University Hospital Würzburg

BACKGROUND Ischemic stroke (IS) is a prevalent cause of death and disability worldwide. Cerebral ischemia induces profound changes at the blood-brain barrier, which lead to a remarkable increase in paracellular permeability, worsening outcomes. Platelets are well known for safeguarding vascular integrity and the prevention of bleeding complications. On the other hand, platelet activation contributes to infarct progression in the context of IS. The manifold, context-dependent roles of platelets, however, have not yet been resolved. METHODS IS was mimicked by transient middle cerebral artery occlusion in wild-type, transgenic, or treated mice, and vascular leakage was assessed by intravital 2-photon microscopy, as well as Western blotting and immunohistochemistry. Barrier property of primary murine brain microvascular endothelial cells was measured as transendothelial electrical resistance of cellular monolayers in response to platelet releasate or recombinant proteins. RESULTS IS induces blood-brain barrier breakdown characterized by time-dependent leakage of albumin in the brain parenchyma. We could show that local platelet activation triggers the release of PDGF (platelet-derived growth factor)-A from α-granules, which induces the loss of brain endothelial cell layer integrity. This translates to a comprised vascular integrity in vivo. In the absence of α-granule content ( Nbeal2 −/− ) or pharmacological blockade of PDGF, no disruption of the endothelial layer or vascular leakage was observed. CONCLUSIONS PDGF-A released from platelets impairs blood-brain barrier integrity, resulting in detrimental vascular leakage and infarct progression. These findings provide important insights on the pivotal role of platelets in IS further elucidating the mechanisms of thromboinflammation in the brain.

This review summarizes the latest developments for the treatment of patients with early-stage breast cancer. Most of the clinically relevant changes were the result of using immune checkpoint inhibitors to treat patients with triple-negative breast cancer (TNBC) and CDK4/6 inhibitors to treat patients with hormone receptor-positive, HER2-negative (HRpos/HER2neg) tumors and a high risk of recurrence. Recent studies are presenting more and more data with long follow-up times and integrating translational analyses to evaluate new biomarkers such as circulating tumor DNA (ctDNA). This review article summarizes the latest developments published in recent months and puts the findings in context.

The use of CDK4/6 inhibitors, the new PI3K/AKT-kinase inhibitors, selective estrogen receptor-degraders (SERDs), antibody-drug conjugates, immune therapies and PARP inhibitors in recent years has resulted in a marked change in the therapy landscape for patients with advanced stage breast cancer. CDK4/6 inhibitors, trastuzumab deruxtecan, and sacituzumab govitecan have all been shown to provide significant overall survival benefits compared to conventional chemotherapy. Other substances are also showing promising results and hold out the hope that further analysis of the overall survival benefits will be available in the near future. The speed at which studies are now being carried out has markedly increased, and conferences and specialist journals are now constant sources of new information. This review summarizes the most recent publications and conference presentations on the treatment of patients with advanced stage breast cancer.

Individuals born very preterm (VPT; < 32 weeks) or with very low birthweight (VLBW; < 1500 g) are at higher risk for internalizing problems compared to those born at term (37–42 weeks) or with normal birthweight (> 2500 g). However, group-level comparisons often overlook individual differences within these populations. Using data from the Bavarian Longitudinal Study, a German population-based birth cohort, this study aims to investigate developmental trajectories of internalizing problems from childhood to adulthood in 368 VPT/VLBW individuals and to identify early-life neonatal, family, neurodevelopmental, and social factors associated with these trajectories. Growth mixture modeling of parent-reported internalizing problems at ages 6, 8, 13, and 26 revealed three distinct trajectories: 61.7% exhibited consistently low levels of internalizing problems, 21.7% showed increasing problems, and 16.6% showed decreasing problems over time. Compared to the consistently low group, the increasing group had lower socioeconomic status at birth, lower gestational age, and more neurosensory impairments; while the decreasing group was characterized by higher family adversity, greater shyness and emotionality, higher birthweight, and fewer parent–infant relationship problems. Multiple births were associated with a higher likelihood of exhibiting consistently low internalizing problems rather than the increasing or decreasing trajectories. Early interventions targeting higher-risk groups—such as those with lower gestational age, neurosensory impairments, socioeconomic disadvantages, family adversity, or challenging temperaments—and promoting resilience factors like positive parenting, have the potential to improve long-term mental health outcomes for VPT/VLBW individuals.

Background Most forms of obesity are associated with chronic diseases that remain a global public health challenge. Aims Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation. Materials and Methods This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long‐term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity‐related cardiometabolic risks. Moreover, the socio‐economic drivers of obesity and its transition across phenotypes remain poorly understood. Results The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community‐level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies. Discussion The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity. Conclusion This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio‐economic model not compatible with optimal human health.

