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Randomised controlled trials (RCTs) are considered the gold standard in clinical research. However, randomization isn't always feasible, e.g., due to ethical considerations. As a result, quasi-experimental designs, such as the regression-discontinuity design (RDD), have been advocated as valuable alternatives and are increasingly employed in health sciences. So far, however, there is no way to take repeated measures into account in an RDD analysis, although repeated measures are not uncommon in medical research. This article proposes an extension of the RDD methodology to incorporate repeated measures within the statistical analysis. The article introduces consistent mathematical notation for combining a univariate RDD with a linear mixed model (LMM) to account for repeated measures. The application is presented using data from the nFC-isPO (N = 1,417), where the Hospital Anxiety and Depression Scale (HADS) was employed to assess anxiety and depression in newly diagnosed cancer patients over a 12-month treatment period. The HADS scores were measured at baseline (T1), after 4 months (T2) and after 12 months (T3). Patients were assigned to control (psychosocial care) or treatment (psycho-oncological-psychotherapeutic care) group based on a predetermined HADS threshold at T1. The average treatment effect (ATE) was similar in both univariate RDD and LMM-RDD when applied to complete cases. Including all available data (T2 and/or T3), univariate RDD analyses were based on different samples for each time point. At T2, the ATE sign reversed from negative to positive, suggesting a change in discontinuity direction. At T3, the ATE magnitude nearly doubled compared to the complete case analysis. LMM-RDD estimated treatment effects were higher than those from univariate RDD. Nevertheless, none reached statistical significance. The time effect ([Formula: see text]), representing the difference in treatment effects between two time points (complete case: [Formula: see text]=0.577; T2 and/or T3 available: [Formula: see text]=0.491), was not significant (p = 0.855; 95%-CI: [-5.589; 6.743]; p = 0.869, 95%-CI: [-5.328; 6.310]). Extending the RDD to incorporate repeated measures within a linear mixed model (LMM-RDD) provides a more robust and comprehensive analytical approach when an RCT is not feasible. This approach not only addresses the challenges of missing data and an unbalanced number of outcome measures, but also allows for the identification of time-varying treatment effects that may not be discernible using traditional RDD. The study was registered in the German Clinical Trials Registry on 30 October 2018 under the ID \"DRKS00015326\".

More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis. Data was obtained after a systematic literature search from clinical trials that enrolled at least 6 patients. Individual patient data meta-analysis was performed by means of conditional logistic regression grouped by study. Twenty nine trials involving a total of 906 patients were identified in prostate cancer (17) and RCC (12). Objective response rates were 7.7% in prostate cancer and 12.7% in RCC. The combined percentages of objective responses and stable diseases (SD) amounted to a clinical benefit rate (CBR) of 54% in prostate cancer and 48% in RCC. Meta-analysis of individual patient data (n = 403) revealed the cellular immune response to have a significant influence on CBR, both in prostate cancer (OR 10.6, 95% CI 2.5-44.1) and in RCC (OR 8.4, 95% CI 1.3-53.0). Furthermore, DC dose was found to have a significant influence on CBR in both entities. Finally, for the larger cohort of prostate cancer patients, an influence of DC maturity and DC subtype (density enriched versus monocyte derived DC) as well as access to draining lymph nodes on clinical outcome could be demonstrated. As a 'proof of principle' a statistically significant effect of DC-mediated cellular immune response and of DC dose on CBR could be demonstrated. Further findings concerning vaccine composition, quality control, and the effect of DC maturation status are relevant for the immunological development of DC-based vaccines.

