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Background: Dopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D 2 /D 3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans., Methods: Healthy, vitamin D-sufficient adults (N = 18, 32.8 ± 6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving 4 total scans over 2 visits consisting of same-day preamphetamine and postamphetamine (0.3 mg/kg) [ 11 C]-PHNO positron emission tomography scanning to examine D 2 /D 3 receptor availability (nondisplaceable binding potential [BP ND ]) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least 6 days apart. Parametric images of [ 11 C]-PHNO positron emission tomography BP ND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra., Results: For preamphetamine scans, there was a medication × region of interest interaction (F 4,153  = 2.59, p = .039) and a main effect of medication (F 1,153  = 4.88, p = .029) on BP ND , with higher BP ND values on calcitriol in the ventral striatum (t 153  = 2.89, p = .004) and dorsal putamen (t 153  = 2.15, p = .033). There was a main effect of medication on postamphetamine change in BP ND (F 4,153  = 5.93, p = .016), with greater decreases in calcitriol in the ventral striatum (t 153  = 3.00, p = .003), substantia nigra (t 153  = 2.49, p = .014), and dorsal caudate (t 153  = 2.29, p = .023)., Conclusions: Results provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders that involve dysregulated dopamine function., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Patients with a penicillin allergy label have an increased risk of surgical site infection. Although a decision tree was published in 2019 to define which patients could benefit from direct cephalosporin use in the perioperative setting, this strategy remains unvalidated. This consensus statement aimed to adapt it based on an expert consensus to cover persisting caveats and to adapt it to an environment with poor allergist resources., Methods: Perioperative antibiotic prophylaxis and allergy experts were invited to participate. The Delphi method was implemented using an online-secured network. The panellists were given 3 weeks to answer each round. A consensus was reached if more than 75% of the experts rated the item ≥ 7 and if less than 25% rated the item ≤ 3., Results: Sixteen experts participated. A high level of agreement was obtained after four rounds, defining four categories of the index reaction: unknown, not compatible, or compatible with an immediate or delayed hypersensitivity reaction. Twelve items were defined to stratify the risk of true penicillin allergy according to the index reaction history. The experts agreed that patients with high-risk reactions could benefit from either an allergy work-up or beta-lactam alternatives use. Those at low risk could benefit from direct cephalosporin administration., Conclusions: This resulted in an adapted decision tree to promote cephalosporin prescription in patients with penicillin allergy labels. It will be used in a stepped-wedge prospective multicentric randomized study to assess its applicability and acceptability to promote first- and second-generation cephalosporin administration in the perioperative period., (© The Author(s) 2025. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS)-driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid-encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector-based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.

Extragonadal choriocarcinoma in men is an extremely rare and highly aggressive malignancy. Inconclusive biopsies due to a high necrotic component often delay diagnosis. Here is such a case, in which suggestive imaging findings on [ 18 F]FDG PET/CT, a raised level of serum β-human chorionic gonadotropin, and gynecomastia clinched the diagnosis., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Water column hypoxia is a key process influencing methylmercury (MeHg) production and availability in waterbodies worldwide. During seasonal destratification, large, short-lived pulses of aqueous MeHg may be released into the subsequently mixed water column, but little is known about the fate of these pulses, particularly whether there are concomitant increases in MeHg uptake into aquatic food webs. We examined the magnitude and timing of MeHg uptake across several trophic guilds relative to the reservoir stratification status using biweekly mercury data from water, zooplankton, and fish (Bluegill, Lepomis macrochirus and Smallmouth Bass, Micropterus dolomieu ). Zooplankton MeHg concentrations increased by up to 250% during destratification, concurrent with increases in aqueous MeHg concentrations. Zooplankton and filter-passing MeHg concentrations were positively correlated when the reservoir was mixed ( R 2 = 0.95) and destratifying ( R 2 = 0.57) but not while the reservoir was stratified ( R 2 = 0.21). Mercury concentrations in adult bluegill and juveniles of both fish species increased 20-70% following destratification, with responses lagging 4-8 weeks behind those in water and zooplankton MeHg. Mercury concentrations in piscivorous adult bass varied little over the course of the study. Our findings demonstrate the responsiveness of reservoir food webs to pulses in MeHg availability, suggesting that these pulses could play an important role in biotic MeHg exposure within and downstream of reservoirs.

