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Mild hyperthermia (39-43°C) combined with re-irradiation improves complete response compared with re-irradiation alone in locoregional recurrent (LRR) breast cancer. Observational studies analyzing a dichotomized hyperthermia thermal dose (TD) parameter showed that higher hyperthermia TD was associated with better tumor response rate compared with a lower TD. Analyzing the TD-effect relationships utilizing a continuous TD parameter would be more powerful, but has not been done so far. We therefore investigated the effect of a continuous TD parameter on locoregional control (LRC) for predicting LRC in patients with LRR breast cancer treated with postoperative re-irradiation and hyperthermia. In this study, we retrospectively analyzed the data of 112 women with LRR breast cancer treated in 2010-2017 with postoperative re-irradiation 8x4Gy (n = 34) or 23x2Gy (n = 78), combined with 4-5 weekly hyperthermia sessions guided by invasive thermometry. Among possible parametrizations of CEM43 (cumulative equivalent minutes at 43°C), including the TD parameter based on time-temperature exposures, the logarithm of the session with the highest invasively measured dose CEM43T50 (median CEM43) was selected based on Weibull univariate and stepwise regression analyses. The best fitted locoregional control model was further analyzed under a Bayesian paradigm, assuming 3 informative priors (continuous highest CEM43T50, tumor location breast/chest wall and lymph node involvement). Twenty-four patients (21.4%) developed an infield recurrence; the median time to recurrence was 3.4 years (interquartile range (IQR) = 2.7–4.6 years). Median highest session CEM43T50 was 7.2 minutes (equivalent to a median temperature T50 of ∼40.5°C), with an IQR between 2.4–15.9 minutes. Continuous TD parameter analysis showed that a higher TD was significantly associated with an increasing LRC (P = 0.001). Univariate and multivariate Weibull regression analysis showed that over the continuous TD range a twofold increase of TD (equivalent to a ∼0.5°C temperature increase) was associated with a decrease of 47% (hazard ratio, 95% confidence interval (CI) 18%-84%) and 28% in hazard ratio for LRR (adjusted hazard ratio, 95% CI 4%-56%), respectively. Bayesian survival regressions lead to a range of comparable decreasing hazard ratios of recurrence when TD increased. These findings were robust under both an optimistic and a skeptic informative prior assumption on the effect of TD. Twofold increase of hyperthermia TD was associated with a significant increase in LRC over the continuous TD range during hyperthermia treatment and postoperative re-irradiation in LRR breast cancer. This result has implications for the importance of achieving excellent dose control during treatment delivery and suggests an Arrhenius-like therapeutic molecular hyperthermia effect in treatment with re-irradiation and hyperthermia. [ABSTRACT FROM AUTHOR]

Objectives: Corticosteroids are used to abort disease flares in PFAPA syndrome. We aimed to obtain a global overview of physicians' corticosteroid usage strategies and analyze the data in the literature regarding corticosteroid use in PFAPA syndrome., Methods: The JIR-CliPS PFAPA questionnaire included nine questions on corticosteroid use in addition to the demographic data questions. The survey was distributed via e-mail to potential respondents. The MEDLINE/PubMed and Scopus databases were searched systematically to extract the data regarding corticosteroid use in PFAPA syndrome., Results: From 47 countries, 144 physicians (F/M = 2.6; 67.4% pediatric rheumatologists) answered the survey. Most respondents (n = 133; 92.4%) prescribe corticosteroids in PFAPA flares. The most frequently prescribed corticosteroid was prednisolone (63.2%). The definition of response to corticosteroid was indicated as "response within 12 h" by the highest number of respondents (n = 61; 42.4%). When corticosteroids cause an increase in attack frequency, most (57.9%) consider another treatment if this causes a decrease in quality of life. Forty-four (30.6%) respondents were "routinely" prescribing corticosteroids to PFAPA patients, and this practice was more frequent among more experienced physicians (p< 0.001).We identified 46 articles in the literature describing 4564 PFAPA patients treated with corticosteroids. Prednisone was the most frequently preferred corticosteroid (48.2%). Response to corticosteroids was around 95%, although an increase in attack frequency was noted in almost 35% of the patients., Conclusion: Physicians frequently use corticosteroids for PFAPA in their routine clinical practice. Regarding treatment modification, the quality of life was a prominent consideration for physicians., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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.

