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Carbonic anhydrase IX (CAIX) is a membrane spanning protein involved in the enzymatic regulation of tumor acid-base balance. CAIX has been shown to be elevated in a number of hypoxic tumor types. The purpose of this study was to determine the efficiency of intact and IgG fragments of cG250 to target CAIX in vivo in a hypoxic tumor model.Conventional biodistribution studies were performed with (111)In-DO3A-cG250, (111)In-DO3A-F(ab')(2)-cG250 and (111)In-DO3A-Fab-cG250. Additional ex vivo analysis of the tumor was performed with markers for tumor hypoxia, blood perfusion and endogenous CAIX expression. All four data sets were digitally correlated to determine the optimal agent for determining hypoxia in a HT29 colon cancer xenograft. The HT29 human colorectal tumor xenografts show strong CAIX expression in hypoxic areas of poor blood perfusion. The intact IgG had an initial high focal uptake at the periphery of these hypoxic regions and penetration into the areas of highest CAIX expression over the 7-day study period. The lower molecular weight antibody fragments had a faster uptake into areas of high CAIX expression, but had a much lower absolute uptake at the optimal imaging times.For the clinical detection of hypoxia induced CAIX using cG250 antibody based agents, imaging with the intact IgG at 7 days post injection would allow for the most sensitive and accurate detection of CAIX.

Abstract Immune checkpoint inhibitors (ICI) have significantly improved overall survival in melanoma patients. However, 60% experience severe adverse events and early response markers are lacking. Circulating tumour DNA (ctDNA) is a promising biomarker for treatment-response and recurrence detection. The prospective PET/LIT study included 104 patients with palliative combined or adjuvant ICI. Tumour-informed sequencing panels to monitor 30 patient-specific variants were designed and 321 liquid biopsies of 87 patients sequenced. Mean sequencing depth after deduplication using UMIs was 6000x and the error rate of UMI-corrected reads was 2.47×10−4. Variant allele fractions correlated with PET/CT MTV (rho=0.69), S100 (rho=0.72), and LDH (rho=0.54). A decrease of allele fractions between T1 and T2 was associated with improved PFS and OS in the palliative cohort (p = 0.008 and p

Abstract Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems.

Abstract Background Invasive blood pressure measurement is the in-hospital gold standard to guide hemodynamic management and consecutively cerebral perfusion pressure in patients with traumatic brain injury (TBI). Its prehospital use is controversial since it may delay further care. The primary aim of this study was to test the hypothesis that patients with severe traumatic brain injury who receive prehospital arterial cannulation, compared to those with in-hospital cannulation, do not have a prolonged time between on-scene arrival and first computed tomography (CT) of the head by more than ten minutes. Methods This retrospective study included patients 18 years and older with isolated severe TBI and prehospital induction of emergency anaesthesia who received treatment in the resuscitation room of the University Hospital of Graz between January 1st, 2015, and December 31st, 2022. A Wilcoxon rank-sum test was used to test for non-inferiority (margin = ten minutes) of the time interval between on-scene arrival and first head CT. Results We included data of 181 patients in the final analysis. Prehospital arterial line insertion was performed in 87 patients (48%). Median (25–75th percentile) durations between on-scene arrival and first head CT were 73 (61–92) min for prehospital arterial cannulation and 75 (60–93) min for arterial cannulation in the resuscitation room. Prehospital arterial line insertion was significantly non-inferior within a margin of ten minutes with a median difference of 1 min (95% CI − 6 to 7, p = 0.003). Conclusion Time-interval between on-scene arrival and first head CT in patients with isolated severe traumatic brain injury who received prehospital arterial cannulation was not prolonged compared to those with in-hospital cannulation. This supports early out-of-hospital arterial cannulation performed by experienced providers.

Abstract Background In Germany, general practitioners play a pivotal role in palliative care provision. Caring for patients with palliative care needs can be a burden for general practitioners, highlighting the importance of self-care and mental health support. This study aimed to explore the role of palliative care in general practitioners’ daily work, the stressors they experience, their coping mechanisms, and the potential benefits of Advance Care Planning in this context. Methods An exploratory approach was employed, combining a short quantitative survey with qualitative interviews. The analysis was based on a structuring qualitative content analysis, following a deductive-inductive procedure and integrating the Stress-Strain Model and Lazarus’ Transactional Model of Stress and Coping. We recruited eleven general practitioners to take part in the study. Results General practitioners viewed palliative care as integral to their practice but faced challenges such as time constraints and perceived expertise gaps. Societal taboos often hindered conversations on the topic of death. Most general practitioners waited for their patients to initiate the topic. Some general practitioners viewed aspects of palliative care as potentially distressing. They used problem-focused (avoiding negative stressors, structuring their daily schedules) and emotion-focused (discussions with colleagues) coping strategies. Still, general practitioners indicated a desire for specific psychological support options. Advance Care Planning, though relatively unfamiliar, was acknowledged as valuable for end-of-life conversations. Conclusions Palliative care can be associated with negative psychological stress for general practitioners, often coming from external factors. Despite individual coping strategies in place, it is advisable to explore concepts for professional psychological relief. Trial registration Not registered.

Abstract Background Multimorbidity is increasingly prevalent among ageing patients, leading to reduced daily functioning. To address the challenges posed by multimorbidity in older adults, a person- and context-centred approach is needed. This study aimed to develop a questionnaire as a self-assessment tool for older adults focusing on functioning in general practice based on the International Classification of Functioning, Disability and Health (ICF). Methods A mixed-methods approach was employed in the development and validation of the German EFA23 (Erfassung Funktionaler Gesundheit im Alter – 23 Fragen; Assessing Functional Health in Old Age – 23 questions) questionnaire. Based on an ICF subset developed in a preparatory phase and consensus study, questionnaire items were formulated and tested in a qualitative pretest, followed by a validation study. A workshop with general practitioners (GPs) was held to develop a supplementary manual for GPs on how to interpret the questionnaire results and discuss them with the patients. Results A total of 69 items were developed and tested in the qualitative pretest with 15 respondents, resulting in 37 items for the validation study. The validation study, involving 237 older adults, showed the presence of one significant principal component. It demonstrated good internal consistency (Cronbach’s alpha = 0.967) and construct validity, showing positive correlations with established assessment tools. Descriptive statistics showed differences between the means of self-assessment by patients and an external GP assessment. The final EFA23 questionnaire consists of 23 items assessing limitations in functioning. Conclusions The EFA23 questionnaire can be used as a valid self-assessment instrument to measure functioning in older adults, supporting a person- and context-centred approach in general practice.

