Innsbruck Medical University

• Median nerve variants within the carpal tunnel have a pooled prevalence of 12%. • Bifid median nerve is the most frequently reported morphological variant. • No consistent association was found between anatomical variants and carpal tunnel syndrome. • Coexisting vascular or muscular anomalies may influence surgical complexity. • Preoperative imaging may aid anatomical identification, although clinical benefit remains uncertain. Anatomical variants of the median nerve (MN) within the carpal tunnel are clinically relevant due to their potential impact on the development, diagnosis, and surgical management of carpal tunnel syndrome (CTS). Reported prevalence estimates vary considerably across populations and study designs. To systematically review the literature and estimate the pooled prevalence of morphological variants of the median nerve within the carpal tunnel, and to assess their laterality, geographic distribution, and reported clinical implications. A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines. MEDLINE, Scopus, Web of Science, CINAHL, and LILACS were searched from inception to November 2024. Google Scholar was used for supplementary screening of gray literature. Observational studies reporting the prevalence of MN variants identified through imaging, surgical exploration, or anatomical dissection were included. Methodological quality was assessed using the Anatomical Quality Assessment (AQUA) tool. Pooled prevalence estimates were calculated using a random-effects model (DerSimonian–Laird) with Freeman–Tukey double arcsine transformation. Sixty-three studies met eligibility criteria for qualitative synthesis, and 19 studies (n = 9,045 subjects) were included in the primary meta-analysis. The pooled prevalence of MN variants within the carpal tunnel was 12% (95% CI: 9–15%), with substantial heterogeneity (I² = 87%). Subgroup analysis showed similar prevalence in imaging-based studies (12%, 95% CI: 9–15%; I² = 87.8%). No clear laterality predominance was observed (right: 46%, 95% CI: 40–52%; I² = 0.0%; left: 53%, 95% CI: 48–59%; I² = 0.0%), whereas bilateral presentation demonstrated greater variability (21%, 95% CI: 6–36%; I² = 90.6%). Geographic subgroup analysis showed pooled prevalence estimates of 22% in Asia (95% CI: 13–31%; I² = 92.6%), 20% in Europe (95% CI: 14–27%; I² = 79.2%), and 18% in America (95% CI: 16–20%; I² = 19.4%). Morphological variants of the median nerve within the carpal tunnel are relatively common anatomical findings. Current evidence does not support their role as independent risk factors for CTS; however, their coexistence with vascular or muscular anomalies may influence local anatomical relationships and surgical complexity. Preoperative imaging may facilitate anatomical identification and surgical planning, although its impact on clinical outcomes and intraoperative complications remains uncertain and requires further prospective investigation.

Although most imaging assessments are made qualitatively, quantitative measurements in orthopedic imaging are becoming more important in detecting subtle findings and assessing degrees of abnormality, which can help direct surgical management. In the knee, patellofemoral maltracking is a common cause of anterior pain, particularly in younger patients. Failure to recognize this pathophysiology may result in accelerated chondral loss and osteoarthritis (OA), and the imaging findings may be subtle. As a result, clinicians and radiologists have developed numerous measurements to detect and quantify patellofemoral alignment. Additional entities, such as femorotibial subluxation or angular abnormalities, may only be detected by using standardized measurements and can help detect ligamentous insufficiency or developmental malalignment, which can lead to instability and OA in the medial and lateral femorotibial compartments. Finally, the proper positioning and hardware selection for knee arthroplasty are critical to preventing early hardware failure and postsurgical pain. This review, which focuses on the knee, is the second in a three-part series discussing the appropriate imaging modalities on which to obtain specific lower extremity measurements as well as proper measurement techniques, grouped by pathology. Furthermore, the normal value or range of values according to current literature is reported, along with the significance of abnormal measurements.