We aimed to estimate the overall apparent prevalence, true prevalence, and the spatial, temporal, and test-specific burden of bovine tuberculosis in Bangladesh. PubMed, Web of Science, Scopus, Google Scholar, and BanglaJOL were searched for bovine tuberculosis publications in Bangladesh from 1 January 1970 to 23 June 2023. Of 142 articles screened, systematic review and meta-analysis were performed on 22 (15.5%) articles. The apparent estimated bovine tuberculosis prevalence was 7%. The apparent Bayesian pooled mean bovine tuberculosis prevalences based on caudal fold test and single intradermal comparative tuberculin test were 7.83% and 9.89%, respectively, and the true pooled mean prevalences were 10.39% and 10.48%, respectively. Targeted interventions are recommended for districts with higher prevalence to effectively reduce the bovine tuberculosis burden in those areas. Current diagnostic practices employed in Bangladesh may not accurately reflect the bovine tuberculosis burden. Our findings highlight the need for better diagnostic tools and supplemental testing methods to ensure accurate diagnosis and surveillance. Efforts should prioritize obtaining 'true' prevalence estimates corrected for misclassification bias, rather than relying solely on apparent prevalence. Underestimating the bovine tuberculosis burden could result in inadequate resource allocation and hinder the implementation of effective control measures.

Background & Methods: This paper describes a pilot application of the Epidemic Volatility Index (EVI) to data from the pulmonary clinic of the University Hospital of Thessaly, Greece, for monitoring respiratory infections, COVID-19, and flu cases. EVI, a simple and easily implemented early warning method based on the volatility of newly reported cases, exhibited consistent and stable performance in detecting new waves of epidemics. The study highlights the importance of implementing early warning tools to address the effects of epidemics, including containment of outbreaks, timely intervention strategies, and resource allocation within real-world clinical settings as part of a broader public health strategy., Results: The results presented in the figures demonstrate the association between successive early warnings and the onset of new waves, providing valuable insights for proactive decision-making. A web-based application enabling real-time monitoring and informed decision-making by healthcare professionals, public health officials, and policymakers was developed., Conclusions: This study emphasizes the significant role of early warning methods in managing epidemics and safeguarding public health. Future research may explore extensions and combinations of multiple warning systems for optimal outbreak interventions and application of the methods in the context of personalized medicine., Competing Interests: Declaration of Competing Interest The authors have no competing or any other interests that might be perceived to influence the results and/or discussion reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The pursuit of conclusive evidence related to an unanswered foreground (decision-making) question has been the driving factor behind multiple ongoing and planned randomized controlled trials as well as meta-analyses. However, a fundamental challenge lies in establishing robust methods for ascertaining whether a collection of synthesized trials has yielded a definitive answer to that foreground question through the process of meta-analysis. This article explores the evolution of methods that attempt to address this challenge. These methods have primarily focused on defining and measuring the sufficiency and stability of evidence within a meta-analytic context. Cumulative meta-analysis and trial sequential analysis are the tools currently used, but they both come with limitations and challenges. We further discuss methods aimed at evaluating the evolution of effects over time more directly, such as the recursive cumulative meta-analysis. The latter method can be considered a better alternative, as it serves to demonstrate whether there is a true underlying treatment effect to which the meta-analysis is converging. However, recursive cumulative meta-analysis falls short of a specific indicator that establishes whether convergence has been reached. We coin the term exit for a meta-analysis where convergence can be demonstrated. Developing methods to determine the exit status of a meta-analysis is the next priority in research synthesis methods, as it will indicate that the research journey has concluded on a particular foreground question with no expectation of a different result with the addition of future trials., Competing Interests: SARD is a member of the JBI Evidence Synthesis editorial advisory board, but was not involved in the editorial processing of this manuscript. The other authors declare no conflict of interest., (Copyright © 2024 JBI.)