Abstract Background Dexmedetomidine and propofol are common sedatives in intensive care units and for interventional procedures. Both may compromise sinus node function and atrioventricular conduction. The objective of this prospective, randomized study is to compare the effect of dexmedetomidine with propofol on sinus node function and atrioventricular conduction. Methods In a tertiary care center in Switzerland we included from September 2019 to October 2020 160 patients (65 ± 11 years old; 32% female) undergoing first ablation for atrial fibrillation by cryoballoon ablation or by radiofrequency ablation. Patients were randomly assigned to deep sedation with dexmedetomidine (DEX group) versus propofol (PRO group). A standard electrophysiological study was performed after pulmonary vein isolation with the patients still deeply sedated and hemodynamically stable. Results Eighty patients each were randomized to the DEX and PRO group. DEX group patients had higher baseline sinus cycle length (1022 vs. 1138 ms; p = 0.003) and longer sinus node recovery time (SNRT400; 1597 vs. 1412 ms; p = 0.042). However, both corrected SNRT and normalized SNRT did not differ. DEX group patients had longer PR interval (207 vs. 186 ms; p = 0.002) and AH interval (111 vs. 95 ms, p = 0.008), longer Wenckebach cycle length of the atrioventricular node (512 vs. 456 ms; p = 0.005), and longer atrioventricular node effective refractory period (390 vs. 344 ms; p = 0.009). QRS width and HV interval were not different. An arrhythmia, mainly atrial fibrillation, was induced in 33 patients during the electrophysiological study, without differences among groups (20% vs. 15%, p = 0.533). Conclusions Dexmedetomidine has a more pronounced slowing effect on sinus rate and suprahissian AV conduction than propofol, but not on infrahissian AV conduction and ventricular repolarization. These differences need to be taken into account when using these sedatives. Trial registration ClinicalTrials.gov number NCT03844841, 19/02/2019

Abstract Experimental High Energy Physics has entered an era of precision measurements. However, measurements of many of the accessible processes assume that the final states’ underlying kinematic distribution is the same as the Standard Model prediction. This assumption introduces an implicit model-dependency into the measurement, rendering the reinterpretation of the experimental analysis complicated without reanalysing the underlying data. We present a novel reweighting method in order to perform reinterpretation of particle physics measurements. It makes use of reweighting the Standard Model templates according to kinematic signal distributions of alternative theoretical models, prior to performing the statistical analysis. The generality of this method allows us to perform statistical inference in the space of theoretical parameters, assuming different kinematic distributions, according to a beyond Standard Model prediction. We implement our method as an extension to the pyhf software and interface it with the EOS software, which allows us to perform flavor physics phenomenology studies. Furthermore, we argue that, beyond the pyhf or HistFactory likelihood specification, only minimal information is necessary to make a likelihood model-agnostic and hence easily reinterpretable. We showcase that publishing such likelihoods is crucial for a full exploitation of experimental results.

Abstract Simulating high-resolution detector responses is a computationally intensive process that has long been challenging in Particle Physics. Despite the ability of generative models to streamline it, full ultra-high-granularity detector simulation still proves to be difficult as it contains correlated and fine-grained information. To overcome these limitations, we propose Intra-Event Aware Generative Adversarial Network (IEA-GAN). IEA-GAN presents a Transformer-based Relational Reasoning Module that approximates an event in detector simulation, generating contextualized high-resolution full detector responses with a proper relational inductive bias. IEA-GAN also introduces a Self-Supervised intra-event aware loss and Uniformity loss, significantly enhancing sample fidelity and diversity. We demonstrate IEA-GAN’s application in generating sensor-dependent images for the ultra-high-granularity Pixel Vertex Detector (PXD), with more than 7.5 M information channels at the Belle II Experiment. Applications of this work span from Foundation Models for high-granularity detector simulation, such as at the HL-LHC (High Luminosity LHC), to simulation-based inference and fine-grained density estimation.

AimAnalysis of data from bicycle accidents reveals that handlebar impacts are a significant cause of injury, particularly among children. Despite existing safety regulations, such as helmet requirements, little attention is given to abdominal injuries. The aim of this study is to investigate the influence of handlebar ends on abdominal loading during bicycle crashes.MethodsThis study delves into the impact of five different handlebar designs on abdominal injuries during bicycle crashes, using finite element simulations with detailed Human Body Models (HBMs) of a six-year-old child (PIPER child model, Version 0.99.0). Four impact locations were identified in the injury scenario, selected according to the anatomical location of the most commonly injured organs, liver, pancreas, spleen and abdomen.ResultsGrip design features, such as shape and rigidity, significantly influence injury outcomes. Grips designed specifically for children demonstrate superior performance in reducing abdominal loading and injury metrics compared to standard grips. The highest injury potential was seen in a damaged handlebar end.ConclusionThese findings underscore the importance of improved handlebar designs and standardized safety measures, especially for children. Implementation of such measures could mitigate the significant health and economic burden associated with handlebar-related injuries and enhance overall bicycle safety for children.

BackgroundThe digital transformation in health care requires training nursing and health professionals in the digitally competent use of digital assistive technologies (DAT). The continuing education training “Beratende für digitale Gesundheitsversorgung” (“Consultant for Digital Healthcare”) was developed to fill this gap. The effectiveness of the training program will be assessed in this study. ObjectiveThe primary objective is to record and measure the participants’ learning success. We will assess whether the previously defined teaching intentions, learning objectives, competencies, and participants’ expectations have been achieved and whether a transfer of learning occurred. The secondary objective is participant satisfaction and feasibility of the training. The tertiary objective is the successful transfer of DAT by participants in their institutions. MethodsApproximately 65 nursing and health care professionals will participate in the pilot phase of the further training and evaluation process, which is planned in a mixed methods design in a nonsequential manner. The different methods will be combined in the interpretation of the results to achieve a synaptic view of the training program. We plan to conduct pre-post surveys in the form of participant self-assessments about dealing with DAT and content-related knowledge levels. Exploratory individual interviews will also be conducted to build theory, to examine whether and to what extent competence (cognition) has increased, and whether dealing (affect) with DAT has changed. Furthermore, an interim evaluation within the framework of the Teaching Analysis Poll (TAP) will occur. The knowledge thereby gained will be used to revise and adapt the modules for future courses. To assess the transfer success, the participants create a practical project, which is carried out within the training framework, observed by the lecturers, and subsequently evaluated and adapted. ResultsWe expect that the learning objectives for the continuing education training will be met. The attendees are expected to increase their level of digital competence in different skills areas: (1) theoretical knowledge, (2) hands-on skills for planning the application and practical use of DAT, (3) reflective skills and applying ethical and legal considerations in their use, (4) applying all that in a structured process of technology implementation within their practical sphere of work. ConclusionsThe aim of this study and appropriate further training program are to educate nursing and health care professionals in the use of DAT, thereby empowering them for a structured change process toward digitally aided care. This focus gives rise to the following research questions: First, how should further training programs be developed, and which focus is appropriate for addressee-appropriate learning goals, course structure, and general curriculum? Second, how should a training program with this specific content and area be evaluated? Third, what are the conditions to offer a continued program? International Registered Report Identifier (IRRID)PRR1-10.2196/57860