School-level infection control measures in Germany during the early Coronavirus Disease 2019 (COVID-19) pandemic differed across the 16 federal states and lacked a dependable evidence base, with available evidence limited to regional data restricted to short phases of the pandemic. This study aimed to assess the (a) infection risks in students and staff; (b) transmission risks and routes in schools; (c) effects of school-level infection control measures on school and population infection dynamics; and (d) contribution of contacts in schools to population cases. For this retrospective observational study, we used German federal state (NUTS-2) and county (NUTS-3) data from public health and education agencies from March 2020 to April 2022. We assessed (a) infection risk as cumulative risk and crude risk ratios and (b) secondary attack rates (SARs) with 95% confidence interval (CI). We used (c) multiple regression analysis for the effects of infection control measures such as reduced attendance, mask mandates, and vaccination coverage as absolute reduction in case incidence per 100,000 inhabitants per 14 days and in percentage relative to the population, and (d) infection dynamic modelling to determine the percentage contribution of school contacts to population cases. We included (a) nationwide NUTS-2 data from calendar weeks (W) 46-50/2020 and W08/2021-W15/2022 with 3,521,964 cases in students and 329,283 in teachers; (b) NUTS-3 data from W09-25/2021 with 85,788 student and 9,427 teacher cases; and (c) detailed data from 5 NUTS-3 regions from W09/2020 to W27/2021 with 12,814 cases (39% male, 37% female; median age 14, range 5 to 63), 43,238 contacts and 4,165 secondary cases for students (for teachers, 14,801 [22% male, 50% female; median age 39, range 16 to 75], 5,893 and 472). Infection risk (a) for students and teachers was higher than the population risk in all phases of normal presence class and highest in the early 2022 omicron wave with 30.6% (95% CI 30.5% to 32.6%) of students and 32.7% (95% CI 32.6% to 32.8%) of teachers infected in Germany. SARs (b) for students and staff were below 5% in schools throughout the study period, while SARs in households more than doubled from 13.8% (95% CI 10.6% to 17.6%) W21-39/2020 to 28.7% (95% CI 27% to 30.4%) in W08-23/2021 for students and 10.9% (95% CI 7% to 16.5%) to 32.7% (95% CI 28.2% to 37.6%) for staff. Most contacts were reported for schools, yet most secondary cases originated in households. In schools, staff predominantly infected staff. Mandatory surgical mask wearing during class in all schools was associated with a reduction in the case incidence of students and teachers (c), by 56/100,000 persons per 14 days (students: 95% CI 47.7 to 63.4; teachers: 95% CI 39.6 to 71.6; p < 0.001) and by 29.8% (95% CI 25% to 35%, p < 0.001) and 24.3% (95% CI 13% to 36%, p < 0.001) relative to the population, respectively, as were reduced attendance and higher vaccination coverage. The contribution of contacts in schools to population cases (d) was 2% to 20%, lowest during school closures/vacation and peaked during normal presence class intervals, with the overall peak early during the omicron wave. Limitations include underdetection, misclassification of contacts, interviewer/interviewee dependence of contact-tracing, and lack of individual-level confounding factors in aggregate data regression analysis. In this study, we observed that open schools under hygiene measures and testing strategies contributed up to 20% of population infections during the omicron wave early 2022, and as little as 2% during vacations/school closures; about a third of students and teachers were infected during the omicron wave in early 2022 in Germany. Mandatory mask wearing during class in all school types and reduced attendance models were associated with a reduced infection risk in schools.