Purpose: Clinical evidence is limited regarding palliative radiation therapy for relieving pancreatic cancer-related pain. We prospectively investigated pain response after short-course palliative radiation therapy in patients with moderate-to-severe pancreatic cancer-related pain., Methods and Materials: In this prospective phase 2 single center nonrandomized trial, 30 patients with moderate-to-severe pain (5-10, on a 0-10 scale) of pancreatic cancer refractory to pain medication, were treated with a short-course palliative radiation therapy; 24 Gy in 3 weekly fractions (2015-2018). Primary endpoint was defined as a clinically relevant average decrease of ≥2 points in pain severity, compared with baseline, within 7 weeks after the start of treatment. Secondary endpoint was global quality of life (QoL), with a clinically relevant increase of 5 to 10 points (0-100 scale). Pain severity reduction and QoL were assessed 9 times using the Brief Pain Inventory and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-PAL, respectively. Both outcomes were analyzed using joint modeling. In addition, acute toxicity based on clinician reporting and overall survival (OS) were assessed., Results: Overall, 29 of 30 patients (96.7%) received palliative radiation therapy. At baseline, the median oral morphine equivalent daily dose was 129.5 mg (range, 20.0-540.0 mg), which decreased to 75.0 mg (range, 15.0-360.0 mg) after radiation (P = .021). Pain decreased on average 3.15 points from baseline to 7 weeks (one-sided P = .045). Patients reported a clinically relevant mean pain severity reduction from 5.9 to 3.8 points (P = .011) during the first 3 weeks, which further decreased to 3.2 until week 11, ending at 3.4 (P = .006) in week 21 after the first radiation therapy fraction. Global QoL significantly improved from 50.5 to 60.8 during the follow-up period (P = .001). Grade 3 acute toxicity occurred in 3 patients and no grade 4 to 5 toxicity was observed. Median OS was 11.8 weeks, with a 13.3% 1-year actuarial OS rate., Conclusions: Short-course palliative radiation therapy for pancreatic cancer-related pain was associated with rapid, clinically relevant reduction in pain severity, and clinically relevant improvement in global QoL, with mostly mild toxicity., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This manuscript introduces the convergence Epidemic Volatility Index (cEVI), a modification of the recently introduced Epidemic Volatility Index (EVI), as an early warning tool for emerging epidemic waves. cEVI has a similar architectural structure as EVI, but with an optimization process inspired by a Geweke diagnostic-type test. Our approach triggers an early warning based on a comparison of the most recently available window of data samples and a window based on the previous time frame. Application of cEVI to data from the COVID-19 pandemic data revealed steady performance in predicting early, intermediate epidemic waves and retaining a warning during an epidemic wave. Furthermore, we present two basic combinations of EVI and cEVI: (1) their disjunction cEVI + that respectively identifies waves earlier than the original index, (2) their conjunction cEVI- that results in higher accuracy. Combination of multiple warning systems could potentially create a surveillance umbrella that would result in early implementation of optimal outbreak interventions., Competing Interests: None., (© 2023 The Authors.)

