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Abstract Background Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. Methods To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. Results Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. Conclusions Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

Mild psoriasis may be burdensome; if symptoms are inadequately controlled, switching therapy may be warranted. In the Phase 3 NAVIGATE trial, patients with moderate-to-severe plaque psoriasis received ustekinumab for 16 weeks. Patients with inadequate response (Investigator’s Global Assessment [IGA] ≥ 2) were randomized to switch to guselkumab or continue ustekinumab. This post-hoc analysis evaluated the patient subgroup with residual mild psoriasis (IGA = 2) after initial ustekinumab therapy. Outcomes assessed included the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Psoriasis Symptoms and Signs Diary (PSSD). Initially, 871 patients received ustekinumab. At Week 16, 161 randomized patients had residual mild psoriasis (IGA = 2). Among guselkumab- vs ustekinumab-treated patients at Week 28, 59.0% vs 27.7% achieved PASI 90, and 50.0% vs 21.0% achieved DLQI 0/1. Mean changes from baseline in PSSD score were –44 vs –28 and –50 vs –32, respectively, with thresholds of –40 considered clinically meaningful. Mean changes in PSSD itch score were –4.6 vs –2.9, with reductions ≥ 4.0 considered clinically meaningful. Treatment differences were maintained/increased through Week 52. Among patients with residual mild psoriasis after 16 weeks of ustekinumab, those switching to guselkumab had greater improvements in skin clearance, health-related quality of life, and patient-reported symptoms and signs than those continuing ustekinumab.

Background: Case reports indicate a clinical connection between SARS-CoV-2 and thyroid dysfunctions. However, evidence from large population-based registry analyses is sparse, especially in Europe, where iodine deficiency is common. This study aimed to analyze the impact of the COVID-19 pandemic on healthcare provision for thyroid diseases in Austria. Methods: We performed a retrospective, population-based registry analysis of the Austrian health insurance fund database, covering more than 9 million inhabitants. Data from all patients with prescriptions of thyroid-specific drugs and/or inpatient thyroid-related diagnoses from 2017 to 2019 (pre-pandemic years) were compared to 2020 and 2021 (pandemic years; characterized by high numbers of SARS-CoV2 infections and population-wide vaccination strategy). The incidence rates of thyroid medication prescriptions for hypothyroidism and hyperthyroidism were calculated for every year to evaluate the impact of the pandemic. Results: The incidence rate for total thyroid medication prescription was 539.07/100,000 individuals (534.23–543.93 95%CI) in 2018 and declined during the pandemic (2020: 387.19/100,000 (383.12–391.29 95%CI); 2021: 336.90/100,000 (333.11–340.73 95%CI)). Similarly, the incidence rate for levothyroxine prescription was higher pre-pandemic (2018: 465.46/100,000 (460.97–469.98 95%CI) and declined during the pandemic (2020: 348.14/100,000 (344.28–352.03 95%CI); 2021: 300.30/100,000 (296.7–303.91 95%CI). The incidence rates of thiamazole prescriptions (2018: 10.24/100,000 (9.58–10.93 95%CI); 2020: 8.62/100,000 (8.03–9.26 95%CI); 2021: 11.17/100,000 (10.49–11.89 95%CI) were stable. Conclusions: These findings suggest no clinically significant impact of SARS-CoV2 and/or vaccination on thyroid function at a population level.