Background A consensus definition for active sacroiliitis by MRI, mentioned in the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), was published in 2009 and included a qualitative and quantitative MRI cut-off component. In 2021, updates to the quantitative component were preliminarily proposed. This post hoc analysis of part A of the phase 3 open-label C-OPTIMISE study (NCT02505542) explores the differences by applying the 2009 and preliminary 2021 inflammatory cut-offs on clinical outcomes of axSpA patients treated with certolizumab pegol.Methods Baseline MRI scans were used to classify 657 patients as MRI+ or MRI– according to the quantitative components of the 2009 and preliminary 2021 MRI cut-offs for inflammatory lesions. Clinical outcomes, including ASAS ≥40% improvement (ASAS40), Ankylosing Spondylitis Disease Activity Score and Bath Ankylosing Spondylitis Disease Activity Index, were reported to week 48.Results Across all analysed outcomes, 2009 MRI+ and preliminary 2021 MRI+ subgroups showed similar results. Notably, clinical outcomes for the discordant group (2009 MRI+but preliminary 2021 MRI– group; 53/657 [8.1%]) were close to those seen in MRI– patients according to either 2009 or preliminary 2021 inflammatory cut-offs, and notably different from the totality of MRI+ subgroups.Conclusion This analysis suggests that the preliminary 2021 cut-offs for MRI inflammatory lesions may slightly increase the specificity of the quantitative part of the 2009 MRI inflammatory lesion definition. The effects of the updated MRI cut-offs need to be assessed on the basis of efficacy outcomes and with the inclusion of aspects of structural changes.Trial registration number NCT02505542.

Introduction This post hoc analysis evaluated the relationship between objective measures of inflammation and clinical outcomes following 12 weeks of certolizumab pegol (CZP) treatment in patients with active axial spondyloarthritis (axSpA).Methods We report the proportion of patients achieving ≥50% and ≥75% improvements in clinical composite outcome measures of disease activity (Axial Spondyloarthritis Disease Activity Score [ASDAS], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) and objective measures of inflammation (C reactive protein [CRP], Ankylosing Spondylitis spine MRI score [ASspiMRI-a] Berlin score and Spondyloarthritis Research Consortium of Canada [SPARCC] MRI Sacroiliac Joints [SIJ] score) following 12 weeks of CZP treatment. Data from two independent readers over four MRI reading campaigns were pooled using a mixed model with repeated measures for each variable.Results 136 patients (radiographic axSpA [r-axSpA]: 76; non-radiographic axSpA [nr-axSpA]: 60) were included. Following CZP treatment, CRP, ASspiMRI-a Berlin score and SPARCC SIJ score were reduced by ≥50% in most patients (CRP: 136/136 [100.0%]; Berlin: 73/136 [53.7%]; SPARCC SIJ: 71/136 [52.2%]), and often by ≥75%. Less than half of patients with r-axSpA and nr-axSpA showed ≥50% reduction in clinical responses (BASDAI: 64/136 [47.1%]; ASDAS: 66/136 [48.5%]). These results were also observed at the individual patient level; ≥50% improvements in MRI/CRP inflammatory measures did not translate into similar improvements in clinical responses for most patients.Conclusion There is a potential disconnect between objective measures of inflammation and clinical outcome responses in patients with axSpA. The use of only clinical response measures as trial endpoints may underestimate anti-inflammatory treatment effects.Trial registration number NCT01087762.

The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70–72 Gy (EQD2/α/β = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic’s multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL.Clinical Trial Registrationclinicaltrials.gov, identifier NCT06137378.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.

Binary systems containing a compact object may exhibit periodic brightening episodes due to gravitational lensing as the compact object transits the companion star. Such "self-lensing" signatures have been detected before for white dwarf binaries. We attempt to use these signatures to identify detached stellar-mass neutron star and black hole binaries using data from the Zwicky Transient Facility (ZTF). We present a systematic search for self-lensing signals in Galactic binaries from a subset of high-cadence ZTF data taken in 2018. We identify 12 plausible candidates from the search, although because each candidate is observed to only brighten once, other origins such as stellar flares are more likely. We discuss prospects for more comprehensive future searches of the ZTF data.

Purpose: to systematically review comparative studies reporting revision rates, clinical outcomes, or radiographic outcomes of total hip arthroplasty (THA) using collared versus collarless conventional-length uncemented hydroxyapatite (HA)-coated stems. Methods: In adherence with PRISMA guidelines, a literature search was performed on Medline, Embase, and Scopus. Comparative clinical studies were eligible if they reported outcomes of collared versus collarless uncemented HA-coated stems for primary THA. Two reviewers screened titles, abstracts, and full-texts to determine eligibility; then performed data extraction; and assessed the quality of studies according to Joanna Briggs Institute (JBI) checklist. Results: The search returned 972 records, 486 were duplicates, and 479 were excluded after title/abstract/full-text screening. Three further studies were included from the references of eligible studies and from discussions with subject matter experts, resulting in 11 included studies. The JBI checklist indicated six studies scored ≥7 points and four studies ≥4 points. Pooled data revealed collared stems had significantly lower revision rates (OR = 0.45; 95% CI = 0.31–0.64) and subsidence (MD = −1 mm; 95% CI = −1.6–-0.3), but no significant difference in intraoperative complication rates (OR = 0.94; 95% CI = 0.67–1.32) in the short term to mid-term. Unpooled data indicated that collared stems provide equivalent survival, equivalent or better outcomes, and equivalent or lower complication rates. Conclusion: In comparative studies, collared stems have lower revision rates than collarless stems, as well as equivalent or better clinical and radiographic outcomes. Differences could be due to a protective effect that the collar offers against subsidence, particularly in undersized or misaligned stems. Further studies are warranted to confirm long-term results and better understand differences between registry data and clinical studies.

Background: Via ferrata (VF) climbing is an increasingly popular mountain activity in the European Alps. The purpose of this study was to determine the nature of injuries incurred by VF climbers and to understand the extent of their First Aid (FA) knowledge and training. Materials and methods: A questionnaire-based cohort study was performed at two alpine locations. Data included basic data (age, gender, climbing activities, exercise), 18 multiple choice questions with 5 answers each concerning First Aid (FA) knowledge and a self-rating of FA knowledge. Statistics were performed with non-parametric tests. Results: 391 questionnaires were completed. Sunburns (23.9%), contusions (17.7%), open wounds (13.1%), and exhaustion-related injuries were the most reported incidents. Exhaustion was the most common emergency call. Only 52% of climbers wore helmets and gloves, less than 25% had adequate physical conditioning, and 28.1% reported having no FA training. The most common causes of emergencies were weather conditions (19%), stumbles (18.6%), falls (13.4%), and fatigue and deficiency in concentration (13.4%). Only 11 of the surveyed climbers scored 75% on their FA knowledge questions. VF climbers showed significant less FA knowledge than alpine mountaineers. They scored quite high on questions related to general FA but low on questions related to high altitude sickness, back, and thoracic injuries. Conclusions: VF climbers should seek out FA training every two years with an emphasis placed on sunburns, contusions, open wounds, and exhaustion injuries. The training should also emphasize the prevention of back and thoracic trauma and developing rescue strategies.