The SARS-CoV-2 pandemic presented a challenge for caregiving relatives in the home care setting. Caregivers can transmit SARS-CoV-2 to their relatives who are often at high risk for a severe course of COVID-19. Regular testing of asymptomatic caregivers for SARS-CoV-2 may reduce the risk of transmission. The optimal method and frequency of regular asymptomatic testing is unknown. We conducted a prospective, randomised trial to assess the feasibility, recruitment and acceptance of different testing frequencies. This serves to inform a future definitive randomised controlled trial. We carried out a parallel three-armed feasibility trial, enrolling adult participants who provided home-based care for a relative at least twice a week. Participants were randomly assigned using sealed envelopes to either conduct saliva-based antigen self-testing at a frequency of once a week (group I), twice a week (group II), or every two days (group III). The participants completed questionnaires on a weekly basis. Main outcome measures were feasibility of recruitment, adherence to self-tests and distress caused by self-testing. We further collected data on the use of mouth-nose mask. From 25 March to 7 May 2021 we assessed 27 participants and randomised 26 in the study: 8 participants in group I, 8 in group II and 10 in group III. All participants completed the study. In group I 48/48 (100.0%; 95% CI 92.6% to 100.0%), in group II 93/96 (96.9%; 95% CI 91.2% to 98.9%) and in group III 209/210 (99.5%; 95% CI 97.4% to 99.9%) self-tests were carried out at home. Participants did not perceive regular self-testing as burdensome in any of the study arms. We did not observe any infection with SARS-CoV-2. During the study, mask adherence decreased from 35% to 19% in all groups. Conducting such a study was feasible. The participants tolerated regular self-testing well, which was reflected in a high level of test adherence. However, regular self-testing may have led to decreased protective behaviour. To demonstrate that regular asymptomatic testing reduces infection transmission, a future definitive trial should be performed at a time of a high prevalence of SARS-CoV-2 and be implemented as a multicentre study. The trial is registered with the German Clinical Trials Register, DRKS00026234.

Background Patients with type 2 diabetes (T2DM) are at high risk for cardiovascular events, which usually arise from the rupture of a vulnerable coronary plaque. The minimal fibrous cap thickness (FCT) overlying a necrotic lipid core is an established predictor for plaque rupture. Recently, coronary calcification has emerged as a relevant feature of plaque vulnerability. However, the impact of T2DM on these morphological plaque parameters is largely unexplored. Therefore, this study aimed to compare differences of coronary plaque morphology in patients with and without T2DM with a particular focus on coronary calcification. Methods In 91 patients (T2DM = 56, non-T2DM = 35) with 105 coronary de novo lesions (T2DM = 56, non-T2DM = 49) plaque morphology and calcification were analyzed using optical coherence tomography (OCT) prior to coronary intervention. Results Patients with T2DM had a lower minimal FCT (80.4 ± 27.0 µm vs. 106.8 ± 27.8 µm, p < 0.001) and a higher percent area stenosis (77.9 ± 8.1% vs. 71.7 ± 11.2%, p = 0.001) compared to non-diabetic subjects. However, patients with and without T2DM had a similar total number of calcifications (4.0 ± 2.6 vs. 4.2 ± 3.1, p = ns) and no significant difference was detected in the number of micro- (0.34 ± 0.79 vs. 0.31 ± 0.71), spotty (2.11 ± 1.77 vs. 2.37 ± 1.89) or macro-calcifications (1.55 ± 1.13 vs. 1.53 ± 0.71, all p = ns). The mean calcium arc (82.3 ± 44.8° vs. 73.7 ± 31.6), the mean thickness of calcification (0.54 ± 0.13 mm vs. 0.51 ± 0.15 mm), the mean calcified area (0.99 ± 0.72 mm 2 vs. 0.78 ± 0.49 mm 2 ), the mean depth of calcification (172 ± 192 μm vs. 160 ± 76 μm) and the cap thickness overlying the calcification (50 ± 71 μm vs. 62 ± 61 μm) did not differ between the diabetic and non-diabetic groups (all p = ns). Conclusion T2DM has an impact on the minimal FCT of the coronary target lesion, but not on localization, size, shape or extent of calcification. Thus, the minimal FCT overlying the necrotic lipid core but not calcification is likely to contribute to the increased plaque vulnerability observed in patients with T2DM.