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effectiveness and safety of total neoadjuvant therapy versus standard therapy in individuals with locally advanced rectal cancer.

Background Pulmonary metastasectomy (PM) is the most frequently performed local ablative therapy for leiomyosarcoma (LMS), synovial sarcoma (SyS), and undifferentiated pleomorphic sarcoma (UPS). This study aimed to assess surgical feasibility, outcome, and clinical prognostic factors, as well as the value of a peri-interventional systemic therapy. Methods This multicenter retrospective study enrolled 77 patients with LMS, SyS, or UPS who underwent first-time complete resection of isolated lung metastases between 2009 and 2021. Disease-free survival (DFS), overall survival (OS), and clinical prognostic factors were analyzed. Results After the first PM, the median DFS was 7.4 months, and the median OS was 58.7 months. A maximal lesion diameter greater than 2 cm was associated with reduced DFS in both the univariable (hazard ratio [HR], 2.29; p = 0.006) and multivariable (HR, 2.60; p = 0.005) analyses. The univariable analysis identified a maximal lesion diameter greater than 2 cm as an adverse prognostic factor for OS (HR, 5.6; p < 0.001), whereas a treatment-free interval longer than 12 months was associated with improved OS (HR, 0.42; p = 0.032). The addition of systemic therapy was associated with a trend toward improved DFS for patients with lesions larger than 2 cm (HR, 0.29; p = 0.063). Severe postoperative complications (grade ≥IIIa) occurred in 2 % of the patients. Conclusion The size of resected lung metastases might be a more relevant prognostic factor than their number for patients with LMS, SyS, or UPS. For patients with lung metastases larger than 2 cm in maximal diameter, additional systemic therapy may be warranted.

Background Rehabilitation is a crucial component of comprehensive disease management and functional recovery. Despite advancements in surgical techniques for chronic lateral ankle instability (CLAI), there is still a lack of standardized, evidence-based rehabilitation protocols. Source of data After nine clinical questions were proposed by the guidance steering group, an independent search strategy was conducted for all clinical questions, encompassing the PubMed, MEDLINE, Web of Science, EMBASE, and Cochrane databases. Areas of agreement Rehabilitation is crucial to optimize surgical outcomes and patient recovery. An appropriate and well-structured rehabilitation plan can optimize a safe return to sports and daily activities. Areas of controversy Rehabilitation for surgical management of CLAI poses significant challenges, especially in the areas of preoperative preparation, control of postoperative swelling and pain, early-stage rehabilitation, advanced rehabilitation, and return to exercise. Growing points Given the lack of established guidelines for rehabilitation following surgical management of CLAI, this clinical practice guideline presents nine key recommendations aimed at addressing the existing controversies in this area. For CLAI patients undergoing surgery, preoperative rehabilitation should include exercise and education, followed by postoperative focus on pain and swelling management. Early rehabilitation emphasizes nonweight-bearing functional training, with gradual progression to weight-bearing exercises, dynamic balance, and strength training over the first 18 weeks. Regular follow-up visits are essential to monitor recovery and promote functional restoration. Areas timely for developing research In patients undergoing surgery for CLAI, there is a pressing need for comparative studies to assess the necessity of immobilization and to determine the optimal selection of braces.

Activation of the JAK/STAT signalling pathway plays a pivotal role in the pathogenesis of cutaneous T-cell lymphomas. Therefore, inhibition of this cardinal pathways is a promising novel treatment option. We herein report the first evidence of rapid response of lymphomatoid papulosis as well as mycosis fungoides upon topical application of the JAK-inhibitor ruxolitinib.

Introduction Psychopharmacotherapy with mirtazapine is commonplace. Lower serum concentrations of mirtazapine were reported in smokers due to CYP1A2 induction. However, no previous study that investigated CYP1A2 genetics and mirtazapine treatment considered CYP1A2- inducing parameters. Aim We aimed to investigate the association of CYP1A2 variants, mirtazapine serum concentration, and treatment outcome, considering the smoking status of the patients. Methods Two depression cohorts were investigated for the association between serum concentration and treatment response of mirtazapine and CYP1A2 -163C>A (rs762551) and -3860G>A (rs2069514) genotype groups, also considering smoking status, sex, and age of the patients. In total, 124 patients (82 non-smokers and 42 smokers) were eligible for the analyses. Results Dose-corrected serum concentration (CD) of mirtazapine was associated with smoking status, sex, and age, with lower CD in smokers, females, and older patients. Considering non-smokers and genotype-grouped smokers, CD of mirtazapine in CYP1A2 normal metabolizer smokers ( N = 6) did not differ from CD of non-smokers. By contrast, smokers carrying the CYP1A2 *1A/*1F and *1F/*1F genotype groups showed 34.4% and 33.4% lower mirtazapine CD compared to non-smokers. Discussion As yet, for clinical practice, it may be more relevant to focus on smoking status than on the CYP1A2 gene variants. Considering the relevant impact of smoking on the mirtazapine CD, physicians should monitor an increase in side effects due to the expected increase in mirtazapine serum concentrations. In these cases, measurement of mirtazapine CD and/or subsequent dosage reduction is recommended. The clinical relevance of CYP1A2 genotyping prior to treatment with drugs metabolized by CYP1A2 needs further investigation.

