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BACKGROUND: Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis. PURPOSE: To assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis. DATA SOURCES: MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources. STUDY SELECTION: Randomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis. DATA EXTRACTION: Primary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data by using a random-effects model, examined funnel plots, and explored heterogeneity by using meta-regression. DATA SYNTHESIS: Eighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, -0.37 [95% CI, -0.46 to -0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of -0.03 (CI, -0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of -0.11 (CI, -0.18 to -0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]). LIMITATIONS: Trial quality was generally low. Safety data were often not reported. CONCLUSION: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events. PRIMARY FUNDING SOURCE: Arco Foundation. [ABSTRACT FROM AUTHOR]

Background and Aims: Radiofrequency denervation (RF) of the lumbar facet joints has been shown to be effective in well-selected patients. However, long-term success varies between studies. We evaluated the influence of selected psychosocial and constitutional factors on the outcome of RF, expressed as the duration of pain relief.Methods: This prospective observational study included 44 patients who received RF denervations at the University Hospital of Berne. Success was defined as at least 50% pain reduction 7-21 days, 6 months and 1 year after RF therapy. The Cox-regression analysis was performed to evaluate the influence of the following factors on the duration of success: age, sex, depression, work inability and previous surgery.Results: Complete follow-up was available for 41 patients. The success rate 7-21 days after the denervation was 76%. It decreased to 32% at 6 months and to 22% at 1 year. The median success duration was 17 weeks (95% CI 10-26). The Cox-regression analysis showed a significant shorter duration of success for patients with depression (hazard ratio [HR] 2.97, 95% CI 1.32-6.65), previous surgery (HR 2.39, 95% CI 1.10-5.21) and number of treated joints (HR 1.95 for each increase in the number of joints, 95% CI 1.14-3.33). In bivariate analyses, only depression was kept to be significant.Conclusions: Depression seems to be related with a short duration of success. Based on these findings, a comprehensive study is warranted to evaluate whether psychosocial factors have to be considered when recruiting patients for radiofrequency denervation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the efficacy and safety of intraarticular hylan and 2 hyaluronic acids (HAs) in osteoarthritis (OA) of the knee. METHODS: This was a multicenter, patient-blind, randomized controlled trial in 660 patients with symptomatic knee OA. Patients were randomly assigned to receive 1 cycle of 3 intraarticular injections per knee of 1 of 3 preparations: a high molecular weight cross-linked hylan, a non-cross-linked medium molecular weight HA of avian origin, or a non-cross-linked low molecular weight HA of bacterial origin. The primary outcome measure was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 6 months. Secondary outcome measures included local adverse events (effusions or flares) in injected knees. During months 7-12, patients were offered a second cycle of viscosupplementation. RESULTS: Pain relief was similar in all 3 groups. The difference in changes between baseline and 6 months between hylan and the combined HAs was 0.1 on the WOMAC pain score (95% confidence interval [95% CI] -0.2, 0.3). No relevant differences were observed in any of the secondary efficacy outcomes, and stratified analyses provided no evidence for differences in effects across different patient groups. There was a trend toward more local adverse events in the hylan group than in the HA groups during the first cycle (difference 2.2% [95% CI -2.4, 6.7]), and this trend became more pronounced during the second cycle (difference 6.4% [95% CI 0.6, 12.2]). CONCLUSION: We found no evidence for a difference in efficacy between hylan and HAs. In view of its higher costs and potential for more local adverse events, we see no rationale for the continued use of hylan in patients with knee OA. [ABSTRACT FROM AUTHOR]

BACKGROUND: Randomized controlled trials (RCTs) reported conflicting results on the impact of high-dose chemotherapy (HDCT) and autologous stem cell transplantation in the first-line treatment of patients with aggressive non-Hodgkin lymphoma (NHL). METHODS: We performed a systematic meta-analysis to assess the efficacy HDCT compared to conventional chemotherapy in aggressive NHL patients with regard to complete response (CR), overall survival (OS), event-free survival (EFS), toxicity, and impact of the age-adjusted International Prognostic Index (aaIPI) risk factors. We searched the Cochrane Library, MEDLINE and other databases (1/1990 to 1/2005). Hazard ratio (HR), relative risks (RR) and 95% confidence intervals (CIs) were calculated using the fixed effect model. RESULTS: Fifteen RCTs including 2728 patients were identified. HDCT improved CR when compared to conventional chemotherapy (RR 1.11, CI 1.04-1.18). Overall, there was no evidence for HDCT to improve OS (HR 1.05, 95% CI 0.92-1.19) or EFS (HR 0.92, 95% CI 0.80-1.05) when compared with conventional chemotherapy. However, subgroup analysis indicated OS differences (p=0.032) between good (HR 1.46, 95% CI 1.02-2.09) and poor risk (HR 0.95, 95% CI 0.81-1.11) patients. Conflicting results were reported for poor risk patients, where some studies reported improved and others reduced OS and EFS after HDCT. CONCLUSION: There was no evidence that HDCT improved OS and EFS in good risk NHL patients. The evidence for poor risk patients is inconclusive. HDCT should not be further investigated in good risk patients with aggressive NHL but high quality studies in poor risk patients are warranted. [ABSTRACT FROM AUTHOR]

