Racial Disparities in Infliximab Efficacy for Ulcerative Colitis: Evidence Synthesis and Effect Modification Assessment.

An increasing amount of research explores the role of race in clinical phenotypes and outcomes in ulcerative colitis (UC). We aimed to investigate racial differences in infliximab (IFX) treatment efficacy in UC. We used aggregate data from IFX trials and evidence synthesis methods to generate race-specific efficacy estimates. Then, we tested the effect modification by race by comparing the race-specific estimates derived from independent evidence syntheses. We computed ratios of relative risks (RRRs) and performed tests of statistical interaction. We analyzed data from five randomized, placebo-controlled trials evaluating IFX as induction and maintenance therapy for adults with moderate-to-severe UC (875 participants; 45% Asians). We found no substantial evidence of racial differences concerning the efficacy of IFX in inducing clinical response (RRR = 0.89, 95% CI: 0.66-1.20; p = 0.44), clinical remission (RRR = 0.58, 95% CI: 0.24-1.44; p = 0.24), and mucosal healing (RRR = 0.99, 95% CI: 0.69-1.41; p = 0.95), or maintaining clinical remission (RRR = 0.81, 95% CI: 0.46-1.42; p = 0.45) and mucosal healing (RRR = 0.84, 95% CI: 0.48-1.46; p = 0.53), between Asian and Caucasian populations. Future clinical studies should expand the participation of racial minorities to comprehensively assess potential racial differences in the effectiveness of advanced therapies, including IFX, in the context of treating UC.

Assessment of hemostatic profile in neonates with necrotizing enterocolitis using Rotational Thromboelastometry (ROTEM).

BACKGROUND: This study aimed to explore the hemostatic profile of neonates with necrotizing enterocolitis (NEC) using Rotational Thromboelastometry (ROTEM) and to investigate if ROTEM parameters have the capacity to play a role in the differentiation of NEC from sepsis at the disease onset. METHODS: This observational study included 62 neonates (mean gestational age 31.6 weeks and mean birth weight 1620g) hospitalized in a neonatal intensive care unit. The neonates were categorized in three groups: neonates with NEC (Bell stage II and above), neonates with sepsis and healthy neonates and they were matched 1:1:1 with regards to gestational age, delivery mode, and sex. Clinical, laboratory data as well as measurements of ROTEM parameters at disease onset were recorded. RESULTS: ROTEM parameters differed between neonates with NEC and neonates with sepsis, indicating that NEC results in accelerated clot formation and higher clot strength compared to sepsis. The EXTEM CFT and A10 parameters demonstrated the highest diagnostic performance for NEC in terms of discrimination between NEC and sepsis (AUC, 0.997; 95% CI: 0.991-1.000 and 0.973; 95% CI: 0.932-1.000, respectively). CONCLUSIONS: Neonates with NEC manifested accelerated clot formation and higher clot strength compared to septic and healthy neonates, as these were expressed by ROTEM parameters. IMPACT: This work reports data on the hemostatic profile of neonates with necrotizing enterocolitis (NEC) using Rotational Thromboelastometry (ROTEM) and the capacity of ROTEM parameters in differentiating of NEC from sepsis at the disease onset. Neonates with NEC present acceleration of coagulation and exhibit a hypercoagulable profile, as this is expressed by ROTEM parameters, in comparison to septic and healthy neonates. ROTEM parameters demonstrated a good diagnostic capacity in differentiating NEC from sepsis at the disease onset.

Diverticular Inflammation and Complication Assessment classification, CODA score and fecal calprotectin in clinical assessment of patients with diverticular disease: A decision curve analysis.