Abstract Breath analysis offers tremendous potential for diagnostic approaches, since it allows for easy and non-invasive sample collection. “Breathomics” as one major research field comprehensively analyses the metabolomic profile of exhaled breath providing insights into various (patho)physiological processes. Recent research, however, primarily focuses on volatile compounds. This is the first study that evaluates the non-volatile organic compounds (nVOCs) in breath following an untargeted metabolomic approach. Herein, we developed an innovative method utilizing a filter-based device for metabolite extraction. Breath samples of 101 healthy volunteers (female n = 50) were analysed using DI-FT-ICR-MS and biostatistically evaluated. The characterisation of the non-volatile core breathome identified more than 1100 metabolites including various amino acids, organic and fatty acids and conjugates thereof, carbohydrates as well as diverse hydrophilic and lipophilic nVOCs. The data shows gender-specific differences in metabolic patterns with 570 significant metabolites. Male and female metabolomic profiles of breath were distinguished by a random forest approach with an out-of-bag error of 0.0099. Additionally, the study examines how oral contraceptives and various lifestyle factors, like alcohol consumption, affect the non-volatile breathome. In conclusion, the successful application of a filter-based device combined with metabolomics-analyses delineate a non-volatile breathprint laying the foundation for discovering clinical biomarkers in exhaled breath.

Vaccinations against COVID-19 are of the utmost importance in long-term care facilities. During the pandemic, mental health issues increased significantly. This cross-sectional analysis aimed to assess the associations of depression and anxiety with health literacy in people in need of care and the association of depression and burnout with vaccination readiness against COVID-19 in health care workers (HCWs). Within our cross-sectional study, people in need of care were assessed for symptoms of depression (PHQ-9), anxiety (GAD-7), and health literacy (HLS-EU-Q16). Among HCWs, we assessed symptoms of depression (PHQ-9) and burnout (MBI-HSS), as well as psychological antecedents of vaccination (5C) to measure vaccination readiness against COVID-19. A multivariate regression analysis was performed. Symptoms of a major depression were significantly associated with reduced health literacy (p = 0.010) in people in need of care. Among HCWs, symptoms of depression and burnout reduced vaccination readiness against COVID-19 significantly. In particular, collective responsibility was reduced in HCWs suffering from burnout symptoms (p = 0.001). People in need of care and their HCWs could benefit from intensified target group-specific vaccination counseling. Additionally, more attention should be paid to the protection of mental health in long-term care facilities.

AIM OF THE STUDY: The purpose of the present study was to evaluate demographic characteristics of inmates in the Canton of Zurich (exposure), and investigate the changes in diseases and drug use between 2015 and 2020 (outcome). METHODS: The study prospectively evaluated 51,989 inmates admitted to the Police Prison Zurich in Switzerland between 1 April 2015 and 31 August 2020 and who were systematically medically assessed. A total of 19,027 (37%) inmates had one or more health conditions, which the authors recorded according to the International Classification of Diseases-10 (ICD-10), in addition to demographic data (country of origin, sex, age, year of imprisonment), as well as details of any drugs used (type and dosage). RESULTS: The 19,027 inmates with medical conditions had a mean age of 35.4±12.5 years (range 10–89) and comprised 16,489 males (87%). The inmates originated from 170 countries, including 4606 from Switzerland (24.2%), 4227 from Eastern Europe (22%) and 3432 from the Middle East & North Africa (18%). A total of 1631 inmates (9%) were enrolled in the medication-assisted treatment (MAT) programme, and 672 patients (4%) received a psychiatric evaluation. The proportions of foreign prisoners did not increase during the study period. There was a significant increase in the use of antipsychotics from year 1 to 5 (y = 0.866x; R2 = 0.902; p = 0.01) and anticonvulsants from year 1 to 4 (y = 1.27x; R2 = 0.823; p = 0.01), and a significant decrease in the use of analgesics from year 2 to 5 (y = -4.42x; R2 = 0.947; p = 0.03) and antianxiety drugs from year 1 to 4 (y = -3.31x; R2 = 0.989; p = 0.005). Inmates from Switzerland were most likely to use antianxiety drugs, while inmates from the Middle East & North Africa were most likely to use antipsychotics (OR 2.09; CI 1.88–2.34) and anticonvulsants (OR 3.52; CI 2.90–4.29), whereas inmates from Latin and North America were most likely to use herbal medicine (OR 1.50; CI 1.05–2.10). CONCLUSIONS: The findings of this study could help anticipate needs of prisons as well as improve treatment of disease and assist with substance use or abuse, particularly in the context of migration.

Objectives Medical overuse exposes patients to unnecessary risks of harm. It is an open question whether and how patients perceive the concept of medical overuse, its causes and negative consequences.Design A qualitative study design, using elements of the Grounded Theory Approach by Strauss and Corbin.Setting Between May 2017 and January 2020, we recruited participants and conducted face-to-face interviews in the participants’ homes. Data collection took place in Bavaria, Germany.Participants We recruited 16 participants (female=8, male=8) with various characteristics for the study. We used different strategies such as flyers in supermarkets, pharmacies, participants spreading information about the study or local multipliers (snowball sampling).Results The participants mostly defined medical overuse as too much being done but understood the concept superficially. During the interviews, most participants could describe examples of medical overuse. They named a variety of direct and indirect drivers with economic factors suspected to be the main driver. As a consequence of medical overuse, participants named the physical and emotional harm (eg, side effects of medication). They found it difficult to formulate concrete solutions. In general, they saw themselves more in a passive role than being responsible for bringing about change and solutions themselves. Medical overuse is a ‘problem of the others’. The participants emphasised that health education is important in reducing medical overuse.Conclusions Medical overuse was little discussed among participants, although many participants reported experiences of too much medicine. Health education and strengthening the patients’ self-responsibility can play a vital role in reducing medical overuse.

BackgroundData on the use of the wearable cardioverter defibrillator in patients suffering from inherited and congenital heart disease are limited. Consequently, evidence for guideline recommendations in this patient population is lacking.MethodsIn total 1,675 patients were included in a multicenter registry of eight European centers. In the present cohort, we included 18 patients suffering from congenital and inherited heart disease.ResultsNine patients (50%) were male with a mean age of 41.3 ± 16.4 years. Four patients suffered from hypertrophic cardiomyopathy (HCM), four patients suffered from non-compaction cardiomyopathy (NCCM), two patients were diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one patient suffered from muscular dystrophy of the limb-girdle type with cardiac involvement, secondary cardiomyopathy. Three patients presented with Brugada syndrome (BrS). One patient suffered from long-QT syndrome type 1 (LQTS1). Furthermore, two patients had congenital heart defects and one patient suffered from cardiac sarcoidosis (CS). There were no appropriate/inappropriate shocks with the WCD in this cohort. One patient had recurrent self-limiting sustained ventricular tachycardia during the wear time, but actively inhibited a shock and was hospitalized. The compliance rate in this cohort was 77.8% with a mean wear time of 45.3 ± 26.9 days with a mean follow-up time of 570 ± 734 days. 55.6% (10/18) of the patients received an ICD after WCD wear time.ConclusionsThis retrospective study of patients with inherited and congenital heart disease shows that WCD use is not beneficial in the majority of patients with inherited and congenital heart disease.