Abstract Background Bleeding is a frequent complication during surgery. The intraoperative administration of blood products, including packed red blood cells, platelets and fresh frozen plasma (FFP), is often live saving. Complications of blood transfusions contribute considerably to perioperative costs and blood product resources are limited. Consequently, strategies to optimize the decision to transfuse are needed. Bleeding during surgery is a dynamic process and may result in major blood loss and coagulopathy due to dilution and consumption. The indication for transfusion should be based on reliable coagulation studies. While hemoglobin levels and platelet counts are available within 15 minutes, standard coagulation studies require one hour. Therefore, the decision to administer FFP has to be made in the absence of any data. Point of care testing of prothrombin time ensures that one major parameter of coagulation is available in the operation theatre within minutes. It is fast, easy to perform, inexpensive and may enable physicians to rationally determine the need for FFP. Methods/Design The objective of the POC-OP trial is to determine the effectiveness of point of care prothrombin time testing to reduce the administration of FFP. It is a patient and assessor blind, single center randomized controlled parallel group trial in 220 patients aged between 18 and 90 years undergoing major surgery (any type, except cardiac surgery and liver transplantation) with an estimated blood loss during surgery exceeding 20% of the calculated total blood volume or a requirement of FFP according to the judgment of the physicians in charge. Patients are randomized to usual care plus point of care prothrombin time testing or usual care alone without point of care testing. The primary outcome is the relative risk to receive any FFP perioperatively. The inclusion of 110 patients per group will yield more than 80% power to detect a clinically relevant relative risk of 0.60 to receive FFP of the experimental as compared with the control group. Discussion Point of care prothrombin time testing in the operation theatre may reduce the administration of FFP considerably, which in turn may decrease costs and complications usually associated with the administration of blood products. Trial registration NCT00656396

Abstract Background The World Health Organization (WHO) has established a set of items related to study design and administrative information that should build the minimum set of data in a study register. A more comprehensive data set for registration is currently developed by the Ottawa Group. Since nothing is known about the attitudes of academic researchers towards prospective study registration, we surveyed academic researchers about their opinion regarding the registration of study details proposed by the WHO and the Ottawa Group. Methods This was a web-based survey of academic researchers currently running an investigator-initiated clinical study which is registered with clinicaltrials.gov. In July 2006 we contacted 1299 principal investigators of clinical studies by e-mail explaining the purpose of the survey and a link to access a 52-item questionnaire based on the proposed minimum data set by the Ottawa Group. Two reminder e-mails were sent each two weeks apart. Association between willingness to disclose study details and study phase was assessed using the chi-squared test for trend. To explore the potential influence of non-response bias we used logistic regression to assess associations between factors associated with non-response and the willingness to register study details. Results Overall response was low as only 282/1299 (22%) principal investigators participated in the survey. Disclosing study documents, in particular the study protocol and financial agreements, was found to be most problematic with only 31% of respondents willing to disclose these publicly. Consequently, only 34/282 (12%) agreed to disclose all details proposed by the Ottawa Group. Logistic regression indicated no association between characteristics of non-responders and willingness to disclose details. Conclusion Principal investigators of non-industry sponsored studies are reluctant to disclose all data items proposed by the Ottawa Group. Disclosing the study protocol and financial agreements was found to be most problematic. Future discussions on trial registration should not only focus on industry but also on academic researchers.

Abstract Background Postal surveys are a popular instrument for studies about continuing medical education habits. But little is known about the accuracy of responses in such surveys. The objective of this study was to quantify the magnitude of inaccurate responses in a postal survey among physicians. Methods A sub-analysis of a questionnaire about continuing medical education habits and information management was performed. The five variables used for the quantitative analysis are based on a question about the knowledge of a fictitious technical term and on inconsistencies in contingency tables of answers to logically connected questions. Results Response rate was 52%. Non-response bias is possible but seems not very likely since an association between demographic variables and inconsistent responses could not be found. About 10% of responses were inaccurate according to the definition. Conclusion It was shown that a sub-analysis of a questionnaire makes a quantification of inaccurate responses in postal surveys possible. This sub-analysis revealed that a notable portion of responses in a postal survey about continuing medical education habits and information management was inaccurate.

Background: The World Health Organization (WHO) has established a set of items related to study design and administrative information that should build the minimum set of data in a study register. A more comprehensive data set for registration is currently developed by the Ottawa Group. Since nothing is known about the attitudes of academic researchers towards prospective study registration, we surveyed academic researchers about their opinion regarding the registration of study details proposed by the WHO and the Ottawa Group.Methods: This was a web-based survey of academic researchers currently running an investigator-initiated clinical study which is registered with clinicaltrials.gov. In July 2006 we contacted 1299 principal investigators of clinical studies by e-mail explaining the purpose of the survey and a link to access a 52-item questionnaire based on the proposed minimum data set by the Ottawa Group. Two reminder e-mails were sent each two weeks apart. Association between willingness to disclose study details and study phase was assessed using the chi-squared test for trend. To explore the potential influence of non-response bias we used logistic regression to assess associations between factors associated with non-response and the willingness to register study details.Results: Overall response was low as only 282/1299 (22%) principal investigators participated in the survey. Disclosing study documents, in particular the study protocol and financial agreements, was found to be most problematic with only 31% of respondents willing to disclose these publicly. Consequently, only 34/282 (12%) agreed to disclose all details proposed by the Ottawa Group. Logistic regression indicated no association between characteristics of non-responders and willingness to disclose details.Conclusion: Principal investigators of non-industry sponsored studies are reluctant to disclose all data items proposed by the Ottawa Group. Disclosing the study protocol and financial agreements was found to be most problematic. Future discussions on trial registration should not only focus on industry but also on academic researchers. [ABSTRACT FROM AUTHOR]

The article discusses the factors considered in partner notification pertaining sexually transmitted infections (STI). In managing STI, it involved identifying sexual partner, informing them of their exposure to STI, evaluating the risk or treating them and providing advice on future prevention. With this, medical experts introduce a systematic review and examined the effectiveness of methods to improve partner notification by patient referral.