BACKGROUND AND AIMS: The Diverticular Inflammation and Complication Assessment (DICA) classification and the Combined Overview on Diverticular Assessment (CODA) were found to be effective in predicting the outcomes of Diverticular Disease (DD). We ascertain whether fecal calprotectin (FC) can further aid in improving risk stratification. METHODS: A three-year international, multicentre, prospective cohort study was conducted involving 43 Gastroenterology and Endoscopy centres. Survival methods for censored observations were used to estimate the risk of acute diverticulitis (AD) in newly diagnosed DD patients according to basal FC, DICA, and CODA. The net benefit of management strategies based on DICA, CODA and FC in addition to CODA was assessed with decision curve analysis, which incorporates the harms and benefits of using a prognostic model for clinical decisions. RESULTS: At the first diagnosis of diverticulosis/DD, 871 participants underwent FC measurement. FC was associated with the risk of AD at 3 years (HR per each base 10 logarithm increase: 3.29; 95% confidence interval, 2.13-5.10) and showed moderate discrimination (c-statistic: 0.685; 0.614-0.756). DICA and CODA were more accurate predictors of AD than FC. However, FC showed high discrimination capacity to predict AD at 3 months, which was not maintained at longer follow-up times. The decision curve analysis comparing the combination of FC and CODA with CODA alone did not clearly indicate a larger net benefit of one strategy over the other. CONCLUSIONS: FC measurement could be used as a complementary tool to assess the immediate risk of AD. In all other cases, treatment strategies based on the CODA score alone should be recommended.

GRADE guidance 35: update on rating imprecision for assessing contextualized certainty of evidence and making decisions.

OBJECTIVES: Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance to rate the certainty domain of imprecision is presently not fully operationalized for rating down by two levels and when different baseline risk or uncertainty in these risks are considered. In addition, there are scenarios in which lowering the certainty of evidence by three levels for imprecision is more appropriate than lowering it by two levels. In this article, we conceptualize and operationalize rating down for imprecision by one, two and three levels for imprecision using the contextualized GRADE approaches and making decisions. METHODS: Through iterative discussions and refinement in online meetings and through email communication, we developed draft guidance to rating the certainty of evidence down by up to three levels based on examples. The lead authors revised the approach according to the feedback and the comments received during these meetings and developed GRADE guidance for how to apply it. We presented a summary of the results to all attendees of the GRADE Working Group meeting for feedback in October 2021 (approximately 80 people) where the approach was formally approved. RESULTS: This guidance provides GRADE's novel approach for the considerations about rating down for imprecision by one, two and three levels based on serious, very serious and extremely serious concerns. The approach includes identifying or defining thresholds for health outcomes that correspond to trivial or none, small, moderate or large effects and using them to rate imprecision. It facilitates the use of evidence to decision frameworks and also provides guidance for how to address imprecision about implausible large effects and trivial or no effects using the concept of the 'review information size' and for varying baseline risks. The approach is illustrated using practical examples, an online calculator and graphical displays and can be applied to dichotomous and continuous outcomes. CONCLUSION: In this GRADE guidance article, we provide updated guidance for how to rate imprecision using the partially and fully contextualized GRADE approaches for making recommendations or decisions, considering alternate baseline risks and for both dichotomous and continuous outcomes.

Assessment of agreement between EXTEM and NATEM thromboelastometry measurement assays in critically ill neonates.

OBJECTIVES: To investigate the agreement between the EXTEM and NATEM measurements. METHODS: In this retrospective observational study, EXTEM and NATEM analyses were performed on blood samples from 162 ill neonates, providing 324 paired measurements. The agreement between EXTEM and NATEM measurements was evaluated by the nonparametric spearman's rank correlation to assess the correlation between the paired measurements, by the Bland-Altman analysis for the graphical presentation of the agreement, and by the Deming regression model to assess the significance of the agreement. The agreement between the two methods for the detection of bleeding events was determined by kappa statistic. RESULTS: Strong correlations were found between EXTEM and NATEM measurements for A10, MCF. The Bland-Altman plots showed good agreement for A10, MCF, LI60, and alpha angle parameters, while CT showed a nearly linear slope indicating that bias increased with the mean. The highest agreement for bleeding events was found for the A10 parameter (κ = 0.70, p < .001), while the lowest for the CT parameter (κ = 0.36, p = .94). CONCLUSIONS: NATEM parameters that reflect clot firmness and fibrinolytic activity are strongly correlated with the corresponding EXTEM measurements with a good agreement between them, indicating that these two methods could be used interchangeably.

Effect of early application of social distancing interventions on COVID-19 mortality over the first pandemic wave: An analysis of longitudinal data from 37 countries.