Pre–coronavirus disease 2019 (COVID‐19) critical care research underscored the importance of muscularity on patient outcomes. This study investigates the association between skeletal muscle mass and quality with clinical and physical function outcomes in critically ill patients with COVID‐19. We systematically searched MEDLINE, EMBASE, and CINAHL from database inception to April 24, 2024, for studies using objective methods to evaluate muscularity in critically ill adults with COVID‐19, without language restrictions. Co–primary outcomes were overall mortality and muscle strength. Random‐effect meta‐analyses were performed in RevMan 5.4.1. We included 20 studies ( N = 1818), assessing muscularity via computed tomography (twelve studies), ultrasound (seven studies), and bioelectrical impedance analysis (one study); none had low risk of bias. In analyses of high vs low muscularity, high muscle mass was significantly associated with lower overall mortality (nine studies; risk ratio = 0.74; 95% CI, 0.57–0.98; P = 0.03). When muscularity was analyzed as a continuous variable, COVID‐19 survivors had higher skeletal muscle area (SMA) (13 studies; mean difference [MD] = 1.18; 95% CI, 0.03–2.33; P = 0.05) confirmed by sensitivity analysis using standardized MD (0.23, 95% CI 0.05–0.42, P = 0.01) and significantly higher muscle quality (five studies; standardized MD = 0.45; 95% CI, 0.20–0.70; P = 0.0004). Muscle strength findings were inconsistent: one study showed significant correlations between muscle strength with muscle mass parameters ( r = 0.365–0.375, P < 0.001) whereas another found no association. In critically ill adults with COVID‐19, high muscle mass was associated with lower mortality risk. Survivors had significantly higher SMA and muscle quality. Findings on physical function outcomes remain inconclusive (PROSPERO ID: CRD42022384155).

Objectives Prospective registration of randomised controlled trials (RCTs) is an international standard of good clinical practice but is often neglected by evidence synthesis producers. This study aims to assess prospective registration of RCTs included in evidence syntheses as part of a research integrity assessment and examine its impact on the study pool. Design Meta-epidemiological study. Data sources COVID-19 Cochrane reviews (CRs) and non-Cochrane systematic reviews (SRs) in MEDLINE via PubMed up to 9 June 2022. Eligibility criteria RCTs from CRs and SRs evaluating 13 investigational medicinal products for SARS-CoV-2 and COVID-19. Data extraction and synthesis We assessed prospective trial registration in RCTs according to domain 2 of the research integrity assessment tool. Prospective registration is defined as registration before participant enrolment. We extracted the trial registration number, registration date, study start date and inconsistencies in dates between study report and registration. RCTs were categorised as ‘no concern’, ‘awaiting classification’ and ‘exclude’. We also analysed the relationship between study settings, publishing journals and prospective registration. Results We included 188 RCTs. In the primary study report, 91% reported a trial registration number. In 84 RCTs, either not or retrospectively registered or with missing or inconsistent dates, we searched and/or contacted study authors for prospective registrations, resolving 17 RCTs. Ultimately, 58% of RCTs were prospectively registered and considered ‘no concern’, 15% were ‘awaiting classification’ due to inconsistent or missing information and 27% were either not registered or retrospectively registered and categorised as ‘exclude’. Prospective registration was higher in larger or international multicentre RCTs and in RCTs conducted in Europe. Conclusions If prospective trial registration is required for inclusion in evidence syntheses, only 6 out of 10 COVID-19 RCTs would be eligible. Restricting eligibility to prospectively registered RCTs would include most large and international multicentre RCTs but exclude many smaller and non-European RCTs. Protocol registration The protocol is available on OSF ( https://osf.io/3bzeg ).