Background: Despite hypertrophic cardiomyopathy (HCM) being the most common inherited heart disease and conferring increased risk for heart failure (HF) and sudden cardiac death (SCD), risk assessment in HCM patients is still largely unresolved., Objectives: This study aims to synthesize and compare the prognostic impact of demographic, clinical, biochemical, and imaging findings in patients with HCM., Methods: The authors searched PubMed, Embase, and Cochrane Library for studies published from 1955 to November 2020, and the endpoints were: 1) all-cause death; 2) an arrhythmic endpoint including SCD, sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and 3) a composite endpoint including (1) or (2) plus hospitalization for HF or cardiac transplantation. The authors performed a pairwise meta-analysis obtaining the pooled estimate separately for the association between baseline variables and study endpoints. A random-effects network meta-analysis was subsequently used to comparatively assess the prognostic value of outcome associates., Results: A total of 112 studies with 58,732 HCM patients were included. Among others, increased brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, late gadolinium enhancement (LGE), positive genotype, impaired global longitudinal strain, and presence of apical aneurysm conferred increased risk for the composite endpoint. At network meta-analysis, LGE showed the highest prognostic value for all endpoints and was superior to all other associates except New York Heart Association functional class >class II. A multiparametric imaging-based model was superior in predicting the composite endpoint compared to a prespecified model based on conventional risk factors., Conclusions: This network meta-analysis supports the development of multiparametric risk prediction algorithms, including advanced imaging markers additively to conventional risk factors, for refined risk stratification in HCM. (Long-term prognosis of hypertrophic cardiomyopathy according to genetic, clinical, biochemical and imaging findings: a systemic review and meta-analysis; CRD42020185219)., Competing Interests: Funding Support and Author Disclosures Dr Georgiopoulos was supported by a training grant from the European Association of Cardiovascular Imaging (training grant 2021). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Difficult cannulation represents a common obstacle during endoscopic retrograde cholangiopancreatography (ERCP). We assessed the efficacy and adverse events of transpancreatic sphincterotomy (TPS), and investigated potential associated confounders., Methods: All patients referred to our department for ERCP during 2015-2020 were eligible if they had intact papilla and visceral anatomy. In addition to standard measures, TPS was combined with pancreatic stent placement. Apart from demographics, we retrieved data related to the indication, periampullary anatomy, necessity for TPS or fistulotomy, their outcomes and complications. Chi-square test was employed to investigate associations between TPS and independent variables. When significance was observed, the respective variables were inserted into a regression model., Results: A total of 1082 individual patients were eligible, with an equal female: male ratio and a mean age of 72.7±15.82 years. Seventy-three patients (6.7%) underwent TPS, with a 95.9% successful cannulation rate. Papilla morphology or regional diverticulum did not affect the decision to perform TPS, though it was significantly associated with malignant common bile duct (CBD) obstruction as the ERCP indication (P=0.001). Considering adverse events, TPS did not increase the incidence of post-ERCP pancreatitis (PEP), though it affected bleeding (P=0.005). Regression analysis revealed a protective role of TPS against PEP (risk ratio [RR] 0.015, 95% confidence interval [CI] 0.23-5.05; P<0.001), while the aforementioned risk of hemorrhage was attributed to previous precut attempts (RR 3.02, 95%CI 1.42-6.43; P=0.004)., Conclusion: TPS combined with pancreatic stenting is an effective and safe modality in difficult cannulation cases and could be the first-choice alternative in malignant CBD obstruction., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: The authors have declared that no competing interests exist.

Increased sizes and dysfunction of the left atrium have been related to adverse outcomes. 3D-echocardiography is more accurate than 2D-echocardiography in estimating LA volumes and ejection fraction. However, the use of 3DE for LA analysis is limited by the absence of established reference values. We performed a systematic review and meta-analysis to provide reference ranges of LA maximum and minimum volumes indexed for body surface area (LAVi max and LAVi min, respectively), and LA-EF assessed by 3DE in healthy adults. Data search was conducted from inception through September 15, 2021, using the following Medical Subject Heading terms: left atrial/atrium, three-dimensional/3D echocardiography. The study protocol was registered in the PROSPERO database (CRD42021252428). 15 studies including 4,226 healthy adults (51% males) and reporting 3DE values of LAVi max, LAVi min and LA-EF were selected. LAVi max, LAVi min and LA-EF mean and reference values were equal to 25.18 ml/m 2 (95% CI 23.10, 27.26), 11.10 ml/m 2 (10.01, 12.18) and 55.94% (51.92, 59.96), respectively. No influential studies were identified. Pooled estimates per age group- and sex were also estimated. By meta-regression analyses, we identified variability in LA volumes and LA-EF depending on participants' age, ethnicity and number of heart cycles at 3D multi-beat acquisition. At individual patient data analysis conducted on 374 subjects, a software effect on LA-EF was shown. This systematic review and meta-analysis provides reference values of LAVi max, LAVi min and LA-EF assessed by 3DE in healthy adults, encouraging 3DE evaluation of the LA evaluation in daily practice., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

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., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