A new study reveals how naturally occurring mutations affect the biophysical properties of nucleocapsid proteins in SARS-CoV-2.

Abstract Ferromanganese (FeMn) crusts are Fe and Mn oxides that typically form on deep‐sea elevations by deposition of colloids from seawater. These mineral deposits are considered a source of critical metals and rare earth elements. Besides their potential economic value, FeMn crusts are extremely relevant in ocean science, since their very slow growth rates result in long‐term paleoenvironmental and paleoceanographic records. In this study, we applied geochemical, mineralogical, and magnetic analyses to unravel paleoenvironmental changes at two locations on opposite sides of the Atlantic Ocean, the Rio Grande Rise in the SW Atlantic and the Tropic Seamount in the NE Atlantic. Our results show that the occurrence of amorphous (non‐crystalline) Fe oxyhydroxides and the absence of Fe oxides in hydrogenetic, non‐phosphatized FeMn crusts prevented the development of primary remanent magnetization. In contrast, phosphatized FeMn crusts may have contained a remanent magnetic signal. Phosphatization resulted from increased primary productivity and occurred at different stages during the growth of the FeMn crusts, leading to suboxic conditions and partial dissolution of pre‐existing, remanence‐carrying magnetic minerals. Carbonate Fluorapatite (CFA) accumulation in the phosphatized layers of FeMn crusts replaced Fe and Mn, decreasing their magnetic content. Thus, magnetic variations do not reflect a primary magnetization but rather result from geochemical alterations. The loss of primary magnetization may hamper the use of FeMn deposits for magnetostratigraphic purposes.

Purpose: Many publications address the epidemiology of secondary osteosarcomas following retinoblastoma. Treatment- and outcome-related information is, however, scarce. We used a large cooperative group’s database to study this issue. Patients and methods: The database Cooperative Osteosarcoma Study Group COSS was searched for patients with osteosarcoma following a previous retinoblastoma. Patients were then analyzed for demographic factors, local/systemic treatments received, and outcomes. Results: 28 eligible patients were identified. Median age at retinoblastoma was .5 years, 89% occurred bilaterally. Retinoblastoma-therapy was by surgery in 26/27, radiotherapy in 26/27, chemotherapy in 10/26 (rest unknown). Osteosarcoma was diagnosed after 13.7 (3.1 – 36.1) years, extremities and head/neck affected in 14/28, each. Four/28 patients had primary metastases. Osteosarcoma treatment included chemotherapy in all cases, local therapy surgery in 27/28. Histological response was good in 9/16 evaluable cases. Surgery of all sites was macroscopically complete in 23/27 operated tumors and microscopically complete in 17/26 (1 unknown). Radiotherapy was administered to 3 craniofacial tumors. Median follow-up was 3.5 (.4 – 30.1) years from osteosarcoma diagnosis, 8/28 patients remaining event-free. Altogether, five patients suffered further secondary malignancies. Actuarial overall and event-free survival at 2 and 5 years from osteosarcoma were 73% (standard error: 8%) / 50% (10%) and 47% (10%) / 22% (9%), respectively. Conclusion: This comparatively large cohort of osteosarcomas after retinoblastoma proves that the latter may be treated curatively. While their prognosis is far worse than that of primary osteosarcomas, partly due to a predilection for craniofacial involvement, selected patients may still become long-term survivors with appropriate therapies.

IntroductionLarynx organ preservation (LOP) in locoregional-advanced laryngeal and hypopharyngeal squamous cell carcinoma (LA-LHSCC) being only R0-resectable (clear margins > 5 mm) by total laryngectomy (TL) is desirable. Based on tumor-specific survival (TSS) and overall survival (OS) data from the RTOG 91-11 trial and meta-analyses of randomized clinical trials (RCTs), cisplatin-based concurrent radiochemotherapy (CRT) is discussed being superior to cisplatin-based induction chemotherapy followed by radiotherapy (IC+RT) and TL followed by postoperative RT (TL+PORT) or radiochemotherapy (TL+PORCT). Outside of RCTs, T4 LHSCC treated with TL+PORCT demonstrated improved OS and TSS compared to CRT alone; comparisons with docetaxel plus cisplatin (TP)-based IC+RT are unpublished. Head-to-head comparisons in RCTs of these four alternatives are missing.Materials and methodsWe utilized monocentric registry data to compare the outcome in the LOP trial DeLOS-II (NCT00508664) and propensity score (PS)–matched LHSCC patients. DeLOS-II utilized endoscopic tumor staging after one cycle of TP-based IC for selecting TL+R(C)T for non-responders versus IC+RT for responders. Main risk factors for survival (localization hypopharynx, T4, N+, tobacco smoking >30 pack years, alcohol consumption >60 g/day, age, sex) were used to calculate the individual PS for each DeLOS-II patient and 330 LHSCC patients suitable for DeLOS-II according to eligibility criteria in Leipzig by CRT (78), TL+PORT (148), and TL+PORCT (104). We performed PS matching with caliper width 0.2.ResultsThe 52 DeLOS-II patients (whole intent-to-treat cohort) and three PS-matched cohorts (52 LHSCC patients each) had equal distribution regarding risk factors including Charlson comorbidity score (CS; all p > 0.05) but differed in outcome. During 12,498.6 months of follow-up, 162 deaths (36/41/43/42 in DeLOS-II/TL+PORCT/TL+PORT/CRT, p = 0.356) occurred; DeLOS-II patients had superior OS and TSS. Compared to DeLOS-II, the HR (95% CI) observed in TL+PORCT, TL+PORT, and CRT for OS and TSS were 1.49 (0.92–2.43), 1.49 (1.15–3.18), and 1.81 (1.11–2.96) for OS; and 2.07 (0.944–4.58), 3.02 (1.32–6.89), and 3.40 (1.58–7.31) for TSS.ConclusionIn addition potential LOP, LA-LHSCC suitable for LOP according the DeLOS-II protocol may achieve improved survival.

Many practicing physicians struggle to properly evaluate clinical research studies – they either simply do not know them, regard the reported findings as ‘truth’ since they were reported in a ‘reputable’ journal and blindly implement these interventions, or they disregard them as having little pragmatic impact or relevance to their daily clinical work. Three aspects for the latter are highlighted: study populations rarely reflect their practice population, the absolute average benefits on specific outcomes in most controlled studies, while statistically significant, are so small that they are pragmatically irrelevant, and overall mortality between the intervention and control groups are unaffected. These observations underscore the need to rethink our research approaches in the clinical context – moving from the predominant reductionist to an eco-systemic research approach will lead to knowledge better suited to clinical decision-making for an individual patient as it takes into account the complex interplay of multi-level variables that impact health outcomes in the real-world setting.