Objective Investigating the association between mental health, quality of life, and SARS-CoV-2 infection in individuals in need of care compared to independent living individuals. Individuals in need of care include both care home residents and those receiving care either through an outpatient care service or from family members. Methods This cross-sectional study assessed symptoms of depression (PHQ-9 > 9) and anxiety (GAD-7 > 9), quality of life (EQ-5D-5L, EQ-VAS), dementia (SIS), SARS-CoV-2 infection and socio-demographic variables in the total sample (N = 978, 64.4% female, mean age: 77.5 ± 13.8 years) and subgroups (study group, STG, n = 532, individuals in need of care, SARS-CoV-2 positive; control group 1, CG1, n = 213, individuals in need of care, SARS-CoV-2 negative; control group 2, CG2, n = 233, independent living individuals, SARS-CoV-2 positive). Multivariate logistic regressions were performed. Results Depressive symptoms (PHQ-9 > 9) were significantly associated with lower quality of life in the total sample (EQ-VAS: OR 0.96, 95% CI 0.95–0.97, p < 0.001; EQ-5D-5L: OR 0.14, 95% CI 0.07–0.29, p < 0.001) and across all subgroups. Anxiety (GAD-7 > 9) was significantly associated with lower quality of life in the total sample (EQ-VAS: OR 0.97, 95% CI 0.95–0.98, p < 0.001; EQ-5D-5L: OR 0.19, 95% CI 0.08–0.50, p < 0.001) and all subgroups except CG1. In individuals in need of care with COVID-19, depressive symptoms were additionally associated with symptomatic infection (OR 3.47, 95% CI 1.45–8.28, p = 0.005). Conclusion Depression and anxiety were significantly associated with reduced quality of life, irrespective of living environment or SARS-CoV-2 infection status, underscoring the need for targeted mental health interventions in older adults. While our model explained a considerable portion of the variability in depression and anxiety, further research is needed to account for the remaining proportion.

Background Parkinson's disease (PD) results from complex interactions among environmental, genetic, and aging factors. Telomeres, which ensure chromosome stability, naturally shorten with cell division, contributing to aging and cellular senescence. However, studies investigating telomere length (TL) in PD have produced inconsistent results. Objective This study aims to explore the relationship between TL and PD using a unique PD‐discordant monozygotic twin design, which minimizes confounding factors such as age, gender, and genetic background. We also examined the impact of PD‐related genetic mutations on TL. Methods We analyzed relative telomere length (RTL) in blood samples from 29 pairs of monozygotic twins discordant for PD. Data was stratified by disease duration, and we investigated the influence of genetic variants ( GBA1 and LRRK2 ) on RTL. Results No significant difference in RTL was observed between PD‐affected twins and their healthy co‐twins overall. However, twins with longer disease duration (≥8 years) showed a significant decline in RTL (0.90 ± 0.18 vs. 1.07 ± 0.24; P = 0.046), which was more pronounced with a 10‐year disease duration cutoff (0.85 ± 0.18 vs. 1.06 ± 0.22; P = 0.015). GBA1 ‐mutated PD twins exhibited significantly longer RTL than non‐mutated twins, a result replicated in non‐twin GBA1 carriers and extended to LRRK2 carriers. Conclusions Our findings suggest that aging and cellular senescence primarily drive sporadic PD, whereas genetic forms are linked to disruptions in cellular pathways, such as lysosomal or mitochondrial functions. These insights highlight the role of genetics in telomere dynamics in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Introduction In cochlear implantation (CI), precise preoperative cochlear duct length (CDL) and angular insertion depth (AID) measurements are pivotal for individualized electrode carrier selection, since recipients benefit from sufficient cochlear coverage of the electrode carrier, enabling electric stimulation of all crucial frequency bands. Since the quality of temporal bone CT largely depends on acquisition and reconstruction settings and is limited by the technical capabilities of the CT scanner, this study aims to assess how radiation dose and reconstruction field-of-view (FOV) affect automatic cochlear morphometry and electrode contact determination in conventional multislice CT. Methods Twenty fresh-frozen human petrous bone specimens were examined at three radiation dose levels (40, 20, and 10 mGy) using a multislice CT scanner. Each dataset was reconstructed with three different FOV settings (250, 125, and 50 mm). Preoperative CDL and AID measurements were performed with dedicated otological planning software. Maxed-out dose images (250 mGy) served as standard of reference for comparing the morphometric results. Results Regardless of the selected combination of dose level and FOV, significant CDL or AID measurement differences were neither ascertained among the individual groups, nor in comparison to the reference scans (all p ≥ 0.05). Likewise, the simulation of all stimulable frequency bandwidths showed no dependency on radiation dose or FOV settings (all p ≥ 0.05). Conclusion The assessment of cochlear morphometry with conventional multislice CT imaging before CI surgery allowed a radiation dose reduction up to 75% without compromising the accuracy of software-based cochlear analysis. Notably, automatic CDL and AID measurements for surgical planning did not benefit from a smaller reconstruction FOV.