Background: The 2013-2016 West African Ebola Virus Disease (EVD) outbreak resulted in 28,600 cases and 11,300 deaths officially reported to the World Health Organization. Previous studies investigating factors associated with death had conflicting findings, interventions showing promising outcomes had small sample sizes, studies were often single- or dual-country based and most focused on laboratory-confirmed EVD and not on clinically-suspected EVD. We used the Ebola data platform of the Infectious Disease Data Observatory (IDDO) to review individual patient records to assess factors associated with death, and particularly whether there were differences between laboratory-confirmed and clinically-suspected cases., Methods: This was a cohort study involving analysis of secondary data in the IDDO database. The study population included all patients classified as having either clinically-suspected or laboratory-confirmed EVD, admitted to 22 Ebola Treatment Units (ETU) in Guinea, Liberia and Sierra Leone between December 2013 and March 2016. Baseline characteristics and treatments were documented along with ETU exit outcomes. Factors associated with death were investigated by multivariable modified Poisson regression., Results: There were 14,163 patients, of whom 6,208 (43.8%) were laboratory-confirmed and 7,955 (56.2%) were clinically-suspected. Outcomes were not recorded in 2,889 (20.4%) patients. Of the 11,274 patients with known outcomes, 4,090 (36.3%) died: 2,956 (43.6%) with laboratory-confirmed EVD and 1,134 (18.8%) with clinically-suspected EVD. The strongest risk factor for death was confirmed disease status. Patients with laboratory-confirmed disease had 2.9 times higher risk of death compared to clinically-suspected patients, after adjusting for other co-variables. Other factors significantly associated with death included a higher risk for patients aged ≥60 years and a lower risk for patients in Sierra Leone., Conclusions: Although laboratory-confirmed patients admitted to ETUs fared worse than clinically-suspected patients, the latter still had a substantial risk of death and more attention needs to be paid to this group in future EVD outbreaks., Competing Interests: No competing interests were disclosed., (Copyright: © 2025 Yeabah TO et al.)