While several algorithms exist for analyzing muscle activity during sleep, none provides information on both muscle tone and movements as open-source software. We aimed to overcome this limitation by developing SOMAS (Sleep Open-source Muscle activity Analysis System). SOMAS processes European Data Format+ (EDF+) files with wake-sleep state and candidate leg movement annotations without online data sharing, quantifies muscle tone using the atonia index and the distribution of normalized electromyography values (DNE), and calculates leg movement indices based on the 2016 World Association of Sleep Medicine criteria. To demonstrate that SOMAS achieves its intended purpose, we analyzed recordings from eight patients with isolated REM sleep behavior disorder (iRBD), five with restless legs syndrome (RLS), seven with sleep breathing disorders, and five controls. SOMAS-derived atonia index and leg movement indices were compared with those from Hypnolab, a non-open access software. Additionally, SOMAS-derived indices were used to differentiate patients with iRBD or with RLS from other patients and/or controls. SOMAS-derived atonia index and leg movement indices strongly correlated with Hypnolab results (Spearman coefficients >0.97) with minimal bias. The DNE and atonia index in REM sleep effectively differentiated patients with iRBD from other patients and controls (AUC 0.89-1.00). The periodic leg movement and periodicity indices differentiated patients with RLS from controls (AUC 0.71-0.75). SOMAS reliably quantifies muscle tone and movements during sleep from EDF+files using open-source algorithms, with the potential of enhancing reproducibility and collaboration in research on sleep-related movement disorders.

As a group, patients with classic galactosemia (CG) demonstrate a high prevalence of long-term complications despite early detection and life-long dietary restriction of galactose, which is the current standard of care. Individual outcomes, however, vary widely. For decades, research teams have sought to identify potential environmental, metabolic, and/or galactose-1-phosphate uridylyltransferase (GALT) allelic differences that might explain this variability-with limited success. Among large cohorts, only severe brain-related disease in infancy has been associated with increased prevalence of complications, and only the presence of predicted or detected residual GALT activity has been associated with decreased prevalence. While significant, these factors fail to account for the majority of long-term outcome variability in CG. Here, we tested whether genetic factors, both inside and outside the GALT locus, might contribute to variability in speech/voice/language, cognitive, and/or motor outcomes among patients. Specifically, we compared outcomes among 66 sets of affected siblings who share both GALT genotype and genetic background, 54 unrelated CG patients who share GALT genotype (p.Gln188Arg/p.Gln188Arg) but not genetic background, and 52 unrelated CG patients who share neither GALT genotype nor genetic background. Heritability estimates for all three complications demonstrate substantial genetic contributions, with point estimates of 100% heritability for all three. Less than 8% of this heritability appears due to residual GALT activity from hypomorphic GALT alleles. Combined with prior data demonstrating clustering of all three outcomes, these results offer compelling evidence for the existence of genetic modifiers of developmental outcomes in CG beyond the GALT locus.

Schizophrenia patho-etiology may involve endothelial inflammation and blood-brain barrier (BBB) dysregulation with cellular adhesion molecules (CAMs) as important mediators. CAMs are essential for cellular integrity but can show increased levels in inflammation. Cognitive dysfunction precedes and exists independently of psychotic symptoms in schizophrenia patients. CAMs could impact cognition through influence on BBB integrity. To gain insights into disease mechanisms and potential therapeutic targets, we explored the relationship between CAMs protein levels and neurocognitive tests in schizophrenia-spectrum disorders in the BeSt InTro study. Seventy-one in- and out-patients underwent CAMs measurements and neuropsychological testing on a minimum of one time point: baseline, 6, 26, or 52weeks. Cognitive domains included working memory, processing speed, verbal abilities, executive functions, and overall cognition. CAMs analyzed were neural CAMs: junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD); vascular CAMs: intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), and platelet (P)-selectin from fasting blood samples. Linear mixed effects models, adjusted for age, sex, body mass index, smoking, education, and drug naivety, estimated CAMs effect on cognitive outcome measures. N-CAD levels correlated positively with overall cognition (p=0.002), working memory (p=0.034), and executive functions (p=0.0011). ICAM-1 levels correlated positively with overall cognition (p=0.037). Conversely, JAM-A levels correlated negatively with executive functions (p=0.021). Associations between CAMs (N-CAD, ICAM-1, JAM-A) and neurocognitive tests suggest CAMs may impact cognition in schizophrenia. Contrary to our hypothesis, most associations between CAMs levels and cognitive tests were positive. Future research on mechanisms is mandatory.

