municipalidad Distrital de Chicche, por los beneficios en la salud y en el medio ambiente contribuyendo a una mejor calidad de vida de la població

Manejo de residuos sólidos en el distrito de Chicche - provincia de Huancayo Departamento de Junín año 2016-2018

Trabajo de investigaciónEl presente Proyecto de Investigación Aplicada (PIA), identifica el problema que es la Inadecuada Gestión Integral de los Residuos Sólidos de la Municipalidad de Distrital de Chicche, a partir de ello se desarrolla un análisis comparativo entre la realidad actual de la generación y gestión de residuos sólidos en el Distrito de Chicche Provincia de Huancayo y la situación ideal que se plantea con la aplicación del presente Plan de Gestión. Para precisar dichos escenarios, se ha realizado el diagnóstico organizacional utilizando la metodología del análisis interno, identificando las brechas existentes a nivel institucional, enfatizado en los subsistemas razón de ser, tecnológico, estructural, psicosocial y de gestión; así como la metodología del análisis del entorno inmediato, intermedio y global de la Municipalidad Distrital de Chicche. Se ha formulado como Objetivo General del presente Trabajo de Investigación “Mejorar la Gestión Integral de Residuos Sólidos Municipales en el Distrito de Chicche -Provincia de Huancayo departamento de Junín del año 2016-2018”, y objetivos específicos como: a) Fomentar una cultura de conservación ambiental implementando estrategias de educación y sensibilización en temas de gestión ambiental y manejo adecuado de residuos sólidos. b) Fortalecer la gestión municipal a través del desarrollo de capacidades en temas de gestión ambiental. c) Fortalecer la institucionalidad municipal promoviendo la interacción institucional, las alianzas estratégicas y la convergencia de esfuerzos en la gestión de los residuos sólidos. Para lograr el objetivo general se propone el Producto: Programa para el manejo de residuos sólidos y los sub productos: a) Educación y Sensibilización Ambiental. b) Fortalecimiento de la gestión ambiental municipal. c) Fortalecimiento institucional, con estos sub producto se alcanzarán los objetivos específicos, tomando como referencia Planes de Gestión similares de otras localidades del país, así como de otros países de la región; así mismo, la consecución de dichos objetivos en los próximos años se verá reflejados en productos. Para la implementación del Plan de Gestión para el manejo de residuos sólidos se ha planteado metas a 3 años considerando los recursos humanos, logístico, financieros y tiempo. La importancia que tiene todo plan de gestión es el monitoreo para el cumplimiento de los objetivos a través de los productos, el monitoreo es constante y su medición se realiza con indicadores propuestos. Se ha analizado y demostrado la factibilidad de los productos elaborados para la ejecución del presente Plan de Gestión, para lo cual se ha desarrollado el método del Sistema de Análisis y Desarrollo de la Capacidad Institucional (SADCI) donde no se han identificado puntos críticos por lo que no se propone un plan de contingencia, también se desarrolló el método de Matriz de Alianzas y Conflictos: Tácticas, Objetivos y Recomendaciones (MACTOR), donde los actores no comprometen el plan de manejo de residuos sólidos y así mismo están de acuerdo con los objetivos propuestos a excepción de los ciudadanos que no están de acuerdo con el cobro por concepto de limpieza pública. Para revertir esta posición se plantea un plan de incidencia. Se ha desarrollado el análisis gerencial enriquecido con otros autores y experiencias, enfatizado a los objetivos propuestos y la pertinencia de los productos propuestos para lograrlos. Finalmente, alcanzamos las conclusiones y recomendaciones resaltando la importancia de la implementación del Plan de Manejo de los Residuos Sólidos por la Municipalidad Distrital de Chicche, por los beneficios en la salud y en el medio ambiente contribuyendo a una mejor calidad de vida de la població

Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis

International audienceBackground Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease. Methods We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (>= 18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values. Findings The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4.53 [95% CI 1.49-13.79]), infliximab combined with azathioprine (7.49 [2.04-27.49]), adalimumab (3.01 [1.25-7.27]), and ustekinumab (2.63 [1.10-6.28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3.76 [1.01-14.03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2.82 [95% CI 1.20-6.62]; low confidence), and risankizumab (2.10 [1.12-3.92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias. Interpretation Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission. Copyright (C) 2021 Elsevier Ltd. All rights reserved

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

Clinical, Endoscopic, and Safety Placebo Rates in Induction and Maintenance Trials of Crohn's Disease: Meta-Analysis of Randomised Controlled Trials

BACKGROUND: Precision in estimating placebo rates is important for clinical trial design. AIM: To quantify placebo rates across relevant endpoints in Crohn's disease [CD] trials and identify the factors influencing these rates in a contemporary meta-analysis. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from inception to March 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for CD. Placebo response and remission rates for induction and maintenance trials were extracted and pooled by random-effects to quantify placebo rates across studies. Mixed-effects meta-regression was used to evaluate the effects of study-level characteristics on placebo rates. RESULTS: In 125 studies [91 induction, 46 maintenance], placebo clinical remission and response rates for induction studies were 18% (95% confidence interval [CI] 16, 21%], and 32% [95% CI 29, 35%], respectively, and for maintenance studies were 28% [95% CI 23, 34%] and 30% [95% CI 24, 37%], respectively. Endoscopic remission and response rates in induction studies were 8% [95% CI 4, 18%] and 16% [95% CI 11, 23%], respectively. Trials enrolling patients with prior biologic exposure, longer disease duration, and higher CD activity index scores were associated with lower placebo clinical remission rates. Increased duration of follow-up, more follow-up visits, and a greater proportion of patients with colonic disease distribution were associated with higher clinical placebo rates. CONCLUSIONS: Placebo remission and response rates in CD trials vary according to the phase of the trial, endpoint assessed, and induction or maintenance design. These contemporary estimates will help to inform future CD trial design

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