The internal mammary vessels are the standard recipient vessels in autologous breast reconstruction. Rib-sparing techniques have evolved to routine use, limiting the surgical field for vessel preparation to a minimum. An inframammary approach for skin-sparing mastectomy provides aesthetically pleasing results but might impede exposure even further. We have developed a simple yet elaborate technique to expose the surgical field for the preparation of the internal mammary vessels in a staff- and cost-efficient manner while using basic surgical tools., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2025 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: People living with dementia often suffer from sleep disturbances. The MoNoPol-Sleep (multimodal, nonpharmacological intervention for sleep disturbances in people with dementia living in nursing homes) study aimed to develop and evaluate a multimodal, nonpharmacological intervention to prevent and reduce sleep disturbances in people with dementia living in nursing homes., Objectives: To investigate implementation fidelity, adoption, barriers and facilitators of the multimodal, nonpharmacological intervention., Design: Mixed-methods process evaluation alongside an exploratory cluster-randomised controlled trial., Setting: Twenty-two nursing homes in three regions in Germany., Subjects: Nursing staff, nursing home managers, sleep nurses and other target groups of the intervention from the participating nursing homes., Methods: Questionnaires, qualitative interviews and documentation of the intervention's implementation., Results: The intervention was predominately implemented as planned, but implementation fidelity varied between the clusters. The most frequently planned and implemented sleep-promoting interventions were daytime activities. There is some evidence that person-centredness slightly increased in the intervention group. The commitment of nursing home managers, the motivation of nurses and good cooperation with the main contact persons of the research team were identified as facilitating context factors. Identified barriers were financial and time resources and low motivation of the nurses. The results of the cRCT have been published elsewhere., Conclusions: For a successful implementation, involvement of nurses from day and night shifts and other stakeholders is crucial. Based on the results of this process evaluation conducted alongside an exploratory trial, the intervention can be adapted and further developed to evaluate its effectiveness in a future full trial., Clinical Trial Registration: ISRCTN No ISRCTN36015309., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Gestational diabetes mellitus (GDM) is increasingly becoming a serious public health challenge. Innovative, effective and scalable lifestyle interventions to support women with GDM to manage their condition and prevent adverse obstetric and neonatal outcomes as well as later morbidity are required. This study aims to evaluate whether a novel, multilingual and scalable mobile health (mHealth) intervention (SPARK; SmartPhone App for gestational diabetes patients suppoRting Key lifestyle behaviours and glucose control) can improve self-management and treatment of GDM and prevent adverse maternal and offspring outcomes., Methods/analyses: SPARK is a multicentre two-arm randomised controlled trial recruiting women diagnosed with GDM in south-eastern Sweden. A total of 412 women will be randomised to either standard care (control) or the SPARK intervention. The SPARK online platform (accessed through a mobile app) provides a behaviour change programme for healthy eating, physical activity and glycaemic control. To increase reach, SPARK is available in Swedish, English, Arabic and Somali. SPARK also comes with a clinician portal where healthcare professionals monitor and intervene when glycaemic control is unsatisfactory (above certain cut-offs). Primary outcomes are glycaemic control that is, time in range and HbA1c, while diet, physical activity (ActiGraph), gestational weight gain, metabolic and inflammatory biomarkers in weeks 37-38, adherence to protocol for daily glucose sampling, as well as adverse obstetric and neonatal outcomes are secondary outcomes. Secondary outcomes also include cardiometabolic risk evaluation, physical activity and healthy eating behaviours 1 year postpartum. A health economic evaluation of SPARK vs standard care will also be conducted., Ethics and Dissemination: This study has been approved by the Swedish Ethical Review Authority (2021-06627-01; 2022-03842-02; 2023-05911-02). Results will be disseminated through scientific papers in peer-reviewed journals, posts in traditional and social media, and presentations at scientific and healthcare professionals' conferences., Trial Registration Number: This trial was registered at the ClinicalTrials.gov register platform (ID NCT05348863) 27 April 2022., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Background: Transcatheter edge-to-edge repair (TEER) using the TriClip tricuspid valve repair system has emerged as a therapy for tricuspid regurgitation (TR). Patients with TR undergoing TEER commonly present with an endocardial lead across the tricuspid valve (TV)., Aims: We sought to examine the effectiveness and safety of tricuspid TEER (T-TEER) in subjects with endocardial leads in the bRIGHT EU Post-Approval Study (PAS)., Methods: The bRIGHT EU PAS is a prospective, single-arm, open-label, multicentre, post-market registry conducted at 26 sites in Europe. Echocardiographic assessments of endocardial lead placement, interaction, and TR grade were performed at a core laboratory., Results: Of the 511 enrolled subjects, a total of 110 had an endocardial lead, and in 80.7% of these subjects, TR was at least partially related to the lead. At 30 days, 71% of subjects with endocardial leads had TR of moderate or less. The percentage of subjects with endocardial leads categorised as New York Heart Association Functional Class I-II increased from 17% at baseline to 75% at 30 days (p<0.0001), and quality of life with the Kansas City Cardiomyopathy Questionnaire showed a mean improvement of 20±24 points from baseline to 30 days (p<0.0001). T-TEER was safe in subjects with endocardial leads, with similar rates of events, including TV reintervention/reoperation and TV surgery, to those in subjects without leads. No reports of lead malfunction were reported., Conclusions: In the bRIGHT EU PAS, T-TEER using the TriClip system was safe and effective in severe TR subjects with an endocardial lead across the TV.

Background: Vascular access site complications are associated with increased morbidity and mortality after transcatheter aortic valve implantation (TAVI). Current results comparing strategies with plug- (P-VCD; MANTA) and suture-based vascular closure devices (S-VCD; Perclose ProGlide) remain inconsistent., Aims: It was our aim to assess the incidence of access-related vascular complications after P-VCD or S-VCD strategies after transfemoral TAVI., Methods: The Plug or sUture based vascuLar cloSurE after TAVI (PULSE) registry retrospectively evaluated 10,120 consecutive patients who had undergone transfemoral TAVI at 10 centres from 2016 to 2021. A propensity score was used to match 900 P-VCD patients with 1,800 S-VCD patients in a 1:2 fashion. The primary outcome measures were major and minor access-related vascular complications at the primary access site, adjudicated according to Valve Academic Research Consortium 3 definitions., Results: The median age was 81.8 years, 46.4% of patients were female, and the median European System for Cardiac Operative Risk Evaluation II was 3.50%. In matched P-VCD and S-VCD groups, large-bore access-related complications occurred in 14.9% vs 10.3% (p<0.001; major: 3.6% vs 4.6%; p=0.218; minor: 11.3% vs 5.8%; p<0.001) of patients. Bleeding accounted for most of these complications (9.6% vs 7.2%; p=0.028) and was treated with endovascular balloon inflation (5.4% vs 2.6%; p<0.001), stent implantation (4.7% vs 0.7%; p<0.001) or surgical repair (0.7% vs 1.7%; p=0.03)., Conclusions: P-VCD were associated with higher rates of primary access-related vascular complications, driven by minor complications, compared to S-VCD. Endovascular treatment was more common after P-VCD failure.

The Food and Drug Administration (FDA) recently approved several novel therapies to treat chronic rhinosinusitis with nasal polyps (CRSwNP), though high prices may burden patients and payers. CRSwNP-specific spending varied widely by prescription drug among commercially insured patients, ranging from $7050 (EDS-FLU) to $28,324 (dupilumab). Condition-specific costs owed out-of-pocket ranged from $1036 (other drugs) to $3549 (mepolizumab)., (© 2025 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

CD47 is a ubiquitous and pleiotropic cell-surface receptor. Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries. In a murine closed-fracture model, CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology. To understand the cellular basis for this phenotype, mesenchymal progenitors (MSC) were harvested from bone marrow. CD47-null MSC showed decreased large fibroblast colony formation (CFU-F), significantly less proliferation, and fewer cells in S-phase, although osteoblast differentiation was unaffected. However, consistent with prior research, CD47-null endothelial cells showed increased proliferation relative to WT cells. Similarly, in a murine ischemic fracture model, CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture. Consistent with our in vitro results, in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice, while staining for CD31 and endomucin demonstrated increased endothelial cell density. Finally, WT mice with ischemic fracture that were administered a CD47 morpholino, which blocks CD47 protein production, showed a callus phenotype similar to that of ischemic fractures in CD47-null mice, suggesting the phenotype was not due to developmental changes in the knockout mice. Thus, inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing, in part, by decreasing MSC proliferation. Furthermore, the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background/aim: Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy of the upper aerodigestive tract, associated with poor survival. As part of the HNSCC microenvironment, the interleukin-18 (IL-18)/IL-18 binding protein (IL-18BP) signaling is becoming increasingly interesting as a potential biomarker and therapeutic target. However, the systemic expression levels of IL-18BP in the context of the immunological environment in HNSCC patients remain unexplored., Materials and Methods: ELISA measurements of plasma IL-18-BP were carried out with regard to associated inflammatory markers such as C-reactive protein, acute phase protein ferritin, and IL-18 in 34 patients with HNSCC before and during the course of radio(chemo)therapeutic treatment and in correlation to the clinicopathological parameters., Results: Plasma IL-18BP concentrations were significantly elevated in HNSCC patients compared to healthy controls and correlated strongly with IL-18 levels before and after treatment. However, plasma ferritin levels, which were also elevated, showed no correlation with IL-18 or IL-18BP. Notably, changes in IL-18BP and IL-18 levels following therapy exhibited a well-maintained balance, indicating a functional feedback mechanism., Conclusion: The results demonstrate a robust IL-18/IL-18BP feedback regulation in HNSCC, which likely aids tumor cells in evading anti-tumor immune responses. This balance, unaffected by radiotherapy or chemoradiotherapy, underscores the potential of IL-18BP as a therapeutic target and a prognostic biomarker in HNSCC., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Hypocalcemia is a relatively common complication after parathyroidectomy for treatment of primary hyperparathyroidism., Objectives: To retrospectively evaluate clinical variables in dogs with primary hyperparathyroidism to determine whether or not an association exists between pre-surgical variables and the development of post-surgical hypocalcemia., Animals: One hundred three dogs diagnosed with primary hyperparathyroidism and treated by parathyroidectomy in seven referral hospitals between 2010 and 2021., Material and Methods: Data collected from medical records included signalment, physical examination findings, concurrent illnesses, ongoing medications, and clinicopathologic test results (including serum ALP activity, iCa, plasma phosphate and PTH concentrations). Dogs were assigned into groups based on lowest iCa post-surgery: Group1 ≥ 1.1 mmol/L, Group2 < 1.1 mmol/L. The Mann-Whitney U test assessed associations between several variables of interest and the occurrence of post-surgery hypocalcemia. ROC analyses were performed to identify variables that had the potential to predict the development of hypocalcemia after surgery., Results: The median plasma PTH concentration pre-surgery in dogs which developed hypocalcemia after surgery was significantly higher (232 pg/mL {[IQR] 108-421}) than in dogs which did not develop hypocalcemia after surgery (81.5 pg/mL {IQR 58.5-145.0}; p < 0.001). Plasma PTH concentration had a fair to good ability to predict the development of post-surgery hypocalcemia, with AUC being 0.78 [95% confidence interval 0.67-0.89]. Using a cut-off of ≥ 75 pg/mL, pre-surgery plasma PTH concentration had a sensitivity of 96.6% and specificity of 42.3% for the development of post-surgery hypocalcemia. Dogs that developed hypocalcemia after surgery were older and had lower body weights., Conclusion: Pre-surgery plasma PTH concentrations might be helpful in predicting those dogs at risk of developing hypocalcemia after parathyroidectomy., (© 2025 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Nonadherence to follow-up after bariatric surgery is associated with lower long-term weight loss. Yet limited data exists on the youngest bariatric population, adolescents and young adults (AYA), who experience life changes in social, psychological, and behavioral domains that can interrupt follow-up. To better understand how age groups affected health outcomes in these populations, this study compared bariatric clinic follow-up adherence between AYA and assessed the impact of follow-up interruption on weight loss., Methods: Using an institutional registry, we retrospectively reviewed adolescents (age 14-18) and young adults (YA) (age ≥19-26) who underwent sleeve gastrectomy between January 2018 and May 2023. Primary outcome was follow-up compliance (1, 3, 6, 12, 18, 24 months). Secondary outcomes included median total weight loss percentage (%TWL). Lost to follow-up (LTF) was determined by the last bariatric clinic visit attended., Results: Of 73 (46.8%) adolescents and 83 (53.2%) YA, median preoperative BMI was higher in adolescents (51.0 [44.5,56.8] vs. 48.5 [43.4,51.7], p = 0.015). Median total weight loss percentage (%TWL) was greater in YA up to 6 months postoperatively (23.3 [20.5,27.4] vs. 20.2 [15.1,24.9], p = 0.008) but did not differ afterward. Median missed follow-up appointments were similar between adolescents (3[3,4]) and YA (4[3,4]). Adolescents were more likely to be LTF at 6 months (34.3% vs. 20.5%, p = 0.053). Patients in both age groups were more likely to be LTF if %TWL was in the lowest tertile at 6 months (OR 4.78, 95% CI [2.04, 11.18], p =  < 0.001) or 1 year (OR 18.45, 95% CI [5.75, 59.2], p < 0.001)., Conclusions: Clinic adherence in the post-bariatric AYA population is poor especially among patients with less %TWL. Identifying when AYA are at risk of LTF allows for targeted interventions to maximize adherence and potentially improve long-term health., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s).)