The functionality of photoreceptors, rods, and cones is highly dependent on their outer segments (POS), a cellular compartment containing highly organized membranous structures that generate biochemical signals from incident light. While POS formation and degeneration are qualitatively assessed on microscopy images, reliable methodology for quantitative analyses is still limited. Here, we developed methods to quantify POS (QuaPOS) maturation and quality on retinal sections using automated image analyses. POS formation was examined during the development and in adulthood of wild-type mice via light microscopy (LM) and transmission electron microscopy (TEM). To quantify the number, size, shape, and fluorescence intensity of POS, retinal cryosections were immunostained for the cone POS marker S-opsin. Fluorescence images were used to train the robust classifier QuaPOS-LM based on supervised machine learning for automated image segmentation. Characteristic features of segmentation results were extracted to quantify the maturation of cone POS. Subsequently, this quantification method was applied to characterize POS degeneration in “cone photoreceptor function loss 1” mice. TEM images were used to establish the ultrastructural quantification method QuaPOS-TEM for the alignment of POS membranes. Images were analyzed using a custom-written MATLAB code to extract the orientation of membranes from the image gradient and their alignment (coherency). This analysis was used to quantify the POS morphology of wild-type and two inherited retinal degeneration (“retinal degeneration 19” and “rhodopsin knock-out”) mouse lines. Both automated analysis technologies provided robust characterization and quantification of POS based on LM or TEM images. Automated image segmentation by the classifier QuaPOS-LM and analysis of the orientation of membrane stacks by QuaPOS-TEM using fluorescent or TEM images allowed quantitative evaluation of POS formation and quality. The assessments showed an increase in POS number, volume, and membrane coherency during wild-type postnatal development, while a decrease in all three observables was detected in different retinal degeneration mouse models. All the code used for the presented analysis is open source, including example datasets to reproduce the findings. Hence, the QuaPOS quantification methods are useful for in-depth characterization of POS on retinal sections in developmental studies, for disease modeling, or after therapeutic interventions affecting photoreceptors.

Objective There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs of inflammation such as MRI or C-reactive protein (CRP) levels. This study reports clinical outcomes up to 3 years of the C-axSpAnd trial, including safety follow-up extension (SFE) from Weeks 52 to 156, stratified by patients’ baseline MRI and CRP status.Methods C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated certolizumab pegol (CZP) in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. In this post hoc analysis, efficacy outcomes are reported to Week 156 of C-axSpAnd for patients stratified according to their MRI and CRP status at Week 0 (MRI+/CRP−, MRI−/CRP+ and MRI+/CRP+).Results Across all outcome measures, including major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) and Assessment of SpondyloArthritis international Society criteria ≥40% response (ASAS40), outcomes were generally sustained in SFE patients from Week 52 to Week 156. MRI+/CRP+ patients showed numerically higher or comparable responses relative to MRI−/CRP+ and MRI+/CRP− patients at Weeks 52 and 156; however, all three subgroups demonstrated substantial improvements from Week 0 (in CZP-randomised patients, ASDAS-MI at Week 156 [observed case]: MRI+/CRP+: 73.1%, MRI–/CRP+: 52.2%, MRI+/CRP–: 30.4%; ASAS40: MRI+/CRP+: 76.9%, MRI–/CRP+: 62.5%, MRI+/CRP–: 65.2%).Conclusions In patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI−/CRP+ and MRI+/CRP− subgroups.

This paper present an initial approach to the analysis of the stationarity of time-variant channels in industrial environments, focusing on three distinct scenarios: 1) communication between a static access point (AP) and a sensor node (SN) mounted on a moving machine within a comprehensive industrial workspace, 2) communication between two static sensor node (SN) with a moving metal plate object between them, and 3) communication between two static robotic manipulators with a moving obstacle with varying movement speeds between them. The assumptions of the wide-sense stationary (WSS) and uncorrelated scatering (US), fundamental to channel modeling, are examined using local scattering function (LSF) collinearity metrics in both time and frequency domains. In blockage scenarios, where we compared the effects of two different types of obstacles – a metal plate and a robotic arm – the channel behavior can be divided into three distinct regions: fully stationary before and after the blockage, non-stationary during the transition periods, and either conditionally stationary or fully non-stationary during partial or full blockage, respectively. These distinctions were influenced by the type of blockage object and whether the scenario involved non-line-of-sight (NLOS) or obstructed-line-of-sight (OLOS) conditions. Notably, the speed of moving obstacles affects the duration and nature of non-stationary regions, with higher speeds leading to shorter and less distinct transition periods. The US assumption was found to be generally valid in the blockage scenarios but not in the AP scenario.

The aim of channel models is the effective prediction of wireless channels in applicationspecific environments in order to successfully design wireless communication systems. For THz communications, deterministic ray-optical channel predictions are very common. This paper shows inherent limitations of ray-tracing based models due to the accuracy of three-dimensional models of the environment in the context of THz communications and presents a new hybrid channel model approach that combines ray-optical channel predictions with an analytic path gain model extracted from measurements. The model is applied for switchable, point-to-point, wireless inter-rack links at THz frequencies in a data center that make the data center network reconfigurable at runtime. The channel parameters derived by the novel hybrid approach show promising results compared with channel parameters extracted from conducted reference measurements with an overall path gain error below 5 dB for residual multipath components.

Abstract Background Despite general practitioners' (GPs') key role in Germany`s primary health care, clinical research in general practice is scarce. Clinical research is mainly conducted at inpatient facilities, although their results are rarely transferable. German GPs have no extra time or funding for research, as well as limited research training. To support clinical research in German primary health care, practice-based research networks (PBRNs) are developed. As they will be based on an active involvement of GPs, we need more information on GPs` participation-readiness. The aim of this study was to explore facilitators and barriers to participation in the Bavarian Research Practice Network (BayFoNet) from the GPs`perspective before clinical trials will be performed. Methods We have performed semi-structured qualitative interviews with a purposive sample of 20 Bavarian GPs in 2022 under the application of the consolidated framework for implementation research (CFIR). Transcriptions were analysed according to Kuckartz` qualitative content analysis. The five domains of the CFIR framework served as initial deductive codes. Results N = 14 interviewees already agreed to participate in BayFoNet, whereas n = 6 interviewees opted not to participate in BayFoNet at the time of data collection. Main facilitators to conduct clinical research within BayFoNet were the motivation to contribute to evidence strength and quality in general practice, professional development and training of practice staff, as well as networking. Barriers for an active participation were bad experiences with previous clinical studies and lack of resources. Conclusions PBRNS in Germany have to be promoted and the entire practice team has to be involved at an early stage of development. Professional training of general practice staff and a living network might enhance engagement. Participatory approaches could help to develop acceptable and feasible study designs. Furthermore, PBRNs should support patient recruitment and data collection in general practices and disseminate the results of their research projects regularly to maintain GPs` engagement. Trial registration DRKS00028805, NCT05667207.

This article presents comprehensive double-directional channel measurements with time-domain channel sounding at 300 GHz that characterize the channel of wireless links in a data center. The channels are classified into three scenario-dependent use cases and are individually analyzed providing channel parameters as a function of the required signal-to-noise ratio of the prospective communication system. The spatial and temporal analysis of the channel reveals relevant propagation effects such as the influence of scattering and derives relations between the channel parameters of the propagation and the radio channel. The analysis shows that multipath propagation becomes relevant for systems with high signal-to-noise ratio requirements despite high-gain directional antennas. A first order approximation of relevant propagation effects complements the analysis. The measurement data of the whole measurement campaign with 18250 calibrated impulse responses including all meta data is published so that the research community has a collective benefit.