OBJECTIVES: To estimate the effect of early application of social distancing interventions on Covid-19 cumulative mortality during the first pandemic wave. METHODS: Ecological longitudinal study using multivariable negative binomial regression for panel data. Daily numbers of Covid-19 cases and deaths, and data on social distancing interventions, for the 37 member countries of the Organization for Economic Cooperation and Development (OECD) were analysed. RESULTS: Covid-19 cumulative mortality over the first pandemic wave varied widely across countries (range, 4.16 to 855 deaths per million population). On average, one-day delay in application of mass gatherings ban was associated with an adjusted increase in Covid-19 cumulative mortality by 6.97% (95% CI, 3.45 to 10.5), whilst a one-day delay in school closures was associated with an increase of 4.37% (95% CI, 1.58 to 7.17) over the study period. We estimated that if each country had enacted both interventions one week earlier, Covid-19 cumulative mortality could have been reduced by an average of 44.1% (95% CI, 20.2 to 67.9). CONCLUSIONS: Early application of mass gatherings ban and school closures in outbreak epicentres was associated with an important reduction in Covid-19 cumulative mortality during the first pandemic wave. These findings may support policy decision making.

Inflammatory bowel disease: estimates from the global burden of disease 2017 study.

BACKGROUND: Inflammatory bowel disease (IBD) is a significant health problem in the industrialised world, currently increasing in developing countries. Understanding the global burden of IBD is important to tackle increasing disease occurrence. AIM: To investigate the GBD (Global Burden of Disease) 2017 Study Database summarising and critically evaluating the global burden of IBD METHODS: We presented age-standardised prevalence estimates, disability-adjusted life years (DALYs) and its components: years lived with disability (YLDs) and years of life lost (YLLs) due to premature mortality. We reported these measures from 1990 to 2017 and stratified by region, socio-demographic index (SDI), gender and age group. RESULTS: The latest IBD prevalence and burden estimates varied widely across regions, and were particularly elevated in high-SDI countries. Despite an increasing prevalence from 1990 to 2017 (+6%), the IBD burden decreased (DALYs -12%). This decrease was driven by IBD-associated premature mortality (YLLs -26%). This measure represented a high share of disease burden in low-SDI countries (86% of DALYs), whereas disability constituted the predominant component in high-SDI countries (71%) in 2017. Disease burden decreased particularly in children (DALYs -39% and YLLs -52%). In the last 10 years, however, prevalence plateaued in middle- to high-SDI countries and steeply increased in low-SDI countries. CONCLUSIONS: These findings highlight significant improvements in IBD care in the last three decades, particularly in children. The global burden of IBD and premature mortality have progressively decreased. The increase in disease frequency observed in developing countries is worrying, especially considering the high associated premature mortality in these areas.

Environmental, Nutritional, and Socioeconomic Determinants of IBD Incidence: A Global Ecological Study.

BACKGROUND AND AIMS: The wide variation in inflammatory bowel disease [IBD] incidence across countries entails an opportunity to recognise global disease determinants and hypothesise preventive policies. METHODS: We fitted multivariable models to identify putative environmental, nutritional, and socioeconomic determinants associated with the incidence of IBD (i.e. ulcerative colitis [UC] and Crohn's disease [CD]). We used the latest available country-specific incidence rates, and aggregate data for 20 determinants, from over 50 countries accounting for more than half of the global population. We presented the associations with exponentiated beta coefficients (exp[ß]) indicating the relative increase of disease incidence per unit increase in the predictor variables. RESULTS: Country-specific incidence estimates demonstrate wide variability across the world, with a median of 4.8 new UC cases (interquartile range [IQR] 2.4-9.3), and 3.5 new CD cases [IQR 0.8-5.7] per 100 000 population per year. Latitude (exp[ß] 1.05, 95% confidence interval [CI] 1.04‒1.06, per degree increase), prevalence of obesity [1.05, 1.02‒1.07, per 1% increase], and of tobacco smoking [0.97, 0.95‒0.99, per 1% increase] explained 71.5% of UC incidence variation across countries in the adjusted analysis. The model for CD included latitude [1.04, 1.02‒1.06], expenditure for health (1.03, 1.01‒1.05, per 100 purchasing power parity [PPP]/year per capita increase), and physical inactivity prevalence [1.03, 1.00‒1.06, per 1% increase], explaining 58.3% of incidence variation across countries. Besides expenditure for health, these associations were consistent in low/middle- and high-income countries. CONCLUSIONS: Our analysis highlights factors able to explain a substantial portion of incidence variation across countries. Further high-quality research is warranted to develop global strategies for IBD prevention.