BACKGROUND The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear. METHODS We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days. RESULTS Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days. CONCLUSIONS In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.) [ABSTRACT FROM AUTHOR]

Objectives: Proton pump inhibitors (PPIs) are widely prescribed medications and commonly used for the treatment of gastric acid-related disorders. Nevertheless, PPIs are often overused leading to potential adverse effects and unnecessary healthcare costs. Deprescribing strategies have emerged to safely reduce or substitute inappropriate PPIs and optimise patient care in an evidence-based manner. This protocol describes a study to evaluate the effectiveness of a PPI deprescribing intervention in comparison to usual care in the Swiss primary care setting., Design: An open-label, cluster randomised controlled trial., Setting: Swiss primary care settings., Participants: Included participants will be adults with inappropriate PPI treatment and will be recruited by general practitioners (GPs). Participants treated by the same GP constitute a cluster. Clusters are randomised 1:1 to either the intervention group or the control group., Interventions: The intervention components consist of deprescribing tools including educational material, decision aids for both participants and GPs, and additional trainings for GPs only. Patients in the control group will receive usual care. Data will be collected at baseline, 3-, 6-, 9- and 12-month follow-up time through online surveys or a phone call for both GPs and participants., Primary and Secondary Outcome Measures: The first co-primary endpoint is the effectiveness of the deprescribing intervention measured by the change of prescribed PPI dose. The second co-primary endpoint is safety, which is measured with the Reflux Disease Questionnaire assessing change in gastrointestinal symptoms. There are several secondary endpoints, such as the total number of prescribed medications, occurrences of changes in prescription patterns, PPI discontinuation and cost-effectiveness., Conclusions: The findings from this study will provide evidence on the effectiveness and safety of a PPI deprescribing intervention for patients and GPs. Successful implementation of our PPI deprescribing strategy has the potential to improve patient outcomes and lower costs., Trial Registration Number: NCT06129474., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Importance: The net clinical effect of early vs later direct oral anticoagulant (DOAC) initiation after atrial fibrillation-associated ischemic stroke is unclear., Objective: To investigate whether early DOAC treatment is associated with a net clinical benefit (NCB)., Design, Setting, and Participants: This was a post hoc analysis of the Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation (ELAN) open-label randomized clinical trial conducted across 103 sites in 15 countries in Europe, the Middle East, and Asia between November 6, 2017, and September 12, 2022, with a 90-day follow-up. Participants included patients with atrial fibrillation-associated acute ischemic stroke, excluding those with therapeutic anticoagulation at stroke onset or with severe hemorrhagic transformation of the ischemic infarct., Intervention: Early DOAC initiation (<48 hours after minor and moderate stroke, 6-7 days after major stroke) vs later initiation (3-4 days after minor stroke, 6-7 days after moderate stroke, and 12-14 days after major stroke)., Main Outcomes and Measures: The main measure was the NCB of early treatment over later treatment, calculated by subtracting the weighted rate of excess bleeding events (major extracranial or intracranial hemorrhage) attributable to early treatment from the rate of excess ischemic events (recurrent stroke or systemic embolism) possibly prevented by early treatment within 30 days (main analysis) or 90 days (ancillary analysis). An established weighting scheme was used to account for the different clinical impact of bleeding relative to ischemic outcomes. Event rates were derived from adjusted logistic models. The analysis included all evaluable randomized ELAN participants., Results: Of the original 2013 ELAN participants, 1966 were eligible for analysis (977 [49.7%] assigned to early DOAC initiation, 989 [50.3%] assigned to later DOAC initiation; median [IQR] age 77 [70-84] years; 1075 [54.7%] male). The 30-day NCB of early treatment over later treatment ranged from 1.73 (95% CI, 0.06-3.40) to 1.72 (95% CI, -0.63 to 3.98) weighted events possibly prevented per 100 participants for intracranial hemorrhage weights 1.5 to 3.3. The 90-day NCB ranged from 2.16 (95% CI, 0.30-3.87) to 2.14 (95% CI, -0.26 to 4.41) weighted events per 100 participants., Conclusions and Relevance: This post hoc analysis of a randomized clinical trial estimated a sizeable NCB of early anticoagulation for patients after atrial fibrillation-associated ischemic stroke. Although estimates cannot exclude the possibility of no benefit or small net harm, the findings suggest that early treatment may be more favorable., Trial Registration: ClinicalTrials.gov Identifier: NCT03148457.

Efficacy of sodium-glucose cotransporter 2 inhibitors for kidney stone prevention in nondiabetic patients is unknown. In a double-blind, placebo-controlled, single-center, crossover phase 2 trial, 53 adults (≥18 and <75 years) with calcium (n = 28) or uric acid (UA; n = 25) kidney stones (at least one previous kidney stone event) without diabetes (HbA1c < 6.5%, no diabetes treatment) were randomized to once daily empagliflozin 25 mg followed by placebo or reverse (2 weeks per treatment). Randomization and analysis were performed separately for both stone types. Primary analyses were conducted in the per protocol set. Primary outcomes were urine relative supersaturation ratios (RSRs) for calcium oxalate (CaOx), calcium phosphate (CaP) and UA-validated surrogates for stone recurrence. Prespecified RSR reductions (≥15%) were met in both groups of stone formers. In patients with calcium stones, empagliflozin reduced RSR CaP (relative difference to placebo, -36%; 95% confidence interval, -48% to -21%; P < 0.001), but not RSRs CaOx and UA. In patients with UA stones, empagliflozin reduced RSR UA (-30%; 95% confidence interval, -44% to -12%; P = 0.002) but not RSRs CaOx and CaP. No serious or prespecified adverse events occurred. Thus, empagliflozin substantially reduced RSRs in nondiabetic adults with calcium and UA kidney stones. ClinicalTrials.gov registration: NCT04911660 ., Competing Interests: Competing interests: D.G.F. served as a consultant for Otsuka, Alnylam, Boehringer Ingelheim and Kyowa Kirin, and received unrestricted research grants from Otsuka, Boehringer Ingelheim and CSL Vifor. The other authors declare no competing interests., (© 2025. The Author(s).)