Background Available evidence supports an association between atrial high-rate episode (AHRE) burden and thromboembolic risk, but the necessary extent and duration of AHREs to increase the thromboembolic risk remain to be defined. The aim of this systematic review and meta-analysis was to identify the thromboembolic risk associated with various AHRE thresholds. Methods and Results We searched PubMed and Scopus until January 9, 2020, for literature reporting AHRE duration and thromboembolic risk in patients with implantable electronic devices. The outcome assessed was stroke or systemic embolism. Risk estimates were reported as hazard ratio (HR) or relative risk alongside 95% CIs. We used the Paule-Mandel estimator, and heterogeneity was calculated with I 2 index. Among 27 studies including 61 919 patients, 23 studies reported rates according to the duration of the longest AHRE and 4 studies reported rates according to the cumulative day-level AHRE duration. In patients with cardiac implantable devices, AHREs lasting ≥30 seconds significantly increased the risk of stroke or systemic embolism (HR, 4.41; 95% CI, 2.32-8.39; I 2 , 5.5%), which remained consistent for the thresholds of 5 minutes and 6 and 24 hours. Patients with previous stroke or transient ischemic attack and AHREs lasting ≥2 minutes had a marginally increased risk of recurrent stroke or transient ischemic attack. The risk of stroke or systemic embolism was higher in patients with cumulative AHRE ≥24 hours compared with those of shorter duration or no AHRE (HR, 1.25; 95% CI, 1.04-1.52; I 2 , 0%). Conclusions This systematic review and meta-analysis suggests that single AHRE episodes ≥30 seconds and cumulative AHRE duration ≥24 hours are associated with increased risk of stroke or systemic embolism.

Background: Smoking has been consistently associated with increased cardiovascular risk in adults. Although exposure to tobacco products often starts in early life, evidence for the possible adverse effects on the cardiovascular system of the young is scarce. We sought to derive pooled estimates of smoking effects on indices of early vascular damage in children and adolescents., Design and Methods: We performed a systematic review and meta-analysis of clinical studies involving young individuals up to 21 years old that provided data on smoking exposure (active or passive) and flow-mediated dilatation, carotid to femoral pulse wave velocity and maximum carotid intima-media thickness. We employed three distinct methodologies of random-effects data synthesis, including the Sidik-Jonkman estimator, the Hartung and Knapp correction and a Bayesian method with a well-informed prior on the level of between-study variance., Results: In 12 studies and 5279 individuals in total, smoking exposure was related to deterioration in all three outcomes (mean adjusted flow-mediated dilatation decrease: -0.77%, 95% confidence interval -1.38--0.15, mean adjusted pulse wave velocity increase: 0.1 m/s, 95% confidence interval 0.02-0.17 and mean adjusted carotid intima-media thickness increase: 0.35 mm, 95% confidence interval 0.16-0.55, for the Sidik-Jonkman estimator). No difference was established between active and passive smoking on associations with arterial damage., Conclusions: Exposure to tobacco products is associated with subclinical vascular damage early in life, even from childhood. Public health initiatives should target these very young age groups to prevent early smoking exposure and associated arterial damage and its sequelae., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Sacubitril/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)., Methods: We 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., Results: There 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., Conclusions: Based 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 Number: PROSPERO ID 186351., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Radiofrequency catheter ablation remains the most effective management option for atrioventricular nodal reentry tachycardia (AVNRT). The risk of atrioventricular (AV) block requiring permanent pacemaker is substantial, but, currently, a reliable method to predict this complication is lacking., Methods: The electrophysiologic studies (EPS) and baseline characteristics of patients who underwent catheter ablation for the treatment of AVNRT were retrospectively analyzed to investigate predisposing factors for AV block after treatment. Patients were followed for AV block at one month and one year after hospital discharge., Results: Among 784 patients treated with catheter ablation for AVNRT between 1999 to 2019, 15 developed AV block. Patients with AV block were older (p = .001). Among the recorded EPS parameters, patients with AV block had significantly higher Atrial His interval (120 vs. 110 ms, p = .049), Wenckebach cycle length (WCL) (400 vs. 353 ms, p < .001) and tachycardia CL (400 vs. 387 ms, P = .01) during the ablation compared to their peers without AV block. Additionally, only WCL (OR = 1.1, 95% CI 1.02-1.19, p = .017) remained significant after adjustment for age, gender, ERP, AH interval, and HR. This association was confirmed by comparing patients with (n = 15) and without (n = 15) AV block using propensity score-matching. A WCL≥400ms was associated with a 4-fold higher incidence of AV block (4.79% vs. 1.25%)., Conclusion: Increased pre-procedural WCL was associated with a high risk for AV block after catheter ablation treatment for AVNRT. These findings suggest that this readily available EPS-derived parameter may be a novel marker of risk for severe complications in these patients., (© 2021 Wiley Periodicals LLC.)