For 5G/6G system simulations and radio planning the availability of both accurate and run-time efficient channel predictors is required. This paper presents a 3D ray tracing channel predictor, which takes into account the relevant propagation phenomena like free space propagation, reflection, scattering, diffraction and transmission. The predictor is validated by two types of measurements and the relevance of the various propagation phenomena is analyzed based on predictions in a city using real base station locations and building data. Based on these results an acceleration methodology for the search of reflected paths is derived, which is able to reduce the computation time to 40% compared to the baseline prediction.

Abstract Exposures of the Earth’s crust-mantle transition are scarce, thus, limiting our knowledge about the formation of subcontinental underplate cumulates, and their significance for metal storage and migration. Here, we investigated chalcophile metals to track sulfide crystallization within the Contact Series, an

Background: The effect of sleeping positions during acclimatization to high altitude on Acute Mountain Sickness (AMS) and High Altitude Pulmonary Edema (HAPE) is unknown. We tested whether sleeping with the upper body raised by 5° reduces prevalence and severity of symptoms of AMS as well as of elevated pulmonary artery systolic pressure (PASP) values as a risk factor of HAPE. Methods: Randomly assigning trekking tourist volunteers n = 44 (25 m, 19 f; mean age 42.9 yr) sleeping at 4280 m or 5170 m to the experimental group (upper body elevated by 5°), or to the control group. After exclusion of other reasons for AMS-like symptoms those assumed to be related to AMS were rated by Lake Louise Score questionnaire in the evening and the following morning of the study. Transthoracic echocardiography was performed on both occasions to estimate PASP. Results: In the study group, symptoms of AMS were significantly reduced in younger subjects (p = 0.021), prevalence of AMS was reduced in women (p = 0.156), and PASP values were significantly reduced in older subjects and men (p = 0.032; p = 0.031 respectively). Conclusion: Results suggest that sleeping with the upper body in elevated position during a high altitude ascent may benefit those suffering from AMS or at risk of HAPE due to elevated PASP values.

Previous work on murine models and humans demonstrated global as well as tissue-specific molecular ageing trajectories of RNAs. Extracellular vesicles (EVs) are membrane vesicles mediating the horizontal transfer of genetic information between different tissues. We sequenced small regulatory RNAs (sncRNAs) in two mouse plasma fractions at five time points across the lifespan from 2–18 months: (1) sncRNAs that are free-circulating (fc-RNA) and (2) sncRNAs bound outside or inside EVs (EV-RNA). Different sncRNA classes exhibit unique ageing patterns that vary between the fcRNA and EV-RNA fractions. While tRNAs showed the highest correlation with ageing in both fractions, rRNAs exhibited inverse correlation trajectories between the EV- and fc-fractions. For miRNAs, the EV-RNA fraction was exceptionally strongly associated with ageing, especially the miR-29 family in adipose tissues. Sequencing of sncRNAs and coding genes in fat tissue of an independent cohort of aged mice up to 27 months highlighted the pivotal role of miR-29a-3p and miR-29b-3p in ageing-related gene regulation that we validated in a third cohort by RT-qPCR.

Abstract This study aimed to examine the influence of COVID-specific stressors on cross-sectional and longitudinal bereavement outcomes. According to the Dual Process Model of grief these stress-inducing factors can relate to the loss (loss-oriented stressors) or to manage everyday life (restoration-oriented stressors) and require coping in the grief process. A total of 491 participants (94.1% female; 43.92 years on average; 44.4% loss of a parent) were included at the first measurement time point (T0), of whom 99 individuals also participated in a follow-up assessment 6 months later (T1). Participants frequently reported loss-oriented (on average 7.30 out of 21 queried) and restoration-oriented stressors (on average 6.99 out of 19 queried). Cross-sectionally, higher acute grief intensity was associated with a higher number of loss-oriented stressors, poorer mental well-being, and sociodemographic variables. This effect disappeared longitudinally, with only acute grief intensity and poorer mental well-being at T0 predicting higher prolonged grief at T1. Common resilience factors did not buffer the effects of the pandemic on grief. Loss-oriented stressors seem to be especially relevant for understanding grief and might be a mediator of higher long-term grief. The findings suggest that COVID-specific strains need to be specifically taken into account in the support of bereaved individuals.

Abstract Recent developments in deep learning have shown success in accurately predicting the location of biological markers in Optical Coherence Tomography (OCT) volumes of patients with Age-Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). We propose a method that automatically locates biological markers to the Early Treatment Diabetic Retinopathy Study (ETDRS) rings, only requiring B-scan-level presence annotations. We trained a neural network using 22,723 OCT B-Scans of 460 eyes (433 patients) with AMD and DR, annotated with slice-level labels for Intraretinal Fluid (IRF) and Subretinal Fluid (SRF). The neural network outputs were mapped into the corresponding ETDRS rings. We incorporated the class annotations and domain knowledge into a loss function to constrain the output with biologically plausible solutions. The method was tested on a set of OCT volumes with 322 eyes (189 patients) with Diabetic Macular Edema, with slice-level SRF and IRF presence annotations for the ETDRS rings. Our method accurately predicted the presence of IRF and SRF in each ETDRS ring, outperforming previous baselines even in the most challenging scenarios. Our model was also successfully applied to en-face marker segmentation and showed consistency within C-scans, despite not incorporating volume information in the training process. We achieved a correlation coefficient of 0.946 for the prediction of the IRF area.

Abstract Molecular subtyping of lung squamous cell carcinoma (LUSC) has been performed at the genomic, transcriptomic, and proteomic level. However, LUSC stratification based on tissue metabolomics is still lacking. Combining high-mass-resolution imaging mass spectrometry with consensus clustering, four tumor- and four stroma-specific subtypes with distinct metabolite patterns were identified in 330 LUSC patients. The first tumor subtype T1 negatively correlated with DNA damage and immunological features including CD3, CD8, and PD-L1. The same features positively correlated with the tumor subtype T2. Tumor subtype T4 was associated with high PD-L1 expression. Compared with the status of subtypes T1 and T4, patients with subtype T3 had improved prognosis, and T3 was an independent prognostic factor with regard to UICC stage. Similarly, stroma subtypes were linked to distinct immunological features and metabolic pathways. Stroma subtype S4 had a better prognosis than S2. Subsequently, analyses based on an independent LUSC cohort treated by neoadjuvant therapy revealed that the S2 stroma subtype was associated with chemotherapy resistance. Clinically relevant patient subtypes as determined by tissue-based spatial metabolomics are a valuable addition to existing molecular classification systems. Metabolic differences among the subtypes and their associations with immunological features may contribute to the improvement of personalized therapy.