The skin is a diverse reservoir of immune cells with strong potential for immunotherapeutic delivery. Langerhans cells in the epidermis are antigen-presenting cells, accessible for vaccination using carbohydrate-conjugated therapeutics targeting their endocytic lectin receptor, Langerin. As carbohydrate-lectin binding is highly dependent on valency, scaffolds that enable control over ligand spacing and stoichiometry are instrumental in enhancing receptor binding and selectivity. Here we utilized a self-assembled nucleic acid-based Holliday Junction scaffold, fully modified for nuclease protection and with a well-defined carbohydrate arrangement to optimize drug delivery to Langerhans cells. In vitro screening with Langerin-expressing cells revealed that mannosylated Holliday Junctions showed the strongest binding. This was confirmed in human epidermal cell suspensions, demonstrating specificity and valency-driven interactions. Topical administration of mannosylated scaffolds on skin explants enabled effective targeting of epidermal Langerhans cells. Finally, in an antigen-presentation assay, in vitro differentiated Langerhans cells loaded with mannosylated and peptide-conjugated scaffolds significantly enhanced T cell activation. Overall, our study presents a promising nucleic acid-based platform for precise Langerhans cell targeting and drug delivery, with broad potential for skin-directed immunotherapies.

Impaired clinical insight is common in schizophrenia spectrum disorders (SSDs) and predicts poor treatment adherence and outcomes. It is linked to disorganised, positive, negative, and hostility symptoms. However, few studies repeatedly assess insight after antipsychotic initiation while comparing pharmacologically distinct agents. This study examined how symptom levels and changes predict the development and endpoint of clinical insight over 6 weeks, contrasting the partial dopamine agonist aripiprazole (PDA) with two dopamine antagonists (DAs). Data from 144 SSD patients in the Bergen-Stavanger-Innsbruck-Trondheim (BeSt InTro) trial, a pragmatic, semi-randomised study of amisulpride, aripiprazole, and olanzapine, were analysed using latent growth curve models. Insight was measured by PANSS Item G12; symptom factors (positive, negative, hostility, cognitive/disorganised) were derived from PANSS. Lower baseline symptoms and greater improvement between weeks 3 and 6 predicted better insight at 6 weeks across all factors. For positive symptoms, improvement between weeks 1 and 3 (b = 0.57, p = 0.009) also predicted better insight. Patients on aripiprazole showed less improvement in insight, though some findings lost significance after correction. Symptom reduction is associated with improved insight, with early changes in positive symptoms exerting the fastest effect. Despite symptom improvement, aripiprazole PDA treatment was linked to less insight gain than DA treatment. These preliminary findings warrant further study.

Avelumab, pembrolizumab, and enfortumab vedotin (EV) demonstrated efficacy in mUC following platinum-based chemotherapy. However, real-world data in patients with urothelial carcinoma with squamous differentiation (UCSD) are limited. The aim of this study is to assess the real-world clinical outcomes of avelumab, pembrolizumab, or EV in mUCSD patients. The ARON-2EV study is a retrospective, international, multicenter analysis in patients with mUC treated with avelumab, pembrolizumab, or EV across 79 centers in 21 countries. Patients were divided into three cohorts: 1 (avelumab), 2 (pembrolizumab), and 3 (EV). Primary endpoints were overall survival (OS) and time on treatment (ToT). Secondary objectives included evaluating clinical factors associated with outcomes and exploring the impact of UCSD histology on response to therapy. Statistical methods included Kaplan-Meier estimates, log-rank tests, Fisher's exact and chi-square tests, and Pearson's correlation coefficients. A total of 1918 patients, 1696 with advanced pure UC (pUC) and 222 with mUCSD (36 in cohort 1, 111 in cohort 2, and 75 in cohort 3), were included. Median OS was shorter in patients with UCSD compared to patients with pUC histology in the three cohorts (1: 13.0 vs 26.8months, HR 2.66,p = 0.003; 2: 10.2 vs 18.5months, HR 1.52,p = 0.008; and 3: 7.6 vs 13.1months, HR 1.68,p = 0.011). Median ToT was shorter in patients with UCSD compared to patients with pUC histology in cohort 1 (3.5 vs 5.6months, HR 1.57,p = 0.044) and 3 (7.6 vs 13.6months, HR 1.83,p = 0.005) but not in cohort 2 (3.7 vs 4.7months, HR 1.19,p = 0.177). Response to therapy was negatively correlated with UCSD histology in cohorts 2 (correlation coefficient 0.094,p = 0.008) and 3 (correlation coefficient 0.107,p = 0.021), while response to avelumab was not correlated with UCSD (correlation coefficient 0.072,p = 0.263). UCSD is a histology with a poor prognosis and response to treatments compared to pUC. Treatments activity and effectiveness in divergent differentiations should be addressed in dedicated prospective studies. NCT05290038.