Excessive daytime sleepiness (EDS) and insomnia (IN) complaints represent the most common sleep/wake disorders. Currently, the specific needs of these patients and their relatives, as well as the overall socio-economic burden of IN and EDS remains widely unexplored. This pilot study to be carried out in Switzerland is a retro- and prospective, national, one-center cohort observational study for the systematic evaluation of the burden of EDS and IN and its evolution 12 months after the first assessment. Patient recruitment will be organized through 7-8 primary care providers (primary/general care practitioners and pharmacies). Primary outcomes are the prevalence of EDS/IN in the primary care setting and the association between EDS/IN with health-related quality of life (QOL) as assessed with the established instruments. Secondary outcomes are the association between EDS/IN with the presence of comorbidities, number of injuries/accidents, and number of sick/leave days for the subgroup of working subjects. Calculation of direct per-patient costs will be undertaken to analyze the economic implications of sleep/wake disorders, providing valuable insights into the financial burden experienced by affected individuals within the healthcare system. This research will provide information on the feasibility of such a study and inform on aspects of the QOL most associated with EDS/IN. Based on this pilot project, a European multicenter study on the burden of sleep/wake disorders will be conducted by the European Academy of Neurology.

Introduction: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS) is a national cohort that was established in 2015 with the aim of improving quality of care of affected adults with eosinophilic esophagitis (EoE). Between 2020 and 2022, paper questionnaires were gradually replaced by fully electronic data capture using Research Electronic Data Capture (REDCap ® ) software. We aim to provide an update of the SEECS 8 years after its launch., Methods: The SEECS prospectively includes adults (≥18 years of age) with EoE as well as patients with gastroesophageal reflux disease (GERD) and healthy control subjects (HC). Upon inclusion and follow-up (typically once every 12-18 months), patients and physicians complete REDCap ® questionnaires, which are available in German, French, and English. Patient-reported outcomes (PROs) and biologic findings are assessed on the same day using validated instruments (EEsAI PRO for symptoms; EoE-QoL-A for QoL; EREFS for endoscopic activity; modified EoE-HSS for histologic activity). The SEECS biobank includes biosamples from patients with EoE, GERD, and HC., Results: As of July 2023, the SEECS included 778 patients (716 [92%] with EoE, 29 [3.8%] with GERD, and 33 [4.2%] HC; 559/778 [71.9%] were male). Mean age ± SD (years) at enrollment according to diagnosis was as follows: EoE 41.9 ± 12.9, GERD 53.6 ± 16.4, HC 51.7 ± 17.2. Concomitant GERD was found in 200 patients (27.9%) of the EoE cohort. Concomitant allergic disorders (asthma, rhinoconjunctivitis, eczema) were present in 500 EoE patients (74.4%). At inclusion, 686 (95.8%) of EoE patients were on ongoing treatment (orodispersible budesonide tablet [Jorveza ® ] in 281 patients [41%]; budesonide or fluticasone syrup or swallowed powder in 290 patients [42.3%]; proton-pump inhibitors in 162 patients [23.6%]; elimination diets in 103 patients [15%]; and esophageal dilation at last visit in 166 patients [24.2%]). A total of 8,698 biosamples were collected, of which 1,395 (16%) were used in the framework of translational research projects., Conclusion: SEECS continuously grows and is operational using fully electronic data capture. SEECS offers up-to-date epidemiologic and real-world clinical efficacy data on EoE and promotes clinical and translational research., Competing Interests: Jeanine Wakim has no relevant financial, professional, or personal relationships to disclose. Ekaterina Safroneeva reports (i) consulting fees from Avir Pharma, Inc., Aptalis Pharma, Inc., Celgene Corp., Novartis, AG, and Regeneron Pharmaceuticals Inc.; (ii) being an employee of Tillotts Pharma AG. Catherine Saner has no relevant financial, professional, or personal relationships to disclose. Jean-Benoit Rossel has no relevant financial, professional, or personal relationships to disclose. Sven Trelle has no relevant financial, professional, or personal relationships to disclose. Marcel Zwahlen has no relevant financial, professional, or personal relationships to disclose. Luc Biedermann received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Andrea Kreienbuehl has no relevant financial, professional, or personal relationships to disclose. Thomas Greuter received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Philipp Schreiner received consulting fees and/or speaker fees from Dr. Falk Pharma, GmbH, Takeda, Regerenon-Sanofi Pharmaceuticals, AbbVie, Janssen-Cilag, Receptos-Celgene-BMS. Peter Netzer has no relevant financial, professional, or personal relationships to disclose. Annett Franke has no relevant financial, professional, or personal relationships to disclose. Stephan Brand has no relevant financial, professional, or personal relationships to disclose. Chantal Hasler has no relevant financial, professional, or personal relationships to disclose. Patrick Aepli has no relevant financial, professional, or personal relationships to disclose. Emanuel Burri has no relevant financial, professional, or personal relationships to disclose. Achim Weber has no relevant financial, professional, or personal relationships to disclose. Christine Sempoux has no relevant financial, professional, or personal relationships to disclose. Ruggero Biral has no relevant financial, professional, or personal relationships to disclose. Wolfram Jochum has no relevant financial, professional, or personal relationships to disclose. Joachim Diebold has no relevant financial, professional, or personal relationships to disclose. Niels Willi has no relevant financial, professional, or personal relationships to disclose. Alex Straumann received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Alain Schoepfer received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The decision to treat an incidental finding in an asymptomatic patient results from careful risk-benefit consideration and is often challenging. One of the main aspects is after how many years the group who underwent the intervention and faced the immediate treatment complications will gain a treatment benefit over the conservatively managed group, which maintains a lower but ongoing risk. We identify a common error in decision-making. We illustrate how a risk-based approach using the classical break-even point at the Kaplan-Meier curves can be misleading and advocate for using an outcome-based approach, counting the cumulative number of lost quality-adjusted life years instead. In clinical practice, we often add together the yearly risk of the natural course up to the time point where the number equals the risk of the intervention and assume that the patient will benefit from an intervention beyond this point in time. It corresponds to the crossing of the Kaplan-Meier curves. However, because treatment-related poor outcome occurs at the time of the intervention, while the poor outcome in the conservative group occurs over a given time period, the true benefit of retaining more quality-adjusted life years in the interventional group emerges at a much later time. To avoid overtreatment of patients with asymptomatic diseases, decision-making should be outcome-based with counting the cumulative loss of quality-adjusted life years, rather than risk-based, comparing the interventional risk with the ongoing yearly risk of the natural course., Competing Interests: Disclosures Dr Raabe receives funding from Carl Zeiss Meditec AG research grants and holds shares in LEM. Dr Fischer is an expert witness for Biogen and Boehringer Ingelheim. Dr Rothwell provides consultancy services for Abbott Vascular, Bayer, Bristol-Myers Squibb, and Sanofi US Services. Dr Gralla offers consultancy services for Johnson & Johnson and Medtronic. None of these affiliations pertain to the current work. The other authors report no conflicts.