Comparative assessment of budesonide-MMX and mesalamine in active, mild-to-moderate ulcerative colitis: A systematic review and network meta-analysis.

AIMS: The comparative efficacy, safety and tolerability of budesonide-MMX and oral mesalamine in active, mild-to-moderate ulcerative colitis (UC) are unclear. We conducted a network meta-analysis to fill this evidence gap. METHODS: We searched PubMed, Scopus, Embase, the Cochrane Library, clinical trial registries, regulatory agencies' websites and international conference proceedings, up to July 2018, to identify randomized controlled trials of adult patients with active, mild-to-moderate UC, comparing budesonide-MMX or mesalamine against placebo, or against each other, or different dosing strategies, for induction of remission. Two reviewers independently abstracted study data and outcomes, and assessed each trial's risk-of-bias. RESULTS: We identified and synthesized evidence from 15 eligible trials including 4083 participants. Budesonide-MMX 9 mg/day and mesalamine >2.4 g/day had similar efficacy for induction of clinical and endoscopic remission (OR = 0.97; 0.59-1.60), both showing superiority over placebo (OR = 2.68; 1.75-4.10, and OR = 2.75; 1.94-3.90, respectively). Furthermore, mesalamine >2.4 g/day was more efficacious than mesalamine 1.6-2.4 g/day (odds ratio = 1.27; 1.03-1.56). Secondary analyses showed that mesalamine >2.4 g/day ranks at the top among comparator treatments regarding safety (serious adverse events; surface under the cumulative ranking area [SUCRA] 79.2%) and tolerability (treatment discontinuations or withdrawals from the study due to adverse events; SUCRA 96.7%). There was no evidence of inconsistency, while heterogeneity between studies and risk of publication bias were low. CONCLUSION: Budesonide-MMX and mesalamine >2.4 g/day had similar efficacy for induction of clinical and endoscopic remission in active, mild-to-moderate UC; however, mesalamine >2.4 g/day showed better tolerability. Further high-quality research is warranted.

Antibiotic and anti-asthmatic drug prescriptions in Italy: geographic patterns and socio-economic determinants at the district level.

PURPOSE: To analyse the prevalence rate of antibiotics and anti-asthmatics in children and adolescents at the healthcare district level. METHODS: Data sources were three regional prescription databases. A total of 175 healthcare districts (3.3 million children/adolescents) participated in the study, providing data for the year 2008. Prevalence rate was standardised by age. The ANOVA test was used to compare prevalence rates of districts in the three regions. The standardised prevalence ratio (SPR) was calculated for each district and a map of the index was elaborated. The correlation among latitude, average annual income per inhabitant, hospitalisation rate, number of paediatricians per 1,000 resident children and prevalence rate was evaluated by district (Spearman's test). RESULTS: The antibiotic prevalence rate was, on average, 47.9 % (34.0 to 67.9 % between districts), while the anti-asthmatic prevalence was 21.4 % (11.7-35.6 %). The prevalence was higher in districts from the southern regions (antibiotics F = 92.1, anti-asthmatics F = 107.5; p < 0.001). There was a significant correlation between the prevalence of antibiotics and anti-asthmatics (rS = 0.77 p < 0.001), and the prevalence of both was inversely related to latitude (respectively rS = -0.71, -0.72; p < 0.001) and average income (rS = -0.77, -0.73; p < 0.001). Children/adolescents living in districts in the lower quintile of average income were more exposed to antibiotic (OR = 1.75; 1.74-1.77) and anti-asthmatic (OR 1.56, 1.55-1.57) prescriptions. CONCLUSIONS: A lower income at the district level is related to higher antibiotic and anti-asthmatic drug prescription rates. Local socio-economic inequities can concur in prescribing distribution and must be considered when planning educational interventions to reduce over-prescription.