In drug development programs, proof-of-concept Phase II clinical trials typically have a biomarker as a primary outcome, or an outcome that can be observed with relatively short follow-up. Subsequently, the Phase III clinical trials aim to demonstrate the treatment effect based on a clinical outcome that often needs a longer follow-up to be assessed. Early-phase outcomes or biomarkers are typically associated with late-phase outcomes and they are often included in Phase III trials. The decision to proceed to Phase III development is based on analysis of the early-Phase II outcome data. In rare diseases, it is likely that only one Phase II trial and one Phase III trial are available. In such cases and before drug marketing authorization requests, positive results of the early-phase outcome of Phase II trials are then likely seen as supporting (or even replicating) positive Phase III results on the late-phase outcome, without a formal retrospective combined assessment and without accounting for between-study differences. We used double-regression modeling applied to the Phase II and Phase III results to numerically mimic this informal retrospective assessment. We provide an analytical solution for the bias and mean square error of the overall effect that leads to a corrected double-regression. We further propose a flexible Bayesian double-regression approach that minimizes the bias by accounting for between-study differences via discounting the Phase II early-phase outcome when they are not in line with the Phase III biomarker outcome results. We illustrate all methods with an orphan drug example for Fabry disease., (© 2021 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

In rare diseases, typically only a small number of patients are available for a randomized clinical trial. Nevertheless, it is not uncommon that more than one study is performed to evaluate a (new) treatment. Scarcity of available evidence makes it particularly valuable to pool the data in a meta-analysis. When the primary outcome is binary, the small sample sizes increase the chance of observing zero events. The frequentist random-effects model is known to induce bias and to result in improper interval estimation of the overall treatment effect in a meta-analysis with zero events. Bayesian hierarchical modeling could be a promising alternative. Bayesian models are known for being sensitive to the choice of prior distributions for between-study variance (heterogeneity) in sparse settings. In a rare disease setting, only limited data will be available to base the prior on, therefore, robustness of estimation is desirable. We performed an extensive and diverse simulation study, aiming to provide practitioners with advice on the choice of a sufficiently robust prior distribution shape for the heterogeneity parameter. Our results show that priors that place some concentrated mass on small τ values but do not restrict the density for example, the Uniform(-10, 10) heterogeneity prior on the log(τ 2 ) scale, show robust 95% coverage combined with less overestimation of the overall treatment effect, across varying degrees of heterogeneity. We illustrate the results with meta-analyzes of a few small trials., (© 2020 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Objective: To compare the efficacy and safety of oral anticoagulants vs antiplatelets in patients with stroke and atherosclerotic plaques in the aortic arch or cervical or intracranial arteries, collectively described as supracardiac atherosclerosis., Methods: We searched PubMed and Scopus until August 28, 2019, for randomized trials comparing oral anticoagulants vs antiplatelets in patients with stroke and supracardiac atherosclerosis using the terms "anticoagulant or anticoagulation" and "antiplatelet or aspirin" and "randomized controlled trial or RCT" and "stroke or cerebral ischemia" and "aortic or carotid or vertebrobasilar or intracranial or atherosclerosis or stenosis or arterial." Four outcomes were assessed: recurrent ischemic stroke, major ischemic event or death, major bleeding, and intracranial bleeding. Treatment effects (relative risk [RR] and 95% confidence interval [CI]) were estimated by meta-analysis using random-effects models., Results: Among 1,117 articles identified in the literature search, results from 10 randomized controlled trials involving 6,068 patients with stroke/TIA with supracardiac atherosclerosis were included in the meta-analysis. Recurrent ischemic stroke rates were 2.94 per 100 patient-years in the anticoagulant-assigned patients vs 3.30 per 100 patient-years in the antiplatelet-assigned patients (RR, 0.91; 95% CI, 0.70-1.18 for the SJ estimator, I 2 = 26%). Major ischemic event or death rates were 4.39 per 100 patient-years in anticoagulant-assigned patients vs 4.32 in antiplatelet-assigned patients (RR, 1.03; 95% CI, 0.79-1.35; I 2 = 54.5%). Major bleeding rates were 2.88 per 100 patient-years in anticoagulant-assigned patients vs 0.82 in antiplatelet-assigned patients (RR, 3.21; 95% CI, 1.96-5.24; I 2 = 46%)., Conclusion: This systematic review and meta-analysis showed that anticoagulant-assigned patients with stroke and supracardiac atherosclerosis were not at different risk of ischemic stroke recurrence and increased risk of major bleeding compared to antiplatelet-assigned patients., (© 2020 American Academy of Neurology.)

