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Early warning tools are crucial for the timely application of intervention strategies and the mitigation of the adverse health, social and economic effects associated with outbreaks of epidemic potential such as COVID-19. This paper introduces, the Epidemic Volatility Index (EVI), a new, conceptually simple, early warning tool for oncoming epidemic waves. EVI is based on the volatility of newly reported cases per unit of time, ideally per day, and issues an early warning when the volatility change rate exceeds a threshold. Data on the daily confirmed cases of COVID-19 are used to demonstrate the use of EVI. Results from the COVID-19 epidemic in Italy and New York State are presented here, based on the number of confirmed cases of COVID-19, from January 22, 2020, until April 13, 2021. Live daily updated predictions for all world countries and each of the United States of America are publicly available online. For Italy, the overall sensitivity for EVI was 0.82 (95% Confidence Intervals: 0.75; 0.89) and the specificity was 0.91 (0.88; 0.94). For New York, the corresponding values were 0.55 (0.47; 0.64) and 0.88 (0.84; 0.91). Consecutive issuance of early warnings is a strong indicator of main epidemic waves in any country or state. EVI’s application to data from the current COVID-19 pandemic revealed a consistent and stable performance in terms of detecting new waves. The application of EVI to other epidemics and syndromic surveillance tasks in combination with existing early warning systems will enhance our ability to act swiftly and thereby enhance containment of outbreaks.

Background Tests have false positive or false negative results, which, if not properly accounted for, may provide misleading apparent prevalence estimates based on the observed rate of positive tests and not the true disease prevalence estimates. Methods to estimate the true prevalence of disease, adjusting for the sensitivity and the specificity of the diagnostic tests are available and can be applied, though, such procedures can be cumbersome to researchers with or without a solid statistical background. This manuscript introduces a web-based application that integrates statistical methods for Bayesian inference of true disease prevalence based on prior elicitation for the accuracy of the diagnostic tests. This tool allows practitioners to simultaneously analyse and visualize results while using interactive sliders and output prior/posterior plots. Methods - implementation Three methods for prevalence prior elicitation and four core families of Bayesian methods have been combined and incorporated in this web tool. | tPRiors | user interface has been developed with R and Shiny and may be freely accessed on-line. Results | tPRiors | allows researchers to use preloaded data or upload their own datasets and perform analysis on either single or multiple population groups clusters, allowing, if needed, for excess zero prevalence. The final report is exported in raw parts either as.rdata or.png files and can be further analysed. We utilize a real multiple-population and a toy single-population dataset to demonstrate the robustness and capabilities of | tPRiors |. Conclusions We expect | tPRiors | to be helpful for researchers interested in true disease prevalence estimation and who are keen on accounting for prior information. | tPRiors | acts both as a statistical tool and a simplified step-by-step statistical framework that facilitates the use of complex Bayesian methods. The application of | tPRiors | is expected to aid standardization of practices in the field of Bayesian modelling on subject and multiple group-based true prevalence estimation.

BackgroundSacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF).MethodsWe compared the treatment arms (sacubitril/valsartan, vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on vericiguat and the HFrEF subgroup of DECLARE-TIMI 58.ResultsThere was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat.ConclusionsBased on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to vericiguat.Registration NumberPROSPERO ID 186351.

Background: Biologic agents used in patients with inflammatory bowel diseases (IBD) may influence the pathophysiology of coexistent metabolic-dysfunction associated steatotic liver disease (MASLD). This study primarily aimed to evaluate the six-month effect of infliximab or vedolizumab vs. no biologics on presumed hepatic steatosis in patients with IBD. Secondary endpoints were their effect on hepatic fibrosis and parameters related to hepatic metabolism. Methods: This prospective, non-randomized, controlled trial assigned adult bio-naïve patients with IBD into three groups: infliximab, vedolizumab, or controls (receiving no biologic). The baseline was the time of the initiation of biologic agents and the endpoint six months later. Hepatic steatosis was evaluated with transabdominal ultrasonography (Hamaguchi score), whereas controlled attenuation parameter (CAP), fatty liver index (FLI), and hepatic steatosis index (HSI) were used as surrogates. Hepatic fibrosis was evaluated with liver stiffness (LS), fibrosis-4 index (FIB-4), and nonalcoholic fatty liver disease (NAFLD) fibrosis score. Results: Sixty-six patients were assigned to infliximab (n = 26), vedolizumab (n = 14), or control (n = 26); At the endpoint, the Hamaguchi score, CAP, FLI, and HSI were not different between groups. LS was not different between groups; however, FIB-4 was increased within all groups, and NAFLD fibrosis score was increased within infliximab and control groups, without significant biologic × time interactions. Conclusions: No positive or adverse effect of infliximab or vedolizumab vs. no biologic agents was shown on presumed hepatic steatosis in patients with IBD, who have not been previously exposed to biologic agents. Although no effect of both biologic agent on LS, a slight but significant increase in FIB-4 and NAFLD fibrosis score warrants further studying.