After a neurological injury, neurorehabilitation aims to restore sensorimotor function of patients. Technological assessments can provide high-quality data on a patient’s performance and support clinical decision making towards the most appropriate therapy. In this study, the ArmeoPower, a robotic exoskeleton for the upper extremities, was used to assess 12 neurological patients and 31 non-disabled participants performing various standardized single joint and frontal plane game-like exercises. From the collected data, kinematic metrics (End-Point Error, Hand-Path Ratio, reaction time, stability, Number of Velocity Peaks, peak, and mean Velocity) and the game score, were calculated and analyzed according to three criteria: the reliability (a), the difference between patients and non-disabled participants (b), as well as the influence of robotic movement assistance (c). In total, 39 metrics were analyzed and the following five most promising assessment variables for different exercises could be identified based on the three above-mentioned criteria: smoothness (RainMug (wrist)), mean speed (RainMug (wrist)), reaction time (Goalkeeper), maximum speed (HighFlyer (elbow)) and accuracy (Connect the dots), with the former showing good validity (rho=0.82, p=0.02) when comparing to the patient’s severity level. The results demonstrate feasibility to extract and analyze various kinematic metrics from the ArmeoPower, which can provide quantitative information about human performance during training and therapy. The generated data increases the understanding of the patient’s movement and can be used in the future in clinical research for better performance evaluation and providing more feedback options, leading towards a more personalized and patient-centric therapy.

Abstract Background Little is known about the exact impact of psoriasis on the disease burden of close relatives and partners of those affected by the disease. Objectives The aim of this single‐centre cross‐sectional study was to evaluate the quality of life in psoriasis patients and the impact of disease on partners and close relatives. Methods 250 plaque‐type psoriasis patients (58.4% males and 41.6% females) with mostly treatment‐controlled disease (mean PASI of 1.7 and Dermatology Life Quality Index (DLQI) of 4.1) were recruited from the Psoriasis Registry Austria (PsoRA) and their close relatives and partners were invited to participate in the study. Patient Family Impact Score (PFIS) was calculated from the FamilyPso questionnaire data to establish categories of disease burden in close relatives and partners. Results Valid FamilyPso questionnaires were returned from 153 (61.2%) close relatives and partners. Correlation analysis revealed a significant association between PASI and DLQI (r = 0.512, p

Cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders of skin-homing T cells causing chronic inflammation. These disorders cause impairment of the immune environment, which leads to severe infections and/or sepsis due to dysbiosis. In this study, we elucidated the host-microbial interaction in CTCL that occurs during the phototherapeutic treatment regime and determined whether modulation of the skin microbiota could beneficially affect the course of CTCL. EL4 T-cell lymphoma cells were intradermally grafted on the back of C57BL/6 mice. Animals were treated with conventional therapeutics such as psoralen + UVA (PUVA) or UVB in the presence or absence of topical antibiotic treatment (neomycin, bacitracin, and polymyxin B sulphate) as an adjuvant. Microbial colonisation of the skin was assessed to correlate with disease severity and tumour growth. Triple antibiotic treatment significantly delayed tumour occurrence (p = 0.026), which prolonged the survival of the mice (p = 0.033). Allocation to phototherapeutic agents PUVA, UVB, or none of these, along with antibiotic intervention, reduced the tumour growth significantly (p = 0.0327, p ≤ 0.0001, p ≤ 0.0001 respectively). The beta diversity indices calculated using the Bray−Curtis model showed that the microbial population significantly differed after antibiotic treatment (p = 0.001). Upon modulating the skin microbiome by antibiotic treatment, we saw an increase in commensal Clostridium species, e.g., Lachnospiraceae sp. (p = 0.0008), Ruminococcaceae sp. (p = 0.0001)., Blautia sp. (p = 0.007) and a significant reduction in facultative pathogens Corynebacterium sp. (p = 0.0009), Pelomonas sp. (p = 0.0306), Streptococcus sp. (p ≥ 0.0001), Pseudomonas sp. (p = 0.0358), and Cutibacterium sp. (p = 0.0237). Intriguingly, we observed a significant decrease in Staphylococcus aureus frequency (p = 0.0001) but an increase in the overall detection frequency of the Staphylococcus genus, indicating that antibiotic treatment helped regain the microbial balance and increased the number of non-pathogenic Staphylococcus populations. These study findings show that modulating microbiota by topical antibiotic treatment helps to restore microbial balance by diminishing the numbers of pathogenic microbes, which, in turn, reduces chronic inflammation, delays tumour growth, and increases survival rates in our CTCL model. These findings support the rationale to modulate the microbial milieu during the disease course of CTCL and indicate its therapeutic potential.