Aim: To investigate the associations of blood pressure variability (BPV), expressed as long-term (visit-to-visit) and short-term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all-cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension-mediated organ damage (HMOD) in adult patients with type 2 diabetes., Materials and Methods: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit-to-visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all-cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta-analysis and meta-regression., Results: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all-cause mortality (HR 1.12, 95% CI 1.04-1.21), MACEs (HR 1.01, 95% CI 1.04-1.17), extended MACEs (HR 1.07, 95% CI 1.03-1.11) and MiCs (HR 1. 12, 95% CI 1.01-1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long-term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima-media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels., Conclusions: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes., (© 2019 John Wiley & Sons Ltd.)

Background and Purpose- It is unclear whether treatment with anticoagulants or antiplatelets is the optimal strategy in patients with stroke or transient ischemic attack of undetermined cause and patent foramen ovale that is not percutaneously closed. We aimed to perform a systematic review and meta-analysis of randomized controlled trials to compare anticoagulant or antiplatelet treatment in this population. Methods- We searched PubMed until July 16, 2019 for trials comparing anticoagulants and antiplatelet treatment in patients with stroke/transient ischemic attack and medically treated patent foramen ovale using the terms: "cryptogenic or embolic stroke of undetermined source" and "stroke or cerebrovascular accident or transient ischemic attack" and "patent foramen ovale or patent foramen ovale or paradoxical embolism" and "trial or study" and "antithrombotic or anticoagulant or antiplatelet." The outcomes assessed were stroke recurrence, major bleeding, and the composite end point of stroke recurrence or major bleeding. We used 3 random-effects models: (1) a reference model based on the inverse variance method with the Sidik and Jonkman heterogeneity estimator; (2) a strict model, implementing the Hartung and Knapp method; and (3) a commonly used Bayesian model with a prior that assumes moderate to large between-study variance. Results- Among 112 articles identified in the literature search, 5 randomized controlled trials were included in the meta-analysis (1720 patients, mean follow-up 2.3±0.5 years). Stroke recurrence occurred at a rate of 1.73 per 100 patient-years in anticoagulant-assigned patients and 2.39 in antiplatelet-assigned patients (hazard ratio, 0.68; 95% CI, 0.32-1.48 for the Sidik and Jonkman estimator). Major bleeding occurred at a rate of 1.16 per 100 patient-years in anticoagulant-assigned patients and 0.68 in antiplatelet-assigned patients (hazard ratio, 1.61; 95% CI, 0.72-3.59 for the Sidik and Jonkman estimator). The composite outcome occurred in 52 anticoagulant-assigned and 54 antiplatelet-assigned patients (odds ratio, 1.05; 95% CI, 0.65-1.70 for the Sidik and Jonkman estimator). Conclusions- We cannot exclude a large reduction of stroke recurrence in anticoagulant-assigned patients compared with antiplatelet-assigned, without significant differences in major bleeding. An adequately powered randomized controlled trial of a non-vitamin K antagonist versus aspirin is warranted.