Background Adenocarcinoma of the gastroesophageal junction (GEJ) Siewert type II can be resected by transthoracic esophagectomy or transhiatal extended gastrectomy. Both allow for a complete tumor resection, yet there is an ongoing controversy about which surgical approach is superior with regards to quality of life, oncological outcomes and survival. While some studies suggest a better oncological outcome after transthoracic esophagectomy, others favor transhiatal extended gastrectomy for a better postoperative quality of life. To date, only retrospective studies are available, showing ambiguous results. Methods This study is a multinational, multicenter, randomized, clinical superiority trial. Patients ( n = 262) with a GEJ type II tumor resectable by both transthoracic esophagectomy and transhiatal extended gastrectomy will be enrolled in the trial. Type II tumors are defined as tumors with their midpoint between ≤1 cm proximal and ≤ 2 cm distal of the top of gastric folds on preoperative endoscopy. Patients will be included in one of the participating European sites and are randomized to either transthoracic esophagectomy or transhiatal extended gastrectomy. The trial is powered to show superiority for esophagectomy with regards to the primary efficacy endpoint overall survival. Key secondary endpoints are complete resection (R0), number and localization of tumor infiltrated lymph nodes at dissection, post-operative complications, disease-free survival, quality of life and cost-effectiveness. Postoperative survival and quality of life will be followed-up for 24 months after discharge. Further survival follow-up will be conducted as quarterly phone calls up to 60 months. Discussion To date, as level 1 evidence is lacking, there is no consensus on which surgery is superior and both surgeries are used to treat GEJ type II carcinoma worldwide. The CARDIA trial is the first randomized trial to compare transthoracic esophagectomy versus transhiatal extended gastrectomy in patients with GEJ type II tumors. Several quality control measures were implemented in the protocol to ensure data reliability and increase the trial’s significance. It is hypothesized that esophagectomy allows for a higher rate of radical resections and a more complete mediastinal lymph node dissection, resulting in a longer overall survival, while still providing an acceptable quality of life and cost-effectiveness. Trial registration The trial was registered on August 2nd 2019 at the German Clinical Trials Register under the trial-ID DRKS00016923 .

Background Acute kidney injury (AKI) is a common complication after cardiopulmonary resuscitation (CPR) and predicts in-hospital mortality. To which extent post-resuscitation disease or the initial event of cardiac arrest and the duration of insufficient cardiac output triggers AKI is challenging to discriminate. Knowledge on molecular mediators of AKI is scarce. Early identification of patients at high risk of AKI is hampered by the low sensitivity of the established tests in clinical routine practice. The present study aimed to determine the diagnostic utility of the novel urine biomarkers tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) for the early recognition of AKI in patients with non-traumatic shock. Methods The performance of [TIMP-2] · [IGFBP7] was prospectively analysed in 48 patients with shock following out-of-hospital cardiac arrest (OHCA). All patients were treated with target temperature management (TTM) for 24 h. Urinary [TIMP-2] · [IGFBP7] samples were collected at 3 and 24 h after determination of OHCA. Results Patients (n = 31 (65%)) developed AKI after an average of 26 ± 12 h. Patients who developed AKI had significantly higher [TIMP-2]·[IGFBP7] compared to individuals that did not develop AKI (1.52 ± 0.13 vs. 0.13 ± 0.14; p  < 0.05) as early as 3 h after determination of OHCA,. For urine [TIMP-2]*[IGFBP7], the area under the curve (AUC) for the development of AKI was 0.97 (CI 0.90–1.00) at 3 h after OHCA. The optimal [TIMP-2]·[IGFBP7] cut-off value for the prediction of AKI was 0.24. The sensitivity was 96.8% and specificity was 94.1%. Conclusions Urinary [TIMP-2]•[IGFBP7] reliably predicts AKI in high-risk patients only 3 h after determination of OHCA with a cut-off at 0.24. This novel test may help to identify patients at high risk of AKI to enrol into clinical studies to further elucidate the pathophysiology of AKI and devise targeted interventions in the future.