Introduction: Children and adolescents with neurological impairments face reduced participation and independence in daily life activities due to walking difficulties. Existing assistive devices often offer insufficient support, potentially leading to wheelchair dependence and limiting physical activity and daily life engagement. Mobile wearable robots, such as exoskeletons and exosuits, have shown promise in supporting adults during activities of daily living but are underexplored for children.Methods: We conducted a cross-sectional study to examine the potential of a cable-driven exosuit, the Myosuit, to enhance walking efficiency in adolescents with diverse ambulatory impairments. Each participant walked a course including up-hill, down-hill, level ground walking, and stairs ascending and descending, with and without the exosuit’s assistance. We monitored the time and step count to complete the course and the average heart rate and muscle activity. Additionally, we assessed the adolescents’ perspective on the exosuit’s utility using a visual analog scale.Results: Six adolescents completed the study. Although not statistically significant, five participants completed the course with the exosuit’s assistance in reduced time (time reduction range: [-3.87, 17.42]%, p-value: 0.08, effect size: 0.88). The number of steps taken decreased significantly with the Myosuit’s assistance (steps reduction range: [1.07, 15.71]%, p-value: 0.04, effect size: 0.90). Heart rate and muscle activity did not differ between Myosuit-assisted and unassisted conditions (p-value: 0.96 and 0.35, effect size: 0.02 and 0.42, respectively). Participants generally perceived reduced effort and increased safety with the Myosuit’s assistance, especially during tasks involving concentric contractions (e.g., walking uphill). Three participants expressed a willingness to use the Myosuit in daily life, while the others found it heavy or too conspicuous.Discussion: Increased walking speed without increasing physical effort when performing activities of daily living could lead to higher levels of participation and increased functional independence. Despite perceiving the benefits introduced by the exosuit’s assistance, adolescents reported the need for further modification of the device design before using it extensively at home and in the community.

Introduction Many climbers believe that they are stronger in crimp finger position than in open hand position. However, compared to open hand, crimped fingers are associated with higher pulley forces increasing the risk of injuries. Climbing expertise may influence the estimation of strength, i.e., the better the climber, the better the self-assessment. This study therefore aimed to find out whether climbing expertise influences self-assessment of finger flexor strength in half-crimp and in open hand position. Methods Data was collected at the Hands-On Science Booth of the Climbing World Championships in Bern. Participants had to fill out a questionnaire including a self-assessment of their climbing expertise and of their maximum finger strength for both hands as well as both finger positions. Afterwards, maximum finger strength was measured on an instrumented campus board: Participants placed the to-be-measured hand on a self-selected rung (depth of 23 mm) and then tried to transfer as much force as possible from their feet to their fingers. Results The analysis was based on 38 intermediate and 36 advanced climbers. Due to the limited number of participants in the lower grade (n = 0) and elite (n = 2) level, those skill levels were not considered. Advanced climbers generated significantly greater forces than intermediate climbers across all four measured conditions (t-tests, all p < 0.01). For both groups, neither in the dominant nor in the non-dominant hand a significant difference in maximum force was observed, e.g., dominant hand, intermediates: or advanced climbers: . Intermediate climbers did neither over- nor underestimate their strength in half-crimp position compared to open hand (paired t-test, p = 0.91 for dominant, p = 0.077 for non-dominant hand). In contrast to the dominant hand, advanced climbers significantly overestimated their strength in half-crimp position for the non-dominant hand (on average 9%, Cohen’s d 0.64, p < 0.01). Discussion/Conclusion Our results confirm the positive correlation between finger strength and climbing level. We also confirm that on a 23 mm rung, greater forces can be generated with in open hand compared to half-crimp (Winkler et al., 2023). With larger hold depths, force generated in open hand significantly increases (Amca et al., 2012), while for smaller holds, force exerted in half-crimp position exceeds that of open hand (Winkler et al., 2023). Hence, at least for larger holds, we recommend adopting an open hand position as preventive measure against finger injuries. Advanced climbers may tend to inaccurately self-assess their strength due to their greater engagement with peers, potentially leading to the circulation of misinformation. Note that participants were instructed to provide a general self-assessment of their strength rather than for a 23 mm deep rung, i.e., they may have had a smaller hold in mind. References Amca, A. M., Vigouroux, L., Aritan, S., & Berton, E. (2012). Effect of hold depth and grip technique on maximal finger forces in rock climbing. Journal of Sports Sciences, 30(7), 669-677. https://doi.org/10.1080/02640414.2012.658845 Winkler, M., Künzell, S., & Auguste, C. (2023). Competitive performance predictors in speed climbing, bouldering, and lead climbing. Journal of Sport Sciences, 41(8), 736-746. https://doi.org/10.1080/02640414.2023.2239598

Epilepsy is an increasing global neurological health issue. Recently, epidemiological and mechanistic studies have raised concern about cardiac involvement in individuals with epilepsy. This has resulted in the “epileptic heart” concept. Epidemiological data linking epilepsy to cardiovascular disease indicate an increased risk for ventricular and atrial arrhythmias, myocardial infarction, heart failure, and sudden death among individuals with epilepsy. Pathways of this interaction comprise increased prevalence of traditional cardiac risk factors, genetic abnormalities, altered brain circuitry with autonomic imbalance, and antiseizure medications with enzyme-inducing and ionic channel-blocking proprieties. Pathophysiological findings in the atria and ventricles of patients with epilepsy are discussed. Echocardiographic findings and future applications of this tool are reviewed. A risk stratification model and future studies on cardiac risk assessment in individuals with epilepsy are proposed.

BackgroundProlonged critical illness is often accompanied by an impairment of adrenal function, which has been frequently related to conditions complicating patient management. The presumed connection between hypoxia and the pathogenesis of this critical- illness- related corticosteroid insufficiency (CIRCI) might play an important role in patients with severe acute respiratory distress syndrome (ARDS). Since extracorporeal membrane oxygenation (ECMO) is frequently used in ARDS, but data on CIRCI during this condition are scarce, this study reports the behaviour of adrenal function parameters during oxygenation support with veno-venous (vv)ECMO in coronavirus disease 2019 (COVID-19) ARDS.MethodsA total of 11 patients undergoing vvECMO due to COVID-19 ARDS at the Medical University of Vienna, who received no concurrent corticosteroid therapy, were retrospectively included in this study. We analysed the concentrations of cortisol, aldosterone, and angiotensin (Ang) metabolites (Ang I–IV, Ang 1–7, and Ang 1–5) in serum via liquid chromatography/tandem mass spectrometry before, after 1 day, 1 week, and 2 weeks during vvECMO support and conducted correlation analyses between cortisol and parameters of disease severity.ResultsCortisol concentrations appeared to be lowest after initiation of ECMO and progressively increased throughout the study period. Higher concentrations were related to disease severity and correlated markedly with interleukin-6, procalcitonin, pH, base excess, and albumin during the first day of ECMO. Fair correlations during the first day could be observed with calcium, duration of critical illness, and ECMO gas flow. Angiotensin metabolite concentrations were available in a subset of patients and indicated a more homogenous aldosterone response to plasma renin activity after 1 week of ECMO support.ConclusionOxygenation support through vvECMO may lead to a partial recovery of adrenal function over time. In homogenous patient collectives, this novel approach might help to further determine the importance of adrenal stress response in ECMO and the influence of oxygenation support on CIRCI.

Background & Aims: Advanced chronic liver disease (ACLD) may affect thyroid hormone homeostasis. We aimed to analyze the pituitary–thyroid axis in ACLD and the prognostic value of free triiodothyronine (fT3). Methods: Patients with ACLD (liver stiffness measurement [LSM] ≥10 kPa) undergoing hepatic venous pressure gradient (HVPG) measurement between June 2009 and September 2022 and available fT3 levels were included. Clinical stages of ACLD were defined as follows: probable ACLD (pACLD; LSM ≥10 kPa and HVPG ≤5 mmHg), S0 (mild portal hypertension [PH]; HVPG 6–9 mmHg), S1 (clinically significant PH), S2 (clinically significant PH with varices), S3 (past variceal bleeding), S4 (past/current non-bleeding hepatic decompensation), and S5 (further decompensation). Results: Among 297 patients with ACLD, 129 were compensated (pACLD, n = 10; S0, n = 33; S1, n = 42; S2, n = 44), whereas 168 were decompensated (S3, n = 12; S4, n = 97; S5, n = 59). Median levels of thyroid-stimulating hormone (TSH) numerically increased with progressive ACLD stage (from 1.2 μIU/ml [pACLD] to 1.5 μIU/ml [S5]; p = 0.152), whereas fT3 decreased (from 3.2 pg/ml [pACLD] to 2.5 pg/ml [S5]; p

Objective: To elucidate the pathogenesis of dupilumab (Dupixent®)–associated ocular surface disease (DAOSD). Design: Prospective single-center cohort study. Subjects: Twenty patients with moderate-to-severe atopic dermatitis (AD) who received dupilumab and 10 age- and sex-matched healthy controls were enrolled in the study. Methods: The study cohort underwent a thorough slit-lamp and entire-body dermatologic examination. Conjunctival swabs and smears were collected at baseline, 4 and 16 weeks after treatment initiation, and during the conjunctivitis episode. To analyse the ocular surface microbiome, 16S ribosomal RNA sequencing was performed, smears were hematoxylin and eosin stained, and serum cytokines were measured by using a multiplex immunobead assay. Main Outcome Measures: Composition of ocular surface microbiome and cellular component as well as serum cytokine levels. Results: Six of the 20 patients with AD developed DAOSD after dupilumab initiation; these patients responded after a delay to treatment as quantified by Eczema Area and Severity Index and Investigator’s Global Assessment score. Conjunctival smears showed massive neutrophilic infiltration and serum analysis revealed increased systemic levels of neutrophil-priming proinflammatory cytokines, in particular interleukin-1β and tumor necrosis factor α, in patients with DAOSD compared with those without it. The ocular surface microbiome of patients with DAOSD was characterized by a diverse and persistent microbial colonization, particularly by Acetobacter aceti. In contrast, microbial diversity decreased in patients with AD without DAOSD after the initiation of dupilumab treatment, especially the abundance of Staphylococcus aureus. In vitro experiments substantiated the potential role of the microbiome, showing increased growth of A. aceti and decreased growth of S. aureus in presence of dupilumab. Conclusions: Persistent neutrophilic infiltration and a unique microbial landscape on the ocular surface associated with elevated levels of systemic proinflammatory cytokines typify DAOSD. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Climbing is a fast-growing sport, with one of the most common injuries being a rupture of the finger flexor tendon pulley. The strain on pulleys increases as finger joints flex. However, to our knowledge, no study has conducted a kinematic analysis of climbers’ fingers. Thus, this study aimed to examine finger kinematics during typical climbing tasks. Eleven elite climbers performed a sequence of four climbing moves, which were recorded by an optical motion capture system. Participants used crimp, half-crimp, and open-hand grips for three trials each, with the fourth condition involving campusing using any grip except crimp. Mean proximal interphalangeal joint (PIP) flexion during the holding phase was 87° (SD 12°), 70° (14°) and 39° (27°) for the crimp, half-crimp and open-hand grip, respectively. Hence, inter-individual PIP flexion ranges overlap between different gripping conditions. Two different movement patterns emerged in the open-hand grip, possibly influenced by the use of the little finger, leading to varying degrees of flexion in the middle and ring fingers. Avoiding little finger usage in the open-hand grip may reduce load during pulley rupture rehabilitation. The implications of PIP joint angle variability on individual pulley injury risk or prevention warrant further investigation. Motion capture proved effective for understanding finger kinematics during climbing and could guide future studies on pulley injury risk factors.