Abstract As the need for higher data rates for communication increases, the terahertz (THz) band has drawn considerable attention. This spectral region promises a much wider bandwidth and the transmission of large amounts of data at high speeds. However, there are still challenges that need to be addressed before the THz telecommunications technology hits the consumer market. One of the recurring concerns is that THz radiation is greatly absorbed by atmospheric water-vapor. Although many studies have presented the attenuation of THz signals under different atmospheric conditions, these results analyze specific temperature or humidity values, leaving the need for a more comprehensive analysis over a wider range of climate conditions. In this work, we present the first study of the attenuation of THz radiation over a broad range of temperatures and humidity values. It is worth noticing that all of our measurements have been undertaken at atmospheric pressure unlike many previous studies where the pressure was not kept constant for various temperatures. Furthermore, we extend our analysis beyond the impact of absolute humidity on the bit error rate in THz communications. We also discuss the refractivity of the atmosphere, examining its variations across different temperatures and humidity levels. THz propagation is studied using two different measurement systems, a long-path THz time-domain spectrometer as well as a quasi-optic setup with vector network analyze. We also compare the results with the ITU-R P.676-13 propagation model. We conclude that the attenuation at the absorption peaks increases linearly with water content and has no dependence on the temperature, while the refractive index, away from absorption lines, namely at 300 GHz shows a sub-linear increase with humidity.

Lichen planus (LP) is a highly prevalent inflammatory skin disease. While various clinical subtypes have been defined, detailed comparisons of these variants are lacking. This study aimed to elucidate differences in gene expression and cellular composition across LP subtypes. Lesional skin biopsies from 28 LP patients (classical, oral, genital, and lichen planopilaris) and seven non-diseased skin controls (NDC) were analyzed. Gene expression profiling of 730 inflammation-related genes was conducted using NanoString. Immune cell compositions were assessed by multiplex immunohistochemistry. Gene expression profiles revealed unique inflammatory signatures for each LP subtype. Lichen planopilaris exhibited the most divergence, with downregulated gene expression and upregulation of complement pathway genes (C5-7), along with elevated M2 macrophages. Oral and genital LP demonstrated similar profiles with strong upregulation of TNF-related and Toll-like receptor-associated genes. Oral LP showed the highest upregulation of cytotoxicity-associated genes, as well as high numbers of CD8+ IL-17A+ (Tc17) cells (8.02%). Interferon gene signatures were strongly upregulated in oral and classical LP. The study highlights distinct differences in inflammatory gene expression and cell composition across LP subtypes, emphasizing the need for tailored therapeutic approaches.

Introduction Uncomplicated urinary tract infections (uUTIs) in women are common infections encountered in primary care. Evidence suggests that rapid point-of-care tests (POCTs) to detect bacteria and erythrocytes in urine at presentation may help primary care clinicians to identify women with uUTIs in whom antibiotics can be withheld without influencing clinical outcomes. This pilot study aims to provide preliminary evidence on whether a POCT informed management of uUTI in women can safely reduce antibiotic use.Methods and analysis This is an open-label two-arm parallel cluster-randomised controlled pilot trial. 20 general practices affiliated with the Bavarian Practice-Based Research Network (BayFoNet) in Germany were randomly assigned to deliver patient management based on POCTs or to provide usual care. POCTs consist of phase-contrast microscopy to detect bacteria and urinary dipsticks to detect erythrocytes in urine samples. In both arms, urine samples will be obtained at presentation for POCTs (intervention arm only) and microbiological analysis. Women will be followed-up for 28 days from enrolment using self-reported symptom diaries, telephone follow-up and a review of the electronic medical record. Primary outcomes are feasibility of patient enrolment and retention rates per site, which will be summarised by means and SDs, with corresponding confidence and prediction intervals. Secondary outcomes include antibiotic use for UTI at day 28, time to symptom resolution, symptom burden, number of recurrent and upper UTIs and re-consultations and diagnostic accuracy of POCTs versus urine culture as the reference standard. These outcomes will be explored at cluster-levels and individual-levels using descriptive statistics, two-sample hypothesis tests and mixed effects models or generalised estimation equations.Ethics and dissemination The University of Würzburg institutional review board approved MicUTI on 16 December 2022 (protocol n. 109/22-sc). Study findings will be disseminated through peer-reviewed publications, conferences, reports addressed to clinicians and the local citizen’s forums.Trial registration number ClinicalTrials.gov NCT05667207.

Summary: Endocrine cells employ regulated exocytosis of secretory granules to secrete hormones and neurotransmitters. Secretory granule exocytosis depends on spatiotemporal variables such as proximity to the plasma membrane and age, with newly generated granules being preferentially released. Despite recent advances, we lack a comprehensive view of the molecular composition of insulin granules and associated changes over their lifetime. Here, we report a strategy for the purification of insulin secretory granules of distinct age from insulinoma INS-1 cells. Tagging the granule-resident protein phogrin with a cleavable CLIP tag, we obtain intact fractions of age-distinct granules for proteomic and lipidomic analyses. We find that the lipid composition changes over time, along with the physical properties of the membrane, and that kinesin-1 heavy chain (KIF5b) as well as Ras-related protein 3a (RAB3a) associate preferentially with younger granules. Further, we identify the Rho GTPase-activating protein (ARHGAP1) as a cytosolic factor associated with insulin granules.

Summary: Zebrafish regenerate their fins which involves a component of cell plasticity. It is currently unclear how regenerate cells divide labor to allow for appropriate growth and patterning. Here, we studied lineage relationships of fluorescence-activated cell sorting-enriched epidermal, bone-forming (osteoblast), and (non-osteoblast) blastemal fin regenerate cells by single-cell RNA sequencing, lineage tracing, targeted osteoblast ablation, and electron microscopy. Most osteoblasts in the outgrowing regenerate derive from osterix+ osteoblasts, while mmp9+ cells reside at segment joints. Distal blastema cells contribute to distal osteoblast progenitors, suggesting compartmentalization of the regenerating appendage. Ablation of osterix+ osteoblasts impairs segment joint and bone matrix formation and decreases regenerate length which is partially compensated for by distal regenerate cells. Our study characterizes expression patterns and lineage relationships of rare fin regenerate cell populations, indicates inherent detection and compensation of impaired regeneration, suggests variable dependence on growth factor signaling, and demonstrates zonation of the elongating fin regenerate.

Abstract The factors that govern the geographical distribution of nitrogen fixation are fundamental to providing accurate nitrogen budgets in aquatic environments. Model-based insights have demonstrated that regional hydrodynamics strongly impact nitrogen fixation. However, the mechanisms establishing this physical-biological coupling have yet to be constrained in field surveys. Here, we examine the distribution of nitrogen fixation in Lake Tanganyika – a model system with well-defined hydrodynamic regimes. We report that nitrogen fixation is five times higher under stratified than under upwelling conditions. Under stratified conditions, the limited resupply of inorganic nitrogen to surface waters, combined with greater light penetration, promotes the activity of bloom-forming photoautotrophic diazotrophs. In contrast, upwelling conditions support predominantly heterotrophic diazotrophs, which are uniquely suited to chemotactic foraging in a more dynamic nutrient landscape. We suggest that these hydrodynamic regimes (stratification versus mixing) play an important role in governing both the rates and the mode of nitrogen fixation.