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Abstract Background SARS-CoV-2 and other viruses rely on the protease function of the TMPRSS2 protein to invade host cells. Despite cancer patients often experience poorer outcomes following SARS-CoV-2 infection, the role of TMPRSS2 in different cancer types has not yet been analyzed in detail. Therefore, the aim of the study was to determine the expression, function and clinical relevance of TMPRSS2 in tumors. Methods Publicly accessible RNA sequencing data from tumors, adjacent tissues and whole blood samples of COVID-19 patients as well as data from human tumor epithelial and endothelial cells infected with SARS-CoV-2 were analyzed for TMPRSS2 expression and correlated to the expression of immune-relevant genes and clinical parameters. In vitro models of cells transfected with TMPRSS2 (TMPRSS2high), siTMPRSS2 or mock controls (TMPRSS2low cells) were analyzed by qPCR, flow cytometry, ELISA and Western blot for the expression of immune response-relevant molecules. Co-cultures of TMPRSS2 model systems with blood peripheral mononuclear cells were employed to evaluate immune cell migration, cytotoxicity and cytokine release. Results Higher expression levels of TMPRSS2 were found in blood from patients infected with SARS-CoV-2, while TMPRSS2 expression levels significantly varied between the tumor types analyzed. TMPRSS2high tumor cells exhibit increased activity of the interferon (IFN) signal pathway accompanied by an increased expression of class I human leukocyte antigens (HLA-I) and programmed cell death ligand 1 (PD-L1) elevated interleukin 6 (IL-6) secretion and reduced NK cell-mediated cytotoxicity compared to TMPRSS2low mock controls. Treatment with a Janus kinase (JAK) 2 inhibitor or TMPRSS2-specific siRNA decreased TMPRSS2 expression. Co-cultures of the in vitro TMPRSS2 models with peripheral blood mononuclear cells in the presence of the immune checkpoint inhibitor nivolumab resulted in a significantly increased migration and infiltration of immune cells towards TMPRSS2high cells and a reduced release of the innate immunity-related cytokines CCL2 and CCL3. Conclusions This study provides novel insights into the role of TMPRSS2 in various tumor systems and the impact of SARS-CoV-2 infection on the host immunogenicity via the activation of immune-relevant pathways. These findings were linked to the efficacy of immune checkpoint inhibitor therapy, offering a potential alternative strategy to mitigate the severity of COVID-19.

Abstract Background Living Labs, as a type of academic-practice partnerships, possess the potential to transform care and research into a participatory partnership and narrow the research-practice gap to improve evidence-based and Person-centred care. Given the lack of systematic investigations of Living Labs in healthcare, we will establish a dementia-specific academic-practice partnership (Living Lab Dementia) in Germany and conduct a process evaluation. The aim of this study is to gain insights into the intervention itself (mechanisms of impact) and its implementation process (degree of implementation, barriers, and facilitators). Methods This process evaluation of the multi-center research project PraWiDem (German acronym for linking professional nursing practice and research in dementia) will be conducted applying a convergent mixed methods design and will be based on the Medical Research Council (MRC) framework for the development and evaluation of complex interventions. The intervention is presented in a logic model which describes relevant basic theoretical assumptions, intervention components, implementation aspects, mechanisms of impact, relevant outcomes, and the context in which the intervention is delivered. Data will be collected before the intervention (T0), during the intervention period, and at follow-up after 18 months (T1). Qualitative data will be collected through semi-structured interviews and focus groups. Quantitative data sources will be process documents and questionnaires. Discussion Our study will provide important insights into the Living Lab Dementia intervention and its implementation processes. The results of this evaluation will contribute to the refinement of the intervention and its implementation processes, and will enable to measure the impact of these processes in future studies.

Various aerosols, including mineral dust, soot, and biological particles, can act as ice nuclei, initiating the freezing of supercooled cloud droplets. Cloud droplet freezing significantly impacts cloud properties and, consequently, weather and climate. Some biological ice nuclei exhibit exceptionally high nucleation temperatures close to 0 °C. Ice-nucleating macromolecules (INMs) found on pollen are typically not considered among the most active ice nuclei. Still, they can be highly abundant, especially for species such as Betula pendula, a widespread birch tree species in the boreal forest. Recent studies have shown that certain tree-derived INMs exhibit ice nucleation activity above −10 °C, suggesting they could play a more significant role in atmospheric processes than previously understood. Our study reveals that three distinct INM classes active at −8.7, −15.7, and −17.4 °C are present in B. pendula. Freeze drying and freeze–thaw cycles noticeably alter their ice nucleation capability, and the results of heat treatment, size, and chemical analysis indicate that INM classes correspond to size-varying aggregates, with larger aggregates nucleating ice at higher temperatures, in agreement with previous studies on fungal and bacterial ice nucleators. Our findings suggest that B. pendula INMs are potentially important for atmospheric ice nucleation because of their high prevalence and nucleation temperatures.

Purpose: The purpose of this study was to explore potential differences in suprathreshold auditory function among native and nonnative speakers of English as a function of age. Method: Retrospective analyses were performed on three large data sets containing suprathreshold auditory tests completed by 5,572 participants who were self-identified native and nonnative speakers of English between the ages of 18-65 years, including a binaural tone detection test, a digit identification test, and a sentence recognition test. Results: The analyses show a significant interaction between increasing age and participant group on tests involving speech-based stimuli (digit strings, sentences) but not on the binaural tone detection test. For both speech tests, differences in speech recognition emerged between groups during early adulthood, and increasing age had a more negative impact on word recognition for nonnative compared to native participants. Age-related declines in performance were 2.9 times faster for digit strings and 3.3 times faster for sentences for nonnative participants compared to native participants. Conclusions: This set of analyses extends the existing literature by examining interactions between aging and self-identified native English speaker status in several auditory domains in a cohort of adults spanning young adulthood through middle age. The finding that older nonnative English speakers in this age cohort may have greater-than-expected deficits on speech-in-noise perception may have clinical implications on how these individuals should be diagnosed and treated for hearing difficulties.

From the perspective of role theory and its attendant construct role strain, we examine open-ended survey responses to an online survey from 47 program coordinators at a R1 university conducted during the 2021-2022 academic year. Results suggest that beyond the era-specific challenges posed by the COVID-19 pandemic and satisfactions realized from working with students, notable sources of role strain derive from issues of compensation and institutional norms relating to how the work gets done by program coordinators. Implications with an eye toward compensation, training, and equity are discussed.

Abstract Effects of the initial peritoneal dialysis (PD) prescription on clinical outcomes are unknown in Japan. We conducted a cohort study using data from Peritoneal Dialysis Outcomes and Practice Patterns Study. The patients were divided into two groups by the volume of the initial PD prescription (≤ 4 L/day or > 4 L/day). Cause-specific Cox proportional hazards survival models were used to model the association between different PD prescriptions and the clinical outcomes. The outcomes included transfer to HD, mortality, the composite of mortality and transfer to HD, peritonitis, hospitalization, and the patient-reported outcomes (PROs). Of the 342 patients, 98 were prescribed ≤ 4 L/day, and 244 were prescribed > 4 L/day. Patients prescribed ≤ 4 L/day were older with a lower percentage being male, had more cardiovascular and cerebrovascular disease but lower diabetes prevalence, were more likely to be receiving CAPD, used more assisted PD, and had lower BMI and mean serum creatinine levels. There were no significant differences between groups in terms of transfer to HD, mortality, transfer to HD or mortality, hospitalization, incidence of peritonitis, and PROs. Patients with initial PD prescriptions of ≤ 4 L/day compared to > 4 L/day had similar clinical outcomes. This practice may provide health economic benefits in Japan.

Abstract As of July 1st, 2021, the US Hispanic/Latinx community is estimated at 62.6 million, making up 18.9% of the population. Despite federal regulations requiring access to medical interpreters, clinicians often resort to alternative translation methods, increasing the risk of errors. Medical Spanish education lacks standardization in US medical schools, and information on curricula provided by International Medical Schools (IMGs) is limited. We aimed to demonstrate the effectiveness of virtual, peer-led Medical Spanish education for an international medical school cohort. The course consisted of 10 weekly one-hour lectures via Zoom. From 2022 to 2023, three cohorts successfully completed the course. Through realistic clinical scenarios, students practiced and reinforced their clinical knowledge in Spanish. The final exam involved a 20-minute patient encounter on Zoom, with the instructor acting as the patient and the student as the physician. Performance evaluation followed a standardized checklist. Each question was worth 3 points, with a total of 63 potential points. The passing score ratio was set at 2, equivalent to 66.7%, calculated by dividing the score by 21 (the number of questions). Student’s self-reported comfort in obtaining a history and physical exam in Spanish, obtained before and after completion of the course post-comfort scores (median, 3), increased significantly compared to pre-course comfort scores (median, 0.5) - increased by an average of 2.5. This Online Spanish Medical Course (OSMC) requires no prior Spanish background or exposure, providing a notable advantage. Most students praised the convenient and effective online format. Despite its short duration, the course yielded significant benefits.

Abstract Early peritoneal dialysis (PD)-related infection is a severe complication. This study investigated the relationship between patient–doctor contact (PDC) duration and early PD-related infection. In the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) Korea, incident dialysis patients receiving PD were divided into two groups based on PDC duration (

Abstract Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician’s Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control.

RATIONALE & OBJECTIVE: The Kidney Failure Risk Equation (KFRE) predicts the 2-year risk of kidney failure for patients with chronic kidney disease (CKD). Translating KFRE-predicted risk or estimated glomerular filtration rate (eGFR) into time to kidney failure could inform decision making for patients approaching kidney failure. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: CKD Outcomes and Practice Patterns Study (CKDOPPS) cohort of patients with an eGFR40%), both KFRE risk and eGFR showed similar relationships with time to kidney failure. Our results demonstrate that estimating time to kidney failure in advanced CKD can inform clinical decisions and patient counseling on prognosis, regardless of whether estimates are based on eGFR or the KFRE. PLAIN-LANGUAGE SUMMARY: Clinicians often talk to patients with advanced chronic kidney disease about the level of kidney function expressed as the estimated glomerular filtration rate (eGFR) and about the risk of developing kidney failure, which can be estimated using the Kidney Failure Risk Equation (KFRE). In a cohort of patients with advanced chronic kidney disease, we examined how eGFR and KFRE risk predictions corresponded to the time patients had until reaching kidney failure. Among those with eGFR 40%), both KFRE risk and eGFR showed similar relationships with time to kidney failure. Estimating time to kidney failure in advanced CKD using either eGFR or KFRE can inform clinical decisions and patient counseling on prognosis.

Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of both pharmacological and non-pharmacological interventions. However, while they are designed to control confounders and ensure internal validity, their usually stringent inclusion and exclusion criteria often limit the generalizability of findings to broader patient populations. Moreover, RCTs are resource-intensive, frequently underpowered to detect rare adverse events, and sometimes narrowly focused due to their highly controlled environments. In contrast, real-world data (RWD), typically derived from electronic health records (EHRs) and claims databases, offers a valuable counterpart for answering research questions that may be impractical to address through RCTs. Recognizing this, the US Food and Drug Administration (FDA) has increasingly relied on real-world evidence (RWE) from RWD to support regulatory decisions and post-market surveillance. Platforms like TriNetX, that leverage large-scale RWD, facilitate collaborations between academia, industry, and healthcare organizations, and constitute an in-depth tool for retrieval and analysis of RWD. TriNetX’s federated network architecture allows real-time, privacy-compliant data access, significantly enhancing the ability to conduct retrospective studies and refine clinical trial designs. With access to currently over 150 million EHRs, TriNetX has proven particularly effective in filling gaps left by RCTs, especially in the context of rare diseases, rare endpoints, and diverse patient populations. As the role of RWD in healthcare continues to expand, TriNetX stands out as a critical tool that complements traditional clinical trials, bridging the gap between controlled research environments and real-world practice. This review provides a comprehensive analysis of the methodologies and applications of the TriNetX platform, highlighting its potential contribution to advance patient care and outcomes.

Objective:. This review aims to consolidate available evidence, identify research gaps, and advocate for a more informed approach to the management of pityriasis rosea in pregnant individuals. Data Sources:. PubMed, Web of Science, and Directory of Open Access Journals were systematically searched based on the keywords “pityriasis rosea,” “pityriasis circinate,” “roseola annulate,” “herpes tonsurans maculosus,” “herald patch,” and “pregnancy” on January 25, 2024 for publications between 1950 to 2024. Study Selection:. Studies containing outcomes data for pregnant patients with established PR were included. Studies must have been written or translated into English and published in a peer-reviewed journal. Studies which did not pertain to PR in the setting of pregnancy were excluded, as screened by two reviewers. Responses, general informational reviews, and letters to the editor without novel data were also excluded. Results:. Eleven relevant articles were identified, encompassing data from 177 patients. Overall, 81% of patients had favorable outcomes while 19% experienced unfavorable outcomes. PR onset before 15 weeks gestation was associated with a higher rate of unfavorable outcomes (41%), including a 27% rate of spontaneous abortion (SA). Conversely, PR onset after 15 weeks had a lower unfavorable outcome rate (21%), and no instances of SA. Conclusion:. Conflicting data exists regarding the impact of PR on pregnancy outcomes. However, PR onset within the first 15 weeks, widespread lesions, constitutional symptoms, and higher human herpesvirus 6 viral loads may increase the risk of unfavorable outcomes such as SA. Close follow-up and consideration of antiviral treatment are recommended for high-risk patients.

IntroductionChronic, non-communicable inflammatory diseases (CIDs) affect a large portion of the population, imposing a significant morbidity, encompassing a substantial mortality. Thus, they are a major medical burden with a high unmet need. CIDs develop over the span of several years, and the risk of developing CIDs has been linked to genetic and environmental factors. Thus, modification of environmental factors is a promising approach for the prevention of CIDs. Among modifiable environmental factors that have been linked to the CID risk is nicotine dependence. However, for only few CIDs, compelling evidence suggests that nicotine dependence increases (e.g., rheumatoid arthritis and asthma) or decreases (e.g., pemphigus) the CID risk. For most CIDs, there are inconsistent, scant, or no reports on the risk of CID associated with nicotine dependence.MethodsTo address this gap, we leveraged TriNetX, analyzing data from over 120 million electronic health records (EHRs). Using propensity score matching (PSM) to control for age, sex, ethnicity, and other CID risk factors, we contrasted the risk of developing any or any of the 38 CIDs in 881,192 EHRs from individuals with nicotine dependence to PSM-matched unexposed counterparts.ResultsThe analytical pipeline was validated by demonstrating an increased risk of individuals exposed to nicotine dependence for subsequent diagnosis of myocardial infarction, malignant neoplasm of the lung, and chronic obstructive pulmonary disease. Overall, 16.8% of individuals with nicotine dependence developed CIDs, compared to 9.6% of individuals not exposed to nicotine dependence (hazard ratio 2.12, confidence interval 2.10–2.14, p < 0.0001). Investigating single CIDs, nicotine dependence imposed increased risks for 23 of the 38 investigated diseases, i.e., dermatomyositis, granulomatosis with polyangiitis, pyoderma gangrenosum, and immune thrombocytopenic purpura. The sex-stratified analysis revealed few sex-specific differences in CID risk.DiscussionOur study emphasizes the importance of preventive measures targeting nicotine addiction to reduce the global burden of CIDs.

BackgroundOverweight and obesity are a global pandemic, contributing to death and disability-adjusted life-years. Obesity is a major factor in the onset of chronic inflammatory diseases (CIDs). Yet, several knowledge gaps remain: For several CIDs, inconsistent results have been reported, relating to their obesity-imposed risk, data on most rare CIDs remain unavailable, sex differences and racial disparities remain mostly unaddressed.MethodsA large-scale cohort study compared the risk of developing 46 CIDs in individuals with overweight/obesity (n=3,101,824) to an equal number of non-overweight/obese individuals. Propensity score matching optimized between-group comparability, and sensitivity analyses assessed study robustness.ResultsThe risk of developing any CID was 28.48% in overweight/obese individuals versus 17.55% in non-overweight/obese controls, with a hazard ratio (95%-confidence interval) of 1.52 (1.509-1.521, p

Accelerometers with low sampling rates (1 Hz) are commercially available as ear tags. While an automated and therefore undisturbed sampling of animal behaviour can be useful not only in behavioural studies but also in ecological or wildlife management studies, the usefulness of such 'a low data collection rate for the prediction of behaviours was the key question addressed here. We classified the behaviour of female wild boar, kept under semi-natural conditions in a large outdoor enclosure, using acceleration data. Predictions were based on a machine learning algorithm, specifically a random forest model in the open software h2o. Remarkably, prediction of many behaviours was possible using ear-tag acceleration sensors that sampled data only at a low frequency. This measurement device was mainly used to minimise the potentially harmful effects caused by the repeated capture of wild animals to exchange batteries. Long battery life will also help to collect long-term accelerometer data and has the potential to explore seasonal and inter-annual trends. Foraging, lateral resting, sternal resting and lactating were identified well, scrubbing, standing and walking not reliably. Balanced accuracy depended on the behaviour type and ranged from 50% (walking) to 97% (lateral resting). Results show that static features of unfiltered acceleration data, as well as of gravitation and orientation filtered data, were used in the prediction of behaviour. The waveform of certain behaviours in the sampled frequency range played no important role. Certain positively identified behaviours, such as food intake and lactation, could be of interest for wildlife managers attempting to control population growth in this pest-species. We provide several R-scripts that allow the analysis of behavioural accelerometer data.

Summary: Background: Cardiovascular comorbidity increases morbidity and mortality in psoriasis. Systemic treatments, particularly biologics, are effective in alleviating skin and joint inflammation. Conversely, the impact of systemic therapy on cardiovascular disease risk and mortality in psoriasis remains uncertain. Methods: Impact of systemic treatments on all-cause mortality and cardiovascular disease risk in psoriasis patients' electronic health records (EHRs) from TriNetX was assessed. Treatment categories included apremilast, IL-17 inhibitors (IL-17i), IL23i, TNFi, and classic antipsoriatic drugs. Index event was the first prescription of each treatment, requiring a two-year continuous treatment with exclusion of other systemic antipsoriatic drugs. Propensity-score matching was used to improve comparability. Sensitivity analyses ensured study robustness. Findings: In descriptive analysis, all-cause mortality rates were 0.61% (classic antipsoriatics, n = 7929), 0.91% (apremilast, n = 1101), 0.00% (IL17i, n = 677), 0.81% (IL23i, n = 1242), and 0.20% (TNFi, n = 6468). Major adverse cardiac events (MACE) were documented in 8.49% (classic antipsoriatics), 5.14% (apremilast), 2.99% (IL17i), 2.09% (IL23i), and 3.74% (TNFi) EHRs. Propensity-score matching showed all-cause mortality rates of 0.23% for any biologic vs. 0.49% for classic antipsoriatics or apremilast, resulting in an HR of 2.21 (95% CI 1.21–3.71, p = 0.0073). MACE risk was also higher with classic antipsoriatics or apremilast (HR 1.66, CI 1.43–1.93, p

The Lübeck Institute of Experimental Dermatology celebrated its 10th Anniversary Symposium on Inflammatory Skin Diseases at the University of Lübeck, Germany, on October 17–18, 2024. This event brought together international key opinion leaders, faculty members, researchers, and clinicians to foster insightful discussions on the diagnosis, pathomechanisms, and treatment of autoimmune skin diseases, with a particular focus on pemphigus, pemphigoid diseases, and systemic sclerosis.