Purpose of Review: Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are commonly prescribed to prevent the recurrence of kidney stones. This review offers a comprehensive up-to-date assessment of the evidence supporting the use of thiazides for kidney stone recurrence prevention, highlights potential harms associated with treatment, and identifies areas of knowledge that require further investigation., Recent Findings: The clinical routine to prescribe thiazides for kidney stone prevention has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50 mg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of recurrence. Yet, adverse events such as new onset diabetes mellitus and gout were more common in patients receiving hydrochlorothiazide compared to placebo. As demonstrated by a novel meta-analysis presented in this review encompassing all randomized placebo-controlled trials with thiazide monotherapy, current trial evidence does not indicate that thiazide monotherapy is significantly better than placebo in preventing kidney stone recurrence., Summary: Given the limited efficacy and possible adverse effects, we advocate for a restrictive use of thiazides for kidney stone recurrence prevention. Clearly, there remains a high unmet medical need for effective, targeted therapies to prevent recurrence of kidney stones., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines., Methods: Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process., Results: As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae/influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae/pneumococcus., Conclusions: The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VACCELERATE Consortium reports financial support was provided by European Union. VACCELERATE Consortium reports financial support was provided by Federal Ministry of Education and Research Bonn Office., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited., Methods: In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed., Results: In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo., Conclusions: Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Surgical care, which is performed by intensely interacting multidisciplinary teams of surgeons, anesthetists, and nurses, remains associated with significant morbidity and mortality. Intraoperative communication has been shown to be associated with surgical outcomes, but tools ensuring efficient intraoperative communication are lacking. In a previous study, we developed the StOP?-protocol that fosters structured intraoperative communication. Before the critical phases of the operation, the responsible surgeon initiates and leads one or several StOP?s. During a StOP?, the surgeon informs about the progress of the operation (status), next steps and proximal goals (objectives), and possible problems (problems) and encourages all team members to voice their observations and ask questions (?). In a before-after study performed mainly in visceral surgery, we found effects of the StOP?-protocol on mortality, length of hospital stay, and reoperation. We intend to assess the impact of the StOP?-protocol in a cluster randomized trial, in a wider variety of surgical specialties (i.e., general, visceral, thoracic, vascular surgery, surgical urology, and gynecology). The primary hypothesis is that the consistent use of the StOP?-protocol by the main surgeon reduces patient mortality within 30 days after the operation. The secondary hypothesis is that the consistent use of the StOP?-protocol by the main surgeon reduces unplanned reoperations, length of hospital stay, and unplanned hospital readmissions., Methods: This study is designed as a multicenter, cluster-randomized parallel-group trial. Board-certified surgeons of participating clinical departments will be randomized 1:1 to the StOP? intervention group or to the standard of care (control) group. The intervention group will undergo a training to use the StOP?-protocol and receive regular feedback on their compliance with the protocol. The surgeons in the control group will communicate as usual during their operations. The unit of observation will be operations performed by cluster surgeons. Consecutive patients will be enrolled over 4 months per cluster. A total of 400 surgeons will be recruited, and we expect to collect patient outcome data for 14,000 surgical procedures., Discussion: The StOP?-protocol was designed as a tool to structure communication during surgical procedures. Testing its effects on patient outcomes will contribute to implementing evidenced-based interventions to reduce surgical complications., Trial Registration: ClinicalTrials.gov NCT05356962. Registered on May 2, 2022., (© 2022. The Author(s).)