The study was aimed to estimate the true prevalence of human tuberculosis (TB); identify risk factors and clinical symptoms of TB; and detect rifampicin (RIF) sensitivity in three study areas of Bangladesh. The cross-sectional study was conducted in three Bangladesh districts during 2018. Potential risk factors, clinical symptoms, and comorbidities were collected from 684 TB suspects. Sputum specimens were examined by LED microscopy. TB hierarchical true prevalence, risk factors and clinical symptoms were estimated and identified using a Bayesian analysis framework. Rifampicin sensitivity of M. tuberculosis (MTB) was detected by GeneXpert MTB/RIF assay. The median TB true prevalence was 14.2% (3.8; 34.5). Although overall clustering of prevalence was not found, several DOTS centers were identified with high prevalence (22.3% to 43.7%). Risk factors for TB identified (odds ratio) were age (> 25 to 45 years 2.67 (1.09; 6.99), > 45 to 60 years 3.43 (1.38; 9.19) and individuals in families/neighborhoods where a TB patient(s) has (ve) already been present (12.31 (6.79; 22.60)). Fatigue, night sweat, fever and hemoptysis were identified as important clinical symptoms. Seven of the GeneXpert MTB/RIF positive sputum specimens (65) were resistant to rifampicin. About one in every seven TB suspects was affected with TB. A number of the TB patients carry multi drug resistant MTB. Hierarchical true prevalence estimation allowed identifying DOTS centers with high TB burden. Insights from this study will enable more efficient use of DOTScenters-based TB surveillance to end the TB epidemic in Bangladesh by 2035.

BackgroundAlthough colchicine is the mainstay of familial Mediterranean fever (FMF) treatment, 5–10% of patients are considered to have colchicine resistance (CR). However, there is no globally agreed CR definition or indications for biological disease-modifying anti-rheumatic drugs (bDMARDs).MethodsA survey on ‘Biologics in Monogenic Autoinflammatory Diseases’, part of the ‘Clinical Practice Strategies’ (CLiPS) initiative, was conducted by a JIR cohort-initiated eCOST network among expert participants worldwide. Our primary aim was to provide a flowchart reflecting the different CR definitions and present data regarding bDMARD indications. The secondary aim was to determine how specific biases influence clinical approaches. We analysed the CliPS according to the experience levels of physicians, country-specific FMF prevalence, countries’ gross domestic product, bDMARD availability and reimbursement policies of the countries.ResultsA total of 223 responses from 46 countries were included in the study. Almost half of the respondents (73/160, 45.6%) indicated that three to four attacks within the preceding 6 months were necessary for their CR definition. The most frequently used acute-phase reactant was C-reactive protein (157/164, 95.7%). Almost three-fourths of the respondents (74%, n=165) considered that supplementary factors, including complications of FMF, attack severity, elevated activity scores, patient-reported outcome and quality of life scales, influenced their CR definition.ConclusionWe present a novel flowchart describing physicians’ general attitudes and unique findings regarding management strategies for colchicine-resistant FMF and shifting trends influenced by epidemiological and socioeconomic factors.

Aims: The relationship between serum uric acid (SUA) and microvascular remodeling in humans remains largely unexplored. We assessed whether SUA provides additional information on the severity of microvascular remodeling than that obtained from the European Heart Score (HS), the patterns of microvascular remodeling associated with changes in SUA levels and the mediation by endothelial function and nitric oxide (NO) availability on this relationship. Methods: A total of 162 patients included in the microvascular dataset of the Italian Society of Hypertension with available information on SUA, media-to-lumen (M/L) ratio, media cross-sectional area (MCSA), endothelial function, NO availability and HS were included in the analysis. The top tertile of M/L ratio and MCSA were used to define severe microvascular remodeling. Results: A U-shaped association was observed between SUA and both M/L ratio and MCSA. Adjustment for HS did not affect these associations. SUA was able to reclassify a significant number of subjects without, and with, severe M/L ratio and MCSA remodeling over the HS alone. The microvascular remodeling associated with SUA levels presented a predominant hypertrophic pattern. SUA was inversely associated with endothelial function and NO availability. Structural equation modeling analysis controlling for the HS suggested that the association of SUA with M/L ratio and MCSA was mediated through changes in endothelial function and NO availability. Conclusions: The addition of SUA to the HS improves the identification of subjects with greater microvascular remodeling. The relationship between SUA and microvascular remodeling is mediated by endothelial function and NO availability.

Background The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. Methods The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were ‘innovative trial designs’ (six methods), ‘level of evidence’ (one method), ‘study endpoints and statistical analysis’ (four methods), and ‘meta-analysis’ (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. Results and discussion Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. Conclusion Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes.