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Deformation characterization of low-symmetry phases such as martensite in SMAs is challenging due to a fine-scale hierarchical microstructure. Using X-ray microLaue diffraction, in-situ deformation of martensite is examined in a notched NiTi specimen. The local deformation is influenced by the notch stress field, initial martensite microstructure, and interaction between notch stress field and the external load. The microstructure evolves heterogeneously and inelastically, with detwinning and twin nucleation occurring simultaneously through loading. These results contrast with the traditional view of martensite deformation that is partitioned in three distinct regimes: elasticity, reorientation and de-twinning.

The main question of this article is when, how and why the political system of the Netherlands has changed from a typical consensus democracy towards a more adversarial-driven system. We examine the change in Dutch politics across time with a special focus on the dynamics of the party system and type of coalition governments emerging after the 1970s. Our analysis indicates that Dutch politics has indeed become less consensus driven and party behaviour in particular tends to a more adversarial modus. In addition, our comparative analysis demonstrates that the Dutch political system has moved in a different direction than most others. Using Lijphart's indicators of Consensus Democracy we find that the direction of change is mainly towards less adversarial politics, whereas the Netherlands moved in an opposite direction. This change, occurring mainly after 1990, persists as a ‘pendulum consociationalism’, strengthening and weakening over time. Apparently, adjustment and flexible response to a changing electoral climate and related party behaviour results in a cyclical movement as regards to party interactions between the established parties and successful ‘newcomers’.Acta Politica (2008) 43, 154–179. doi:10.1057/ap.2008.4 [ABSTRACT FROM AUTHOR]

We present a method to combine expert opinion on the likelihood of under-reporting with an operational risk data set. Under-reporting means that not all losses are identified and therefore an incorrect distributional assumption may be made, and ultimately an incorrect assessment made of capital required. Our approach can be applied to help insurers and other financial services companies make better assessments of capital requirements for operational risk using either external or internal sources. We conclude that operational risk capital evaluation can be significantly biased if under-reporting is ignored.The Geneva Papers (2007) 32, 178–189. doi:10.1057/palgrave.gpp.2510129 [ABSTRACT FROM AUTHOR]

Purpose: In 15 patients with idiopathic uveitis associated with retinal vasculitis, HLA DRB1 gene testing was performed to detect a possible association. 11 patients tested positive and 4 negative for the HLA DRB1 × 15 allele. The presence of the HLA DRB1 × 15 haplotype might be associated with a higher susceptibility to develop Multiple Sclerosis (MS)., Methods: In this case series, we describe the ophthalmological and neurological findings in 10 HLA DR15-positive patients and 4 HLA DR15-negative patients that had neurological workup, including Magnetic Resonance Imaging (MRI) of the brain., Results: All patients had granulomatous ocular inflammation with either panuveitis or intermediate uveitis. MRI of the brain showed white matter lesions in 13 patients (9/10 and 4/4 respectively) of which 4 patients were eventually diagnosed with MS (3/10 and 1/4 respectively)., Conclusion: Although the majority of tested patients was carrying at least one HLA DRB1-15 allele, there was no difference in ophthalmological and neurological findings in both groups.

Partnerships that effectively engage in certain key structural and process functions are more likely to meet their research goals and contribute to longer-term health equity outcomes. Ongoing evaluation of partnerships' level of achievement of these key functions, along with their fidelity to the guiding principles of community-based participatory research (CBPR), is therefore essential to understand how they can achieve desired partnership outcomes. This article describes the validated Measurement Approaches to Partnership Success (MAPS) Questionnaire and the use of an accompanying Facilitation Guide in helping members of CBPR partnerships evaluate their partnership's state of development and interpret findings to improve its structure, processes, and outcomes. We describe the conceptual framework guiding the development of the MAPS Questionnaire and its 81-item across seven key outcome dimensions, along with 28 items measuring precursor characteristics of CBPR partnership outcomes. The Facilitation Guide provides general guidelines for sharing, interpreting, and applying results within partnerships using a participatory process, definitions and items for each dimension, an example of presenting summary means, and dimension-specific reflective questions for discussion. We offer recommendations for practical uses of the MAPS Questionnaire and Facilitation Guide. Whether used as a comprehensive tool or by dimension, the MAPS Questionnaire is conceptually sound and empirically validated for evaluating how CBPR partnerships can achieve long-standing success. CBPR partnerships at any stage of development will find the MAPS Questionnaire and Facilitation Guide useful in measuring and interpreting indicators of partnership success, sharing results, and improving their ability to contribute to achieving health equity goals.

Objective: The aim of the study was to investigate the impact of dipyrone administration on postoperative analgesia and acetylsalicylic acid (ASA) effect in patients undergoing coronary artery bypass grafting (CABG)., Design: A prospective randomized study., Setting: Single-university hospital setting., Participants: Ninety-eight patients who underwent CABG between April 2022 and May 2023., Interventions: The ASA effect was measured at 6 time points with impedance aggregometry (Multiplate) and thromboelastography (TEG6s Platelet Mapping). Patients were randomized to 1 of 3 groups: intravenous ASA and dipyrone at the same time (group 1), intravenous ASA and dipyrone with a 2-hour delay (group 2), and intravenous ASA alone (group 3). Postoperative analgesic effects (numeric rating scale) and the prevalence of potential ASA non-response (defined as ASPI >40 U and TEG-ASA inhibition <50%) were recorded., Measurements and Main Results: Of 90 analyzed patients, 80 took ASA preoperatively. All patients received intravenous ASA 100 mg from postoperative day 1. The effect of ASA did not significantly differ between the study groups at any time for either platelet function test. NRS values did not differ between the study groups at any time (p = 0.469). Patients in group 3 received significantly more additional co-analgesics than patients who received dipyrone (p = 0.005). ASA non-response was detected in 38.9% and 67.8% on the seventh postoperative day, respectively., Conclusions: Dipyrone given after CABG seems safe and did not show any significant effect on platelet inhibition after ASA administration. Patients taking dipyrone postoperatively need significantly fewer additional coanalgesics. The ASA effect on platelet function should be checked at least once after surgery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Insertion of a peritoneal dialysis (PD) catheter in end-stage renal disease (ESRD) patients with cirrhosis and tense ascites remains a challenge for nephrologists. Ascitic fluid leak at the surgical site, a common postoperative occurrence, leads to the disqualification of many patients who could be otherwise great candidates for PD. The ascitic fluid leak has been described to occur during or immediately after surgery even after the entire volume of ascitic fluid has been drained. In this study, we report a case study of three patients with ESRD, liver cirrhosis, and tense ascites on hemodialysis. The patients required super large volume paracentesis (SLVP), draining 9,000 - 15,000 cc of ascitic fluid twice weekly in an interventional radiology setup. Besides ascitic fluid drainage, the patients needed in-center hemodialysis (ICHD) 3 days a week, leading to their engagement in procedures 5 days a week. In addition, intradialytic symptomatic hypotension, hypoalbuminemia, and other adverse effects of hemodialysis lead to their poor lifestyle. To improve their lifestyle, all patients desired to switch to PD from ICHD. Upon the PD catheter insertion and drainage of the entire ascitic fluid, leaks developed at the insertion site within a few hours. To overcome these leaks, PD catheters of all three patients were attached via a transfer set to a bag for continuous drainage of ascitic fluid for about 2 weeks. No leak or complication was noted, leading to complete healing of insertion site. We recommend, for the patients with tense ascites requiring SLVP, approximately 2 weeks of healing period continuously be performed till initiation of PD training,., Competing Interests: None of the authors declare any conflict of interest., (Copyright 2024, Mehandru et al.)

Herpes simplex virus type 2 (HSV-2) treatment faces challenges due to antiviral resistance and systemic side effects of oral therapies. Local delivery of antiviral agents, such as tenofovir (TDF) and zinc acetate dihydrate (ZAD), may offer improved efficacy and reduced systemic toxicity. This study's objective is to develop and evaluate local unit dose formulations of TDF and ZAD combination for local treatment of HSV-2 infection and exploring their individual and combinatory effects in vitro. The study involved the development of immediate-release film and pessary formulations containing TDF and ZAD. These formulations were characterized for physicochemical properties and in vitro drug release profiles. Cytotoxicity and antiviral activity assays were conducted to evaluate the individual and combinatory effects of TDF and ZAD. Film formulations released over 90% of the drugs within 1 h, and pessary formulations within 90 min, ensuring effective local drug delivery. ZAD showed moderate antiviral activity while TDF exhibited significant antiviral activity at non-cytotoxic concentrations. The combination of TDF and ZAD demonstrated synergistic effects in co-infection treatments, reducing the concentration required for 50% inhibition of HSV-2. Developed film and pessary formulations offer consistent and predictable local drug delivery, enhancing antiviral efficacy while minimizing systemic side effects. The combination of TDF and ZAD showed potential synergy against HSV-2, particularly in co-infection treatments. Further preclinical studies on pharmacokinetics, safety, and efficacy are necessary to advance these formulations toward clinical application., (© 2024. The Author(s).)

Objective: To present a rare case of cancer-associated retinopathy secondary to gallbladder carcinoma., Methods: Retrospective case report. Drugs used in case report: methylprednisolone (Medrol), CAS number: 83-43-2, producer: Pfizer; carboplatin, CAS number: 41575-94-4, producer: Accor; etoposide, CAS number: 33419-42-0, producer: Teva; methotrexate (Ledertrexate), CAS number: 59-05-2, producer: Pfizer., Results: A 57-year-old Moroccan man was referred with bilateral progressive vision loss in the last 4 months. At presentation, best corrected visual acuity (BCVA) was counting fingers for the right eye and 20/500 for the left eye. Examination demonstrated signs of vitritis, an electronegative full-field electroretinography (FF-ERG), ocular coherence tomography (OCT) abnormalities and multiple hyperautofluorescent round lesions on fundus autofluorescence imaging (FAF). The diagnosis of cancer-associated retinopathy (CAR) was considered, thus a positron emission tomography-computed tomography (PET-CT) was performed and revealed the presence of a metastasized gallbladder carcinoma. Additional fluorescence in situ hybridization (FISH) showed seropositivity for anti-retinal autoantibodies. High-dose corticosteroids together with anti-tumoral medication (carboplatin-etoposide) gradually improved the BCVA to 20/66 for the right eye and 20/20 for the left eye., Conclusions: Consider the diagnosis of CAR in patients with progressive concentric visual field loss, uveitis and fundus abnormalities, especially if bilateral. If CAR is suspected, perform a full work-up: FF-ERG, OCT, and whole-body PET-CT. In the treatment of CAR, immunosuppressives are mostly used, combined with antitumoral therapy. However, in the long-term, progressive visual loss is expected in most cases., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Goyvaerts et al.)

Combinatorial and guided screening of materials space with density-functional theory and related approaches has provided a wealth of hypothetical inorganic materials, which are increasingly tabulated in open databases. The OPTIMADE API is a standardised format for representing crystal structures, their measured and computed properties, and the methods for querying and filtering them from remote resources. Currently, the OPTIMADE federation spans over 20 data providers, rendering over 30 million structures accessible in this way, many of which are novel and have only recently been suggested by machine learning-based approaches. In this work, we outline our approach to non-exhaustively screen this dynamic trove of structures for the next-generation of optical materials. By applying MODNet, a neural network-based model for property prediction, within a combined active learning and high-throughput computation framework, we isolate particular structures and chemistries that should be most fruitful for further theoretical calculations and for experimental study as high-refractive-index materials. By making explicit use of automated calculations, federated dataset curation and machine learning, and by releasing these publicly, the workflows presented here can be periodically re-assessed as new databases implement OPTIMADE, and new hypothetical materials are suggested.

Abstract: The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as natural killer (NK) cells that are mandatory for MM surveillance and therapy. Here, we performed a single-cell RNA sequencing analysis of NK cells from 10 patients with MM and 10 age/sex-matched healthy donors that revealed important transcriptomic changes in the NK cell landscape affecting both the bone marrow (BM) and peripheral blood compartment. The frequency of mature cytotoxic CD56dim NK cell subsets was reduced in patients with MM at the advantage of late-stage NK cell subsets expressing NF-κB and interferon-I inflammatory signatures. These NK cell subsets accumulating in patients with MM were characterized by low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced lymphocyte function-associated antigen 1 (LFA-1) integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM-infiltrating NK cells in a retrospective cohort of 177 patients with MM from the Intergroupe Francophone du Myélome (IFM) 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively affect patients' clinical outcomes. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Aedes is the most globally distributed mosquito genus in the 21st century and transmits various arboviral diseases. The rapid expansion of Ae. Aegypti and Ae. albopictus breeding habitats is a significant threat to global public health, driven by temperature and precipitation changes. In this study, bioclimatic variables were employed to predict the spatial distribution of Ae. aegypti and Ae. albopictus in India. The reference coordinate points of (n = 583) Aedes occurrences at a scale of ∼1 km and nineteen bioclimatic factors were retrieved to train SDM (Species Distribution Models) for both species. Maximum entropy modelling was used to predict the species' fundamental climatic niche distributions. Future projections were made using global climate models for 2021-2040 and 2081-2100 separately. The models performed reasonably well (AUC > 0.77). Both species thrived in reduced diurnal temperature and higher annual mean temperatures, with suitability increasing alongside precipitation. Ae. aegypti's projected present and future distribution was broader than that of Ae. Albopictus. The expansion of Aedes suitability varied under different future climatic scenarios. Suitability for Ae. aegypti could expand from between 17.6 and 41.1 % in 2100 under SSP (shared socioeconomic pathways) scenarios 1 and 3, respectively, whereas for Ae. albopictus suitability increased from between 10.2 and 25 % under SSP scenarios 1 and 3 respectively. Preparing for future epidemics and outbreaks requires robust vector distribution models to identify high-risk areas, allocate resources for surveillance and control, and implement prevention strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Seasonal influenza vaccine effectiveness is low. Carbohydrate fatty acid monosulphate ester (CMS), a new oil-in-water adjuvant, has proven potency in animal models with suggested capacity for dose-sparing. The objective was to evaluate safety and immunogenicity of CMS when added to a low-dose influenza vaccine (QIV) in humans. In a randomised, double-blind, active-controlled, first-in-human study, sixty participants (18-50 years) received either 0.5 mg CMS or 2 mg CMS with 1/5th dose QIV, or a full dose QIV without CMS. Adverse events (AE) were monitored until 7 days post-vaccination. Haemagglutinin inhibition (HI) titres in serum and CD4+ T cells in PBMCs were determined at day 0, 7, 28, and 180. Mean age was 37.6 (±10.1) years and 42/60 (70.0%) were female. Pain at injection site (42/60, 86.7%) and headache (34/60, 56.7%) were reported most and more frequently in the 2 mg CMS group. HI titres and the frequency of influenza specific CD4+ T cells were equal across strains for the three cohorts on all visits, increased until day 28 and decreased at day 180 to values higher than baseline. CMS was safe in humans. Humoral and cell-mediated immunogenicity was similar across vaccines, even with 1/5th antigen dose. CMS can have beneficial implications in low-resource settings or in a pandemic context.

Background: Human activities have significantly contributed to a persistent climate change trend, posing substantial threats to human health. Nurses regularly interact with patients experiencing the consequences of climate change, making their engagement in addressing this issue crucial. Nonetheless, our understanding of nurses' viewpoints regarding climate change remains limited., Aim: This scoping review aims to identify practicing nurses' and nursing students' perceptions of climate change., Design: To fulfil this objective, a documentary search strategy was developed using an iterative process., Methods: The search strategy was tested in four bibliographic databases, as well as in the grey literature. A 2-stage selection process was conducted, and relevant data were extracted from selected articles for analysis., Results: Twenty-two scientific articles and 11 documents from nursing associations were selected. The findings suggest that while many nurses and nursing students are concerned about climate change and its effects on their patients' health, their role in addressing the climate crisis is not well understood. Many barriers such as having a heavy workload and the lack of support hindered their ability to adjust their practice in response to the changing climate. Furthermore, many expressed a need for trainings on climate change issues., Conclusions: These results raise a great and urgent demand for these professionals to receive appropriate training to cope with climatic threats to health. Future research should focus on the development of nursing climate leadership, and healthcare organizations should support nursing initiatives and help raise nurses' awareness regarding climate change., (© 2024 The Author(s). Nursing Open published by John Wiley & Sons Ltd.)

Purpose: Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations., Methods: We reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases., Results: Among 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1-84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations., Conclusion: DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Effective postoperative pain management is essential for patient satisfaction and an uneventful postoperative course, particularly in body contouring procedures. Systemic analgesic regimens can be supported by regional procedures, such as the transverse abdominis plane (TAP) block, but these have a limited duration of action. In contrast, thoracic epidural analgesia offers the possibility of a longer-lasting, individualized regional anesthesia administered by a patient-controlled analgesia pump., Objectives: The aim of this study was to investigate the effects of a patient-controlled epidural analgesia to better classify the clinical value of this procedure in abdominoplasties., Materials and Methods: This work reviewed the digital medical charts of patients who underwent selective abdominoplasty without combined surgical procedures between September 2018 and August 2022. Evaluated data comprise the postoperative analgesia regimen, including on-demand medication, mobilization time, inpatient length of stay, and clinical outcome. The patients were grouped by the presence of a thoracic epidural catheter. This catheter was placed before anesthetic induction and a saturation dose was preoperatively applied. Postoperative PCEA patients received a basal rate and could independently administer boluses. Basal rate was individually adjusted during daily additional pain visits., Results: The study cohort included 112 patients. Significant differences in the demand for supportive nonepidural opiate medication were shown between the patient-controlled epidural analgesia (PCEA) group (n = 57) and the non-PCEA group (n = 55), depending on the time after surgery. PCEA patients demanded less medication during the early postoperative days (POD 0: PCEA 0.13 (±0.99) mg vs non-PCEA 2.59 (±4.55) mg, P = 0.001; POD 1: PCEA 0.79 mg (±3.06) vs non-PCEA 2.73 (±3.98) mg, P = 0.005), but they required more during the later postoperative phase (POD 3: PCEA 2.76 (±5.60) mg vs non-PCEA 0.61 (±2.01) mg, P = 0.008; POD 4: PCEA 1.64 (±3.82) mg vs non-PCEA 0.07 (±2.01) mg, P = 0.003). In addition, PCEA patients achieved full mobilization later (PCEA 2.67 (±0.82) days vs non-PCEA 1.78 (±1.09) days, P = 0.001) and were discharged later (PCEA 4.84 (±1.23) days vs non-PCEA 4.31 (±1.37) days, P = 0.005)., Conclusion: Because the postoperative benefits of PCEA are limited to potent analgesia immediately after abdominoplasty, less cumbersome, time-limited regional anesthesia procedures (such as TAP block) appear not only adequate but also more effective., Competing Interests: Disclosure Statement: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. The authors declare that they have no conflict of interest. This research received no specific grant neither from National Institutes of Health (NIH), Wellcome Trust, Howard Hughes Medical Institute (HHMI), RCUK, nor from any other funding agency in the public, commercial, or not-for-profit sectors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Urban greenways are multipurpose and multi-user trails that provide a range of socio-ecological and health benefits, including active transportation, social interactions, and increased well-being. However, despite their numerous benefits, barriers exist that limit urban greenway access and use, particularly among older and disadvantaged adults. This study addresses a significant research gap by examining the nuanced factors that influence the choices and experiences of these specific user groups in Québec City, Canada. We use a mixed-methods' approach to explore the facilitators of and barriers to access and use of two urban greenway trails among older and disadvantaged adults. Our methods included a greenway user count, 96 observation time slots, and 15 semi-structured user interviews. The results revealed significant use of greenway trails by older adults for afternoon walks in both seasons studied (autumn and winter). We also observed variations in use patterns, such as higher levels of solitary walking, reduced levels of winter cycling, and the impracticality of the secondary greenway trail owing to snow conditions. In addition, the findings revealed a wide range of factors that influence greenway access and use, categorized as individual or personal, physical or built environment, social environment, and meteorological or climatic dimensions. Future research can build on these insights to design and assess interventions that capitalize on the facilitators and address any barriers, enhancing the value of urban greenways for older and disadvantaged adults., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Intratympanic corticosteroids are commonly used in the treatment of Menière's disease (MD). However, few and small randomised controlled trials (RCT) on the effectiveness of intratympanic corticosteroids have been performed. A recent Cochrane review suggested that a well-conducted placebo-controlled RCT with a large study population is required to evaluate the effectiveness of the use of intratympanic corticosteroids in MD. The following protocol describes a phase-3 multicentre, double-blinded, randomised, placebo-controlled trial to compare the effectiveness of methylprednisolone (62.5 mg/mL) to a placebo (sodium chloride 0.9%)., Methods and Analysis: We aim to recruit 148 patients with unilateral MD from six hospitals in the Netherlands. Patients will be randomly assigned to either the methylprednisolone or the placebo group. Two injections will be given, one at baseline and one after 2 weeks. Follow-up assessments will be done at 3, 6, 9 and 12 months. The primary outcome will be the frequency of vertigo attacks. Attacks will be evaluated daily with the DizzyQuest app. Secondary outcomes include hearing loss, tinnitus, health-related quality of life, use of co-interventions and escape medication, (serious) adverse events and cost-effectiveness. These will be evaluated with audiometry and multiple commonly used, validated questionnaires. For the primary and secondary outcomes mixed model analysis, generalised estimating equation analysis and logistic regression analysis will be used., Ethics and Dissemination: This study was submitted via the Clinical Trials Information System, reviewed and approved by the Medical Research Ethics Committee Leiden The Hague Delft and the local institutional review board of each participating centre. All data will be presented ensuring the integrity and anonymity of patients. Results will be published in scientific journals and presented on (inter)national conferences., Trial Registration Number: This study is registered at ClinicalTrials.gov Protocol Registration and Results System, with the registration ID: NCT05851508., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs)., Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed., Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10 -3 ) in PSP., Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions., (© 2024. The Author(s).)

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Metrics for health-care sustainability are crucial for tracking progress and understanding the advantages of different operations or systems as the health-care sector addresses the climate crisis and other environmental challenges. Measurement of the key metrics of absolute energy use and greenhouse gas emissions now has substantial momentum, but our overall measurement framework generally has serious deficiencies. Because existing metrics are often borrowed from other sectors, many are unconnected to the specifics of health-care provision or existing health system performance indicators, the potential negative effects of health care on public health are largely absent, a consistent and standardised set of health-care sustainability measurement concepts does not yet exist, and current dynamics in health systems such as privatisation are largely ignored. The next generation of health-care sustainability metrics must address these deficiencies by expanding the scope of observation and the entry points for interventions. Specifically, metrics should be standardised, reliable, meaningful, integrated with data management systems, fair, and aligned with the core mission of health care. Incentives with the potential to contradict sustainability goals must be addressed in future planning and implementation if the next generation of metrics is to be effective and incentivise positive systemic change., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Identifying the evolving needs of patients with advanced heart failure (AdHF) and triaging those at high risk of death can facilitate timely referrals to palliative care and advance patient-centered individualized care. There are limited models specific for patients with end-stage HF. We aim to identify risk factors associated with up to three-year all-cause mortality (ACM) and describe prognostic models developed or validated in AdHF populations. Methods: Frameworks proposed by Arksey, O'Malley, and Levac were adopted for this scoping review. We searched the Medline, EMBASE, PubMed, CINAHL, Cochrane library, Web of Science and gray literature databases for articles published between January 2010 and September 2020. Primary studies that included adults aged ≥ 18 years, diagnosed with AdHF defined as New York Heart Association class III/IV, American Heart Association/American College of Cardiology Stage D, end-stage HF, and assessed for risk factors associated with up to three-year ACM using multivariate analysis were included. Studies were appraised using the Quality of Prognostic Studies tool. Data were analyzed using a narrative synthesis approach. Results: We reviewed 167 risk factors that were associated with up to three-year ACM and prognostic models specific to AdHF patients across 65 articles with low-to-moderate bias. Studies were mostly based in Western and/or European cohorts ( n = 60), in the acute care setting ( n = 56), and derived from clinical trials ( n = 40). Risk factors were grouped into six domains. Variables related to cardiovascular and overall health were frequently assessed. Ten prognostic models developed/validated on AdHF patients displayed acceptable model performance [area under the curve (AUC) range: 0.71-0.81]. Among the ten models, the model for end-stage-liver disease (MELD-XI) and acute decompensated HF with N-terminal pro b-type natriuretic peptide (ADHF/proBNP) model attained the highest discriminatory performance against short-term ACM (AUC: 0.81). Conclusions: To enable timely referrals to palliative care interventions, further research is required to develop or validate prognostic models that consider the evolving landscape of AdHF management.

Background: Tuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients., Methods: New, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen [ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly] or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment., Results: Of the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1-97.8) and 94.5% (95% CI: 90.8-98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction., Conclusion: The 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen., (© 2024. The Author(s).)

KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS -driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aβ can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aβ and tau pathologies in postmortem brain tissues across cases and Aβ peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aβ peptides with MS-brain imaging. While intraparenchymal Aβ deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aβ deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aβ deposits in capillaries. Investigation of Aβ peptide profiles showed a specific increase in Aβx-37, Aβx-38 and Aβx-40 but not Aβx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aβ2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aβ peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aβ deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aβ peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments., (© 2024. The Author(s).)

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T (" hi T") cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hi T cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hi T mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD., Competing Interests: Competing interests statement:C.J.W. is the author of patents PCT/US2016/049598, WO2017/040594, and PCT/US2019/017879. R.C. and K.L.B. are co-authors on patent PCT/US2019/017879. PCT/US2016/049598 and WO 2017/040594 are licensed by Cedars-Sinai Medical Center to T-Neuro Pharma, Inc. C.J.W. has received salary and ownership interest in T-Neuro Pharma, Inc.

In the wake of the COVID-19 pandemic, respiratory tract infections have emerged as a significant global threat, yet their impact on public health was previously underappreciated. This study investigated the antiviral efficacy of the nano-coating agent BARRIER90, composed of silicon-quaternary ammonium compound and a naturally derived biopolymer, against three distinct respiratory viruses: Influenza A (H1N1), Adenovirus Type 1, and Enterovirus-Coxsackie B1. BARRIER90 exhibited robust and sustained virucidal activity, persisting up to 90 days post-coating, against the enveloped virus, Influenza A, with significant reduction in viral plaques. Contrastingly, its efficacy against non-enveloped viruses revealed transient activity against Enterovirus-Coxsackie B1, with almost no antiviral activity observed against Adenovirus Type 1. These findings indicate the potential of antimicrobial coatings in mitigating viral transmission through contaminated surfaces (fomites), which harbour pathogenic viruses for longer periods. Antimicrobial coatings may facilitate infection control in various settings, including healthcare facilities and shared workspaces., Competing Interests: He authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Background: Few studies have described the insights of frontline health care providers and patients on how the diagnostic process can be improved in the emergency department (ED), a setting at high risk for diagnostic errors. The authors aimed to identify the perspectives of providers and patients on the diagnostic process and identify potential interventions to improve diagnostic safety., Methods: Semistructured interviews were conducted with 10 ED physicians, 15 ED nurses, and 9 patients/caregivers at two separate health systems. Interview questions were guided by the ED-Adapted National Academies of Sciences, Engineering, and Medicine Diagnostic Process Framework and explored participant perspectives on the ED diagnostic process, identified vulnerabilities, and solicited interventions to improve diagnostic safety. The authors performed qualitative thematic analysis on transcribed interviews., Results: The research team categorized vulnerabilities in the diagnostic process and intervention opportunities based on the ED-Adapted Framework into five domains: (1) team dynamics and communication (for example, suboptimal communication between referring physicians and the ED team); (2) information gathering related to patient presentation (for example, obtaining the history from the patients or their caregivers; (3) ED organization, system, and processes (for example, staff schedules and handoffs); (4) patient education and self-management (for example, patient education at discharge from the ED); and (5) electronic health record and patient portal use (for example, automatic release of test results into the patient portal). The authors identified 33 potential interventions, of which 17 were provider focused and 16 were patient focused., Conclusion: Frontline providers and patients identified several vulnerabilities and potential interventions to improve ED diagnostic safety. Refining, implementing, and evaluating the efficacy of these interventions are required., (Copyright © 2024 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

The growth of omic data presents evolving challenges in data manipulation, analysis and integration. Addressing these challenges, Bioconductor provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming offers a revolutionary data organization and manipulation standard. Here we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analyzing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas, spanning six data frameworks and ten analysis tools., (© 2024. Crown.)

Introduction: Bluetongue (BT) poses a significant threat to the livestock industry, affecting various animal species and resulting in substantial economic losses. The existence of numerous BT virus (BTV) serotypes has hindered control efforts, highlighting the need for broad-spectrum vaccines., Methodology: In this study, we evaluated the conserved amino acid sequences within key non-structural (NS) proteins of BTV and identified numerous highly conserved murine- and bovine-specific MHC class I-restricted (MHC-I) CD8+ and MHC-II-restricted CD4+ epitopes. We then screened these conserved epitopes for antigenicity, allergenicity, toxicity, and solubility. Using these epitopes, we developed in silico-based broad-spectrum multiepitope vaccines with Toll-like receptor (TLR-4) agonists. The predicted proinflammatory cytokine response was assessed in silico using the C-IMMSIM server. Structural modeling and refinement were achieved using Robetta and GalaxyWEB servers. Finally, we assessed the stability of the docking complexes through extensive 100-nanosecond molecular dynamics simulations before considering the vaccines for codon optimization and in silico cloning., Results: We found many epitopes that meet these criteria within NS1 and NS2 proteins and developed in silico broad-spectrum vaccines. The immune simulation studies revealed that these vaccines induce high levels of IFN-γ and IL-2 in the vaccinated groups. Protein-protein docking analysis demonstrated promising epitopes with strong binding affinities to TLR-4. The docked complexes were stable, with minimal Root Mean Square Deviation and Root Mean Square Fluctuation values. Finally, the in silico-cloned plasmids have high % of GC content with > 0.8 codon adaptation index, suggesting they are suitable for expressing the protein vaccines in prokaryotic system., Discussion: These next-generation vaccine designs are promising and warrant further investigation in wet lab experiments to assess their immunogenicity, safety, and efficacy for practical application in livestock. Our findings offer a robust framework for developing a comprehensive, broad-spectrum vaccine, potentially revolutionizing BT control and prevention strategies in the livestock industry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kolla, Dutt, Kumar, Hebbandi Nanjunadappa, Karakach, Singh, Kelvin, Clement Mertens and Umeshappa.)

Purpose: Black birthing parents and their newborns disproportionately experience newborn drug testing for prenatal substance exposure by health care professionals (HCPs), which contributes to Child Protective Services (CPS) reporting, family separation, and termination of parental rights. This qualitative study aims to interrogate dominant power structures by exploring knowledge, attitudes, and experiences of HCPs and CPS professionals regarding the influence of structural racism on inequities in newborn drug testing practices., Methods: We conducted semistructured interviews with 30 physicians, midwives, nurses, social workers, and CPS professionals guided by an explanatory framework, and conducted inductive, reflexive thematic analysis., Results: We identified 3 primary themes: (1) levels of racism beyond the hospital structure contributed to higher rates of drug testing for Black newborns; (2) inconsistent hospital policies led to racialized application of state law and downstream CPS reporting; and (3) health care professionals knowledge of the benefits and disproportionate harms of CPS reporting on Black families influenced their decision making., Conclusion: Health care professionals recognized structural racism as a driver of disproportionate newborn drug testing. Lack of knowledge and skill limitations of HCPs were barriers to dismantling power structures, thus impeding systems-level change. Institutional changes should shift focus from biologic testing and reporting to supporting the mutual needs of birthing parent and child through family-centered substance use treatment. State and federal policy changes are needed to ensure health equity for Black families and eliminate reporting to CPS for prenatal substance exposure when no concern for child abuse and neglect exists., (© 2024 Annals of Family Medicine, Inc.)

While mixed methods research is increasingly used to examine determinants of unwarranted variability in healthcare delivery and outcomes, novel integrative approaches are required to meet the needs of mixed methods healthcare delivery research. This article describes novel refining strategies that enhance the linkage between qualitative and quantitative dimensions of a mixed methods healthcare delivery research study. Leveraging our study experiences, this paper demonstrates several refining strategies: (1) using mediated allocation concealment to facilitate qualitative sampling; (2) informing qualitative inquiry through quantitative analytics; and (3) training and immersing multidisciplinary researchers in qualitative data collection and analysis. Developing and implementing strategies in mixed methods healthcare delivery research could advance methodological rigor and strengthen multidisciplinary collaboration.

Objectives: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions., Methods: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject., Results: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers., Conclusions: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health., (© 2024. The Author(s).)

Raoultella planticola is a Gram-negative, aerobic, nonmotile bacterium that is ubiquitous in the environment usually implicated in opportunistic infections. There have been very few reported cases of Raoultella planticola infection in the pediatric population. Most of these reports have been in cases of neonatal septicemia. This case report describes a case of a 3-day-old Hispanic full-term male that presented with recalcitrant hyperbilirubinemia despite maximal phototherapy found to have urinary tract infection with Raoultella planticola on multiple cultures. The patient's hyperbilirubinemia appropriately responded to treatment of the UTI. This report highlights that, albeit rare, neonatal UTI can present as recalcitrant hyperbilirubinemia. Raoultella planticola is a rare organism that is normally found in the environment but may be a bona fide etiologic agent in neonatal UTI., (Copyright© South Dakota State Medical Association.)

Noroviruses constitute a significant aetiology of sporadic and epidemic gastroenteritis in human hosts worldwide, especially among young children, the elderly, and immunocompromised patients. The low infectious dose of the virus, protracted shedding in faeces, and the ability to persist in the environment promote viral transmission in different socioeconomic settings. Considering the substantial disease burden across healthcare and community settings and the difficulty in controlling the disease, we review aspects related to current knowledge about norovirus biology, mechanisms driving the evolutionary trends, epidemiology and molecular diversity, pathogenic mechanism, and immunity to viral infection. Additionally, we discuss the reservoir hosts, intra-inter host dynamics, and potential eco-evolutionary significance. Finally, we review norovirus vaccines in the development pipeline and further discuss the various host and pathogen factors that may complicate vaccine development.

Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents determining whether the same allele is responsible, indicating a shared underlying mechanism. Here, using a collection of 129,058 cases and controls across 6 diseases, we show that ~40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles twofold by combining cases and controls across diseases, allowing us to identify more expression quantitative trait loci driven by the shared alleles. The patterns indicate widespread sharing of pathogenic mechanisms but not a single global autoimmune mechanism. Our approach can be applied to any set of traits and is particularly valuable as sample collections become depleted., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Describe and compare the experiences and preferences of Deaf and hearing individuals with different levels of health literacy in accessing, interpreting, and acting upon online health information., Methods: We conducted semi-structured interviews with 17 Deaf and 10 hearing participants with high and low health literacy from three healthcare sites. We conducted thematic analysis of the transcripts to explore information navigation experiences, information sources and dissemination preferences., Results: We found thematic differences between Deaf and hearing participants with high and low health literacy in terms of information needs, information search experiences, information search perceptions, and preferred information dissemination approaches. Relative to hearing counterparts, Deaf participants were more likely to encounter challenges in accessing and understanding online information. Deaf participants with low health literacy were more likely to rely on visual graphics to support their understanding of the information than those with high health literacy. Deaf participants advocated for tailored approaches to disseminate health information to Deaf communities., Conclusion: Our findings suggest that differences in online health information navigation experiences and accessibility may inform disparities in health literacy outcomes between Deaf and hearing individuals., Practice Implications: Online health information should be presented in a manner accessible to Deaf community members., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose. The work was supported in part by the National Institute on Deafness and Other Communication Disorders (NIDCD) [R01 DC014703]; and the National Institute of General Medical Sciences [K12 GM106997]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We report a case of congenital multisystem Langerhans cell histiocytosis with cutaneous and hematopoietic involvement. After the failure of first-line (vinblastine and prednisolone) and second-line (vincristine and cytarabine) therapies, treatment with cobimetinib, a mitogen-activated protein kinase (MEK) inhibitor, led to the remission of disease and a sustained response after 11 months of ongoing treatment. Protein kinase inhibitors targeting BRAF or MEK could represent a promising future therapeutic option, also in children with LCH., (© 2024 Wiley Periodicals LLC.)

Apparent treatment-resistant hypertension (aTRH), defined as blood pressure (BP) that remains uncontrolled despite unconfirmed concurrent treatment with three antihypertensives, is associated with an increased risk of developing cardiovascular and renal complications compared with controlled hypertension. We aimed to identify the characteristics of aTRH patients with an elevated risk of major adverse cardiovascular events plus (MACE+; defined as stroke, myocardial infarction, or heart failure hospitalization) and end stage renal disease (ESRD). This retrospective cohort study included aTRH patients (BP ≥140/90 mmHg and taking ≥3 antihypertensives) from the United States-based Optum ® de-identified Electronic Health Record dataset and used machine learning models to identify risk factors of MACE+ or ESRD. Patients had claims for ≥3 antihypertensive classes within 30 days between January 1, 2015 and June 30, 2021, and two office BP measures recorded 1-90 days apart within 30 days to 11 months after the index regimen date. Of a total 18 797 070 patients identified with any hypertension, 71 100 patients had aTRH. During the study period (mean 25.5 months), 4944 (7.0%) patients had a MACE+ and 2403 (3.4%) developed ESRD. In total, 22 risk factors were included in the MACE+ model and 16 in the ESRD model, and most were significantly associated with study outcomes. The risk factors with the largest impact on MACE+ risk were congestive heart failure, stages 4 and 5 chronic kidney disease (CKD), age ≥80 years, and living in the Southern region of the United States. The risk factors with the largest impact on ESRD risk, other than pre-existing CKD, were anemia, congestive heart failure, and type 2 diabetes. The overall study cohort had a 5-year predicted MACE+ risk of 13.4%; this risk was increased in those in the top 50% and 25% high-risk groups (21.2% and 29.5%, respectively). The overall study cohort had a predicted 5-year risk of ESRD of 6.8%, which was increased in the top 50% and 25% high-risk groups (10.9% and 17.1%, respectively). We conclude that risk models developed in our study can reliably identify patients with aTRH at risk of MACE+ and ESRD based on information available in electronic health records; such models may be used to identify aTRH patients at high risk of adverse outcomes who may benefit from novel treatment interventions., (© 2024 Janssen Scientific Affairs, LLC. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics., Objective: To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data., Design, Setting, and Participants: From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146)., Outcome Measurements and Statistical Analysis: Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data., Results and Limitations: The most common comorbidities were hypertension (35-73%), obesity (9.2-54%), and type 2 diabetes (11-28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12-25%) and emergency department visits (10-14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent., Conclusions: Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data., Patient Summary: Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The crane hook is a widely utilized component in several industries for the purpose of lifting things. The crane hook must possess the capacity to withstand the intended load without encountering any complications, hence ensuring the safety of both personnel and the objects being lifted. The process of analysis is crucial for the effective utilization of a crane hook. The primary aim of this study was to determine the most efficient cross-sectional crane hook among five distinct geometric profiles. This was achieved through the application of finite element analysis using Solidworks software. Subsequently, the identified cross-sectional profile was further examined using the Python programming language, taking into account the classical equation of a curved beam. The five cross-sectional shapes seen in the study were circular, rectangular, trapezoidal, I-shaped, and T-shaped. For the purposes of this investigation, the chosen material for each cross-sectional crane hook model was 34CrMo4 steel. Despite the identical boundary constraints imposed on all the chosen cross-sectional crane hook profiles, it was observed that the trapezoidal cross-sectional crane hook exhibited superior performance compared to the others. The trapezoidal cross-sectional crane hook model exhibited a Von Mises stress of 203 MPa, with a corresponding factor of safety of 3.20. Further experimentation was conducted using Python to examine the trapezoidal profile. The results indicated that an increased level of parallelism in the inner side of the trapezoidal shape corresponded to a higher factor of safety. Hence, it is advisable to maintain the trapezoidal cross-sectional profile of the crane hook, with due consideration given to maximizing the length of the inner parallel side. The enhancement of design leads to a decrease in the likelihood of failure and the occurrence of undesirable accidents., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Sea-level rise submerges terrestrial permafrost in the Arctic, turning it into subsea permafrost. Subsea permafrost underlies ~ 1.8 million km 2 of Arctic continental shelf, with thicknesses in places exceeding 700 m. Sea-level variations over glacial-interglacial cycles control subsea permafrost distribution and thickness, yet no permafrost model has accounted for glacial isostatic adjustment (GIA), which deviates local sea level from the global mean due to changes in ice and ocean loading. Here we incorporate GIA into a pan-Arctic model of subsea permafrost over the last 400,000 years. Including GIA significantly reduces present-day subsea permafrost thickness, chiefly because of hydro-isostatic effects as well as deformation related to Northern Hemisphere ice sheets. Additionally, we extend the simulation 1000 years into the future for emissions scenarios outlined in the Intergovernmental Panel on Climate Change's sixth assessment report. We find that subsea permafrost is preserved under a low emissions scenario but mostly disappears under a high emissions scenario., (© 2024. The Author(s).)

Background and Objective: The treatment landscape of metastatic prostate cancer (mPCa) has evolved significantly over the past two decades. Despite this, the optimal therapy for patients with mPCa has not been determined. This systematic review identifies available predictive models that assess mPCa patients' response to treatment., Methods: We critically reviewed MEDLINE and CENTRAL in December 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Only quantitative studies in English were included with no time restrictions. The quality of the included studies was assessed using the PROBAST tool. Data were extracted following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews criteria., Key Findings and Limitations: The search identified 616 citations, of which 15 studies were included in our review. Nine of the included studies were validated internally or externally. Only one study had a low risk of bias and a low risk concerning applicability. Many studies failed to detail model performance adequately, resulting in a high risk of bias. Where reported, the models indicated good or excellent performance., Conclusions and Clinical Implications: Most of the identified predictive models require additional evaluation and validation in properly designed studies before these can be implemented in clinical practice to assist with treatment decision-making for men with mPCa., Patient Summary: In this review, we evaluate studies that predict which treatments will work best for which metastatic prostate cancer patients. We found that existing studies need further improvement before these can be used by health care professionals., (© 2024 The Author(s).)