Background: Lichen sclerosus (LS) is a chronic inflammatory skin disease that mostly affects the anogenital region of women and lowers patients' quality of life. Current standard treatment of LS is topical steroids., Objective: To evaluate the efficacy of topical progesterone 8% ointment and compare to standard therapy with topical clobetasol propionate 0.05% in premenopausal women presenting with previously untreated early onset LS., Study Design: Randomized, double-blind, 2-arm, single center superiority trial in premenopausal women with histologically confirmed vulvar LS who were randomized in a 1:1 ratio to receive clobetasol propionate 0.05% ointment or progesterone 8% ointment. The primary outcome was the clinical severity LS score after 12 weeks, which consists of six clinical features assessed by the physician. Secondary outcomes were the symptom severity LS score, which consists of three symptoms rated by the patient, the Short Form SF-12 physical and mental health scores, and adverse events. Response to medication was assessed by biopsy at the end of the treatment to evaluate inflammatory parameters., Results: Overall, 105 women were screened, 102 underwent vulvar biopsy and 37 received a histologically confirmed diagnosis of LS and were randomized: 17 to progesterone and 20 to clobetasol propionate. At 12 weeks, the mean clinical LS scores improved from 4.6 (SD 2.0) to 4.5 (SD 1.7) in the progesterone arm, and from 4.6 (SD 2.8) to 2.9 (SD 2.2) in the clobetasol propionate arm (difference in favor of clobetasol 1.61; 95% CI 0.44 to 2.77, p = 0.009), and the mean symptom severity LS scores improved from 4.5 (SD 3.8) to 3.1 (SD 3.0) in the progesterone arm, and from 4.7 (SD 2.8) to 1.9 (SD 1.8) in the clobetasol propionate arm (difference in favor of clobetasol 1.32; 95% CI -0.25 to 2.89, p = 0.095). LS was in complete remission in 6 out of 10 patients (60%) with available biopsy in the progesterone arm, and in 13 out of 16 patients (81.3%) in the clobetasol propionate arm (odds ratio in favor of clobetasol 0.35; 95% CI 0.06 to 2.06, p = 0.234). No drug-related serious adverse event occurred during the trial., Conclusions: Topical progesterone 8% ointment is inferior to standard therapy with topical clobetasol propionate 0.05% in previously untreated premenopausal women with vulvar LS after 12 weeks treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Rituximab has improved response rates and overall survival in B-cell lymphoma (DLBCL). Radiotherapy is an effective treatment modality for lymphomas, but there is uncertainty on its use as consolidation after chemo-immunotherapy mainly in advanced stages. We evaluated its efficacy with a comprehensive meta-analysis and a systematic search of Pubmed, Embase, Cochrane, and abstracts from ASCO, ASH, ESMO and ASTRO published from June 1966 and December 2018. We identified 11 trials that evaluated consolidation radiotherapy following chemotherapy in a randomized fashion in 4'584 patients. The primary endpoint of this meta-analysis was PFS. As three of the eleven trials were retracted, this data is based on 2414 patients. For the primary endpoint (PFS), we found a hazard ratio (HR) of 0.77 (0.51 to 1.17, pooled (tau2: 0.25; I2: 85%), and a HR of 0.80 (0.53 to 1.21, pooled (bivariate meta-analysis). For overall survival, the HR is 0.93 (0.61 to 1.40; pooled (tau2: 0.25; I2: 74%) and 0.86 (0.58 to 1.27) in a bivariate meta-analysis. The lack of benefit did not change over time (p-value: 0.95 (tau2: 0.32; I2: 88%), and was also absent for PFS when stratifying for chemotherapy, the use of Rituximab, age, the dose of radiotherapy, application to patients in complete remission and with bulky disease. None of the trials used a PET-guided approach. This meta-analysis revealed no survival benefit when consolidation radiotherapy is given to unselected DLBCL patients following chemotherapy. These results need to be considered in future trials in the PET-CT era.

Background: Iodine-induced hyperthyroidism (IIH) was a common issue in the early twentieth century after introduction of iodine supplementation in dietary salt. Currently, IIH is mostly encountered in Western countries as a consequence of radiographic procedures involving the administration of iodinated contrast media (ICM). However, little is known about the magnitude and clinical relevance of this issue. To assess the incidence of hyperthyroidism after ICM exposure, we performed a systematic review and meta-analysis of the literature. Methods: MEDLINE, Embase, and the Cochrane Library were systematically searched for studies published between 1946 and May 2018. Studies were considered eligible if they investigated the association between hyperthyroidism and iodinated contrast. Data on study design, baseline characteristics, and outcomes were extracted independently by two reviewers. Results: Thirty out of 1493 retrieved studies were included in the analysis. The time endpoint to assess thyroid hormone levels after ICM exposure varied between 1 and 541 days among studies, with most studies having a time endpoint between 7 and 56 days. The overall estimated prevalence of overt hyperthyroidism after ICM exposure was extremely low (0.1% [confidence interval, CI 0-0.6%]), and did not change after adjustments for baseline thyroid function status (0.3% in euthyroid patients at baseline [CI 0-1.7%]). There were no cases with overt hyperthyroidism at 7 days after ICM exposure, and the incidence was very low at 30 days (0.2% [CI 0-0.8%]). Conclusion: The incidence of IIH after ICM administration during radiographic procedures is extremely low.

Background: International oncology societies recommend early palliative care. Specific models to integrate early palliative care efficiently into clinical practice are debated. The authors designed a study to look at the quantitative and qualitative outcomes of an early palliative care intervention in oncological care to decrease stress and improve quality of life., Aims: To compare a single structured early palliative care intervention added to a usual oncology care in terms of distress and health-related quality of life at baseline compared to 6 months after enrollment., Design: This multicenter randomized controlled trial (NCT01983956) enrolled adult patients with advanced cancer. Participants were either randomly assigned to usual oncology care alone or usual care plus a structured early palliative care intervention., Setting/participants: One hundred fifty adult patients with a variety of advanced cancer diagnoses were randomized. Seventy-four participants were in the intervention and 76 participants in the control group. The primary outcome was the change in patient distress assessed by the National Comprehensive Cancer Network distress thermometer at 6 months. Health-related quality of life, the secondary outcome, was assessed by the Functional Assessment of Cancer Therapy-General Questionnaire., Results: The results showed no significant effect of the early palliative care intervention neither on patient distress nor on health-related quality of life., Conclusion: The addition of an early intervention to usual care for patients with advanced cancer did not improve distress or quality of life. Thus, patients may need more intensive early palliative care with continuous professional support to identify and address their palliative needs early.

Background: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19)., Methods: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry., Results: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration., Conclusions: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)., (Copyright © 2020 Massachusetts Medical Society.)

Introduction: The SARS-CoV-2 pandemic has led to one of the most critical and boundless waves of publications in the history of modern science. The necessity to find and pursue relevant information and quantify its quality is broadly acknowledged. Modern information retrieval techniques combined with artificial intelligence (AI) appear as one of the key strategies for COVID-19 living evidence management. Nevertheless, most AI projects that retrieve COVID-19 literature still require manual tasks., Methods: In this context, we pre-sent a novel, automated search platform, called Risklick AI, which aims to automatically gather COVID-19 scientific evidence and enables scientists, policy makers, and healthcare professionals to find the most relevant information tailored to their question of interest in real time., Results: Here, we compare the capacity of Risklick AI to find COVID-19-related clinical trials and scientific publications in comparison with clinicaltrials.gov and PubMed in the field of pharmacology and clinical intervention., Discussion: The results demonstrate that Risklick AI is able to find COVID-19 references more effectively, both in terms of precision and recall, compared to the baseline platforms. Hence, Risklick AI could become a useful alternative assistant to scientists fighting the COVID-19 pandemic., (© 2021 S. Karger AG, Basel.)