Objectives: To investigate the implications of addressing informative missing binary outcome data (MOD) on network meta-analysis (NMA) estimates while applying the missing at random (MAR) assumption under different prior structures of the missingness parameter., Methods: In three motivating examples, we compared six different prior structures of the informative missingness odds ratio (IMOR) parameter in logarithmic scale under pattern-mixture and selection models. Then, we simulated 1000 triangle networks of two-arm trials assuming informative MOD related to interventions. We extended the Bayesian random-effects NMA model for binary outcomes and node-splitting approach to incorporate these 12 models in total. With interval plots, we illustrated the posterior distribution of log OR, common between-trial variance (τ 2 ), inconsistency factor and probability of being best per intervention under each model., Results: All models gave similar point estimates for all NMA estimates regardless of simulation scenario. For moderate and large MOD, intervention-specific prior structure of log IMOR led to larger posterior standard deviation of log ORs compared to trial-specific and common-within-network prior structures. Hierarchical prior structure led to slightly more precise τ 2 compared to identical prior structure, particularly for moderate inconsistency and large MOD. Pattern-mixture and selection models agreed for all NMA estimates., Conclusions: Analyzing informative MOD assuming MAR with different prior structures of log IMOR affected mainly the precision of NMA estimates. Reviewers should decide in advance on the prior structure of log IMOR that best aligns with the condition and interventions investigated., (© 2019 John Wiley & Sons, Ltd.)

Background: The link between adiposity, metabolic abnormalities, and arterial disease progression in children and adolescents remains poorly defined. We aimed to assess whether persistent high adiposity levels are associated with increased arterial stiffness in adolescence and any mediation effects by common metabolic risk factors., Methods: We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had detailed adiposity measurements between the ages 9-17 years and arterial stiffness (carotid to femoral pulse wave velocity [PWV]) measured at age 17 years. Body-mass index (BMI) and waist-to-height ratio were calculated from weight, height, and waist circumference measurements whereas fat mass was assessed using repeated dual-energy x-ray absorptiometry (DEXA) scans. We used total and trunk fat mass indices (FMIs) to classify participants as normal (<75th percentile) or high (>75th percentile) FMI. We classified participants as being metabolically unhealthy if they had three or more of the following risk factors: high levels of systolic blood pressure, triglycerides, or glucose (all >75th percentile) or low levels of high-density lipoprotein (<25th percentile). We used multivariable linear regression analysis to assess the relationship between PWV and exposure to adiposity, and tested for linear trend of PVW levels across ordinal groups. We used latent class growth mixture modelling analysis to assess the effect of longitudinal changes in adiposity indices through adolescence on arterial stiffness., Findings: We studied 3423 participants (1866 [54·5%] female and 1557 [45·5%] male). Total fat mass was positively associated with PWV at age 17 years (0·004 m/s per kg, 95% CI 0·001-0·006; p=0·0081). Persistently high total FMI and trunk FMI between ages 9 and 17 years were related to greater PWV (0·15 m/s per kg/m 2 , 0·05-0·24; p=0·0044 and 0·15 m/s per kg/m 2 , 0·06-0·25; p=0·0021) compared with lower FMI. Metabolic abnormalities amplified the adverse effect of high total FMI on arterial stiffness (PWV 6·0 m/s [95% CI 5·9-6·0] for metabolically healthy participants and 6·2 m/s [5·9-6·4] for metabolically unhealthy participants). Participants who restored normal total FMI in adolescence (PWV 5·8 m/s [5·7-5·9] for metabolically healthy and 5·9 m/s [5·6-6·1] for metabolically unhealthy) had comparable PWV to those who had normal FMI throughout (5·7 m/s [5·7-5·8] for metabolically healthy and 5·9 m/s [5·8-5·9] for metabolically unhealthy)., Interpretation: Persistently high fat mass during adolescence was associated with greater arterial stiffness and was further aggravated by an unfavourable metabolic profile. Reverting to normal FMI in adolescence was associated with normal PWV, suggesting adolescence as an important period for interventions to tackle obesity in the young to maximise long-term vascular health., Funding: UK Medical Research Council, Wellcome Trust, British Heart Foundation, and AFA Insurances., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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.