Load forecasting is an integral part of the power industries. Load-forecasting techniques should minimize the percentage error while prediction future demand. This will inherently help utilities have an uninterrupted power supply. In addition to that, accurate load forecasting can result in saving large amounts of money. This article provides a systematic review based on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) framework. This article presents a complete framework for short-term load forecasting using metaheuristic algorithms. This framework consists of three sub-layers: the data-decomposition layer, the forecasting layer, and the optimization layer. The data-decomposition layer decomposes the input data series to extract important features. The forecasting layer is used to predict the result, which involves different statistical and machine-learning models. The optimization layer optimizes the parameters of forecasting methods to improve the accuracy and stability of the forecasting model using different metaheuristic algorithms. Single models from the forecasting layer can predict the results. However, they come with their limitations, such as low accuracy, high computational burden, stuck to local minima, etc. To improve the prediction accuracy, the hyperparameters of these models need to be tuned properly. Metaheuristic algorithms cab be used to tune these hyperparameters considering their interdependencies. Hybrid models combining the three-layer methods can perform better by overcoming the issues of premature convergence and trapping into a local minimum solution. A quantitative analysis of different metaheuristic algorithms and deep-learning forecasting methods is presented. Some of the most common evaluation indices that are used to evaluate the performance of the forecasting models are discussed. Furthermore, a taxonomy of different state-of-the-art articles is provided, discussing their advantages, limitations, contributions, and evaluation indices. A future direction is provided for researchers to deal with hyperparameter tuning.

Fire in the Northern Alps is comparatively rare. Yet, previous human-ignited fire events in subalpine forests up to the treeline have triggered severe fire damage to vegetation and soil. Here, we investigate post-fire vegetation dynamics in the Northern Limestone Alps about 80 years after disturbance. We observed higher species richness in burned compared to unburned vegetation and clearly distinct floristic communities emerging after fire-driven forest removal, with several alpine specialist species uniquely found in the burned subalpine sites. The functional composition of vegetation was also distinct, with higher relative forb cover in burned plots. This difference was likely driven by disturbance-related environmental changes, such as increased light availability, offering safe sites for subalpine and alpine species. Due to a general lack of tree encroachment, we consider this a case of arrested succession after fire. We conclude that the recovery of fire-affected subalpine forests is modulated by complex interactions of climatic and biotic filters producing extreme site conditions, controlling the recolonization of the disturbed areas by forest species while providing safe sites for the establishment of a rich subalpine and alpine low-statured flora. The coupling of disturbance and abiotic filters makes high-elevation treeline ecotones very vulnerable to climate change.

This paper examines how Australian residential load profiles may evolve in the short to medium term future. These profiles can be used to support simulation studies of the future Australian network within an environment that is transitioning to renewable energy and broader use of electricity as a tool for decarbonisation. The daily profiles rely heavily on the Australian Energy Market Operator (AEMO) forecasts for future annual energy usage. The period from 2024 to 2050 will be transformational. In the residential networks, two secular trends are particularly important in expanding residential generation and electrification. New daily load profiles have been constructed using historical Australian profiles and adding additional components for solar generation, battery operation and electrification activities. The entire aggregated residential network is expected to have reverse midday power flow on any average day from 2024 onwards due to the rapid increase in electric vehicle (EV) usage. The domestic energy demand forecasting methodology presented in this work related to Australia can easily be adopted to carry out similar forecasting for any country of the world.