Background: Over the last 20 years, diverse outcome measures have been used to evaluate the effectiveness of therapies for eosinophilic esophagitis (EoE). This systematic review aims to identify the readouts used in observational studies of topical corticosteroids, diet, and dilation in adult EoE patients., Methods: We searched MEDLINE and Embase for prospective and retrospective studies (cohorts/case series, randomized open-label, and case-control) evaluating the use of diets, dilation, and topical corticosteroids in adults with EoE. Two authors independently assessed the articles and extracted information about histologic, endoscopic, and patient-reported outcomes and tools used to assess treatment effects., Results: We included 69 studies that met inclusion criteria. EoE-associated endoscopic findings (assessed either as absence/presence or using Endoscopic Reference Score) were evaluated in 24/35, 11/17, and 9/17 studies of topical corticosteroids, diet, and dilation, respectively. Esophageal eosinophil density was recorded in 32/35, 17/17, and 11/17 studies of topical corticosteroids, diet, and dilation, respectively. Patient-reported outcomes were not uniformly used (only in 14, 8, and 3 studies of topical corticosteroids, diet, and dilation, respectively), and most tools were not validated for use in adults with EoE., Conclusions: Despite the lack of an agreed set of core outcomes that should be recorded and reported in studies in adult EoE patients, endoscopic EoE-associated findings and esophageal eosinophil density are commonly used to assess disease activity in observational studies. Standardization of outcomes and data supporting the use of outcomes are needed to facilitate interpretation of evidence, its synthesis, and comparisons of interventions in meta-analyses of therapeutic trials in adults with EoE., (© 2021 S. Karger AG, Basel.)

Background: Poor recruitment of patients is the predominant reason for early termination of randomized clinical trials (RCTs). Systematic empirical investigations and validation studies of existing recruitment models, however, are lacking. We aim to provide evidence-based guidance on how to predict and monitor recruitment of patients into RCTs. Our specific objectives are the following: (1) to establish a large sample of RCTs (target n = 300) with individual patient recruitment data from a large variety of RCTs, (2) to investigate participant recruitment patterns and study site recruitment patterns and their association with the overall recruitment process, (3) to investigate the validity of a freely available recruitment model, and (4) to develop a user-friendly tool to assist trial investigators in the planning and monitoring of the recruitment process., Methods: Eligible RCTs need to have completed the recruitment process, used a parallel group design, and investigated any healthcare intervention where participants had the free choice to participate. To establish the planned sample of RCTs, we will use our contacts to national and international RCT networks, clinical trial units, and individual trial investigators. From included RCTs, we will collect patient-level information (date of randomization), site-level information (date of trial site activation), and trial-level information (target sample size). We will examine recruitment patterns using recruitment trajectories and stratifications by RCT characteristics. We will investigate associations of early recruitment patterns with overall recruitment by correlation and multivariable regression. To examine the validity of a freely available Bayesian prediction model, we will compare model predictions to collected empirical data of included RCTs. Finally, we will user-test any promising tool using qualitative methods for further tool improvement., Discussion: This research will contribute to a better understanding of participant recruitment to RCTs, which could enhance efficiency and reduce the waste of resources in clinical research with a comprehensive, concerted, international effort.

Background and Aims: The treatment options for eosinophilic esophagitis (EoE) patients include drugs (proton pump inhibitors [PPIs], swallowed topical corticosteroids [STCs]), elimination diets, and dilation. Given the lack of data, we aimed to assess adult EoE patients' satisfaction with different EoE-specific treatment modalities., Patients and Methods: We evaluated therapy satisfaction recalled over a 12-month period using the validated Treatment Satisfaction Questionnaire for Medication that assesses effectiveness, side effects, convenience, and overall satisfaction. The score for each scale ranges from 0 (dissatisfied) to 100 (satisfied). To evaluate satisfaction with nonpharmacologic therapies, the questionnaire was modified and debriefed into three focus groups. The final questionnaire was sent to 147 patients., Results: The patient response rate was 74%. In the last 12 months, 24, 75, 19, and 9% were treated with PPIs, STCs, elimination diet, and dilation, respectively. Patients identified the following considerations as important for therapy choice: effect on symptoms (89%), effect on esophageal inflammation (76%), side effects (69%), and ease of use (58%). Patients found STCs to be effective (83 points), convenient (83 points), and experienced no side effects when using this therapy. When using STCs alone (43%), overall patient satisfaction was high (86 points). Patients judged PPIs to be most convenient (89 points), STCs to be a bit less convenient (83 points), and diet to be most inconvenient (46 points) of the three therapies examined., Conclusions: Adult EoE patients consider both therapy effect on symptoms and esophageal inflammation as important criteria when choosing EoE therapy and appear to be satisfied with STC use., (© 2019 S. Karger AG, Basel.)

Introduction: Clinical trial data management (DM) conducted during outbreaks like that of Ebola virus disease (EVD) in West Africa, 2014-2016, has to adapt to specific, unique circumstances. CTU Bern was asked to set up a safe data capture/management system that could be launched within a few weeks and cover two different vaccine trials. This article describes some of the challenges we faced and our solutions during the two different trials., Methods: Setting up a DM system was split into four phases/tasks: (1) quick set-up of the (electronic) data capture system (EDC) and mobile infrastructure in Bern, (2) moving the EDC and infrastructure to Conakry, Guinea and implementation of a local data management centre (DMC), (3) running the DMC, and (4) data cleaning. The DMC had to meet the following criteria: (1) quick implementation, (2) efficient maintenance and handling of data, and (3) procedures to guarantee data quality. The EDC (REDCap) was setup as a local area network. In order to ensure high data quality, double data entry, and then review of inconsistencies and offline plausibility checks were implemented., Results: From the start of CTU Bern's involvement to the productive EDC took 11 weeks. It was necessary to adapt processes for dealing with data continuously throughout the trial conduct phase. The data management team processed 171,794 case report form pages from a total of 14,203 participants in the period between March and December 2015., Conclusion: Data management is a key task supporting trial conduct. For trials in emergency situations, many of our approaches are suitable, but we also provide a list of aspects that might be done differently., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Evidence of the oncological benefit of scheduled follow-up in head and neck squamous cell carcinoma is weak; symptom-oriented self-referral may be an alternative. Patients' preferences regarding follow-up remain poorly investigated., Methods: We conducted a cross-sectional survey among patients undergoing follow-up at a tertiary outpatient clinic, focusing on their preferences, correlating factors, fear of recurrence, and willingness for participation in a randomized trial on follow-up., Results: Of 101 patients, 89.1% preferred scheduled follow-up to self-referral, 57% favored fewer visits than the current standard, and 85.1% endorsed regular imaging. Recurrence or second primary was associated with preference of intensive follow-up schedules (P = 0.02). There were trends for women and patients with high fear of recurrence score to favor intensive follow-up. Two-third of the participants declared willingness to participate in a randomized controlled trial., Conclusions: Patients' preferences only partially correspond to current follow-up guidelines. Recruitment for randomized controlled studies evaluating the value of follow-up seems feasible., (© 2019 Wiley Periodicals, Inc.)

In several areas of clinical research, it is common for trials to assign different sites of the participants' bodies to different interventions. For example, a randomized controlled trial comparing surgical techniques for correcting myopia may randomize each eye of a participant to a different operation. Under such bilateral ('split-body') interventions, the observations from each participant are correlated. It is challenging to account for these correlations at the meta-analysis level, especially when the outcome is rare. Here, we present a meta-analysis model based on the bivariate binomial distribution. Our model can synthesize studies on patients who received one intervention at one body site, patients who received two interventions at different sites or a mixture of these two groups. The model can analyse studies with zero events in one or both treatment arms and can handle the case of incomplete data reporting. We use simulations to assess the performance of our model and to compare it with the bivariate beta-binomial model. In the case of bilateral interventions, our model performed well and outperformed the bivariate beta-binomial model in all scenarios explored. We illustrate our methods using two previously published meta-analyses from the fields of orthopaedics and ophthalmology. We conclude that our model constitutes a useful new tool for the meta-analysis of binary outcomes in the presence of split-body interventions.

Background: 'Conditional trial design' is a framework for efficiently planning new clinical trials based on a network of relevant existing trials. The framework considers whether new trials are required and how the existing evidence can be used to answer the research question and plan future research. The potential of this approach has not been fully realized., Methods: We conducted an online survey among trial statisticians, methodologists, and users of evidence synthesis research using referral sampling to capture opinions about the conditional trial design framework and current practices among clinical researchers. The questions included in the survey were related to the decision of whether a meta-analysis answers the research question, the optimal way to synthesize available evidence, which relates to the acceptability of network meta-analysis, and the use of evidence synthesis in the planning of new studies., Results: In total, 76 researchers completed the survey. Two out of three survey participants (65%) were willing to possibly or definitely consider using evidence synthesis to design a future clinical trial and around half of the participants would give priority to such a trial design. The median rating of the frequency of using such a trial design was 0.41 on a scale from 0 (never) to 1 (always). Major barriers to adopting conditional trial design include the current regulatory paradigm and the policies of funding agencies and sponsors., Conclusions: Participants reported moderate interest in using evidence synthesis methods in the design of future trials. They indicated that a major paradigm shift is required before the use of network meta-analysis is regularly employed in the design of trials.

Introduction: Multimorbidity and polypharmacy are important risk factors for drug-related hospital admissions (DRAs). DRAs are often linked to prescribing problems (overprescribing and underprescribing), as well as non-adherence with drug regimens for different reasons. In this trial, we aim to assess whether a structured medication review compared with standard care can reduce DRAs in multimorbid older patients with polypharmacy., Methods and Analysis: OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people is a European multicentre, cluster randomised, controlled trial. Hospitalised patients ≥70 years with ≥3 chronic medical conditions and concurrent use of ≥5 chronic medications are included in the four participating study centres of Bern (Switzerland), Utrecht (The Netherlands), Brussels (Belgium) and Cork (Ireland). Patients treated by the same prescribing physician constitute a cluster, and clusters are randomised 1:1 to either standard care or Systematic Tool to Reduce Inappropriate Prescribing (STRIP) intervention with the help of a clinical decision support system, the STRIP Assistant. STRIP is a structured method performing customised medication reviews, based on Screening Tool of Older People's Prescriptions/Screening  Tool to Alert to Right Treatment criteria to detect potentially inappropriate prescribing. The primary endpoint is any DRA where the main reason or a contributory reason for the patient's admission is caused by overtreatment or undertreatment, and/or inappropriate treatment. Secondary endpoints include number of any hospitalisations, all-cause mortality, number of falls, quality of life, degree of polypharmacy, activities of daily living, patient's drug compliance, the number of significant drug-drug interactions, drug overuse and underuse and potentially inappropriate medication., Ethics and Dissemination: The local Ethics Committees in Switzerland, Ireland, The Netherlands and Belgium approved this trial protocol. We will publish the results of this trial in a peer-reviewed journal., Main Funding: European Union's Horizon 2020 programme., Trial Registration Number: NCT02986425 , SNCTP000002183 , NTR6012, U1111-1181-9400., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known., Methods: The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response., Discussion: The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support., Trial Registration: ClinicalTrials.gov, NCT03057431 . Registered on February 20 2017.