ObjectivesPulmonary arterial hypertension (PAH) is a devastating disease with limited survival and occurs as a frequent complication in patients with systemic sclerosis (SSc). A definite diagnosis of PAH is obtained by right heart catheterisation (RHC); however, the initial suspicion is raised by non-invasive methods. We assessed the diagnostic accuracy of key parameters derived from cardiopulmonary exercise testing (CPET) for detecting and ruling out SSc-associated PAH.MethodsIn a multicentre setting, we prospectively evaluated 173 consecutive patients with SSc without known PAH, but with clinical suspicion of PAH. Each patient underwent CPET and RHC.ResultsRHC identified PAH in 48 patients (27.8%), postcapillary pulmonary hypertension (PH) in 10 patients (5.8%) and ruled out PH in 115 patients (66.5%). CPET parameters correlated significantly with pulmonary haemodynamics. PeakVO2 and VE/VCO2 showed highest correlations with pulmonary arterial pressure, transpulmonary pressure gradient and pulmonary vascular resistance. Several parameters showed high sensitivity and specificity for PAH detection by receiver operating characteristic analysis. However, peakVO2 showed highest diagnostic accuracy (sensitivity 87.5%, specificity 74.8% at a threshold level of 13.8 mL/min/kg). A peakVO2 of >18.7 mL/kg/min was reached by 38/173 patients (22%) and excluded PAH in our cohort (negative predictive value 1.0). A nadir VE/VCO2 ratio of >45.5 showed a positive predictive value of 1.0. Diagnostic accuracy was highest in patients with low pulmonary arterial wedge pressure (<12 mm Hg). There were no study-related serious adverse events.ConclusionsCPET is a safe and valuable method in the non-invasive detection of SSc-associated PAH. It may be particularly beneficial for reducing unnecessary RHC procedures.

Background Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT. Methods/design LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema ( n =405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction. The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy. Discussion LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema. Trial registration ClinicalTrials.gov NCT04272827. Registered on February 14, 2020. Trial status Protocol version is 02_0, December 17, 2019

Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic properties in recent clinical trials. While it has also been suggested a promising candidate for the treatment of neurodegenerative disorders, it failed to demonstrate efficacy in cognitive impairments associated with schizophrenia as an add-on treatment (600 mg/day for 6 weeks) in 18 chronically ill patients co-treated with a variety of psychopharmacologic drugs. Here, we report on the results of parallel-group, active-controlled, mono-therapeutic, double-blind, randomized clinical trial (CBD-CT1; ClinicalTrials.gov identifier: NCT00628290) in 42 acute paranoid schizophrenic patients receiving either CBD (up to 800 mg/day) or amisulpride (AMI, up to 800 mg/day) for four weeks in an inpatient setting with neurocognition as a secondary objective. Twentynine patients (15 and 14 in the CBD and AMI group, respectively) completed two cognitive assessments at baseline and the end of the treatment period. We investigated the following cognitive domains: pattern recognition, attention, working memory, verbal and visual memory and learning, processing speed, and verbal executive functions. When applying the Bonferroni correction for multiple testing, p < 0.0004 would indicate statistical significance. There was no relevant difference in neurocognitive performance between the CBD and the AMI group at baseline, and we observed no post-treatment differences between both groups. However, we observed improvements within both groups from pre-to post-treatment (standardized differences reported as Cohen’s d ) in visual memory (CBD: 0.49, p = 0.015 vs. AMI: 0.63, p = 0.018) and processing speed (CBD: 0.41, p = 0.004 vs. AMI: 0.57, p = 0.023). Furthermore, CBD improved sustained attention (CBD: 0.47, p = 0.013, vs. AMI: 0.52, p = 0.085), and visuomotor coordination (CBD: 0.32, p = 0.010 vs. AMI: 0.63, p = 0.088) while AMI led to enhanced working memory performance in two different paradigms (Subject Ordered Pointing Task–AMI: 0.53, p = 0.043 vs. CBD: 0.03, p = 0.932 and Letter Number Sequencing–AMI: 0.67, p = 0.017 vs. CBD: 0.08 p = 0.755). There was no relevant correlation between changes in neurocognitive parameters and psychotic symptoms or anandamide serum levels. This study shows that both CBD and AMI improve neurocognitive functioning with comparable efficacy in young and acutely ill schizophrenia patients via an anandamide-independent mechanism.