In a longitudinal study in a first-level hospital in Luanda, Angola, we found rifampin-resistant and multidrug-resistant tuberculosis (TB) in 38 (8%, 95% CI 5.7-10.8) of 474 patients with no previous history of TB. Of note, 2 patients (0.4%, 95% CI 0.1-1.5) demonstrated pre-extensively drug-resistant TB.

Asthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy-resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4 + T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)-4, IL-5, IL-9, and IL-13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8 + cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy-resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids-the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid-resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non-type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non-type 2 lymphocytes, placing special emphasis on severe disease forms., (© 2025 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.)

Purpose: Total hip arthroplasty (THA), a commonly performed surgical procedure for management of end-stage osteoarthritis, is considered minimally invasive and the popularity of the direct anterior approach (DAA) is increasing. The objective of this study is to analyze the current literature on DAA THA through conduct of a comprehensive bibliometric analysis., Materials and Methods: A comprehensive search of the Web of Science Core Collection was conducted for identification of articles published between 1993 and 2022. Specific keywords associated with hip replacement and the anterior approach were used as an attempt to identify articles published in scientific journals., Results: As a result of the analysis, 743 articles were linked to DAA THA. The highest number of annual publications was reported for 2021, with 120 articles, followed by 2022 with 113 articles, 2020 with 104 articles, and 2018 with 69 articles. The United States led in contributions with 34.1% in production. The Medical University of Innsbruck contributed the highest number of studies with 263 articles, followed by the University of Ottawa with 229. The Journal of Arthroplasty emerged as the most influential journal with 903 articles and 4,571 citations. Keywords including "dislocation," "posterior approach," and "revision" were used frequently in 2015-2020, along with the increasing emphasis on perioperative complications and comparing different approaches., Conclusion: The findings of this analysis provide helpful insights into the current attitude regarding DAA THA research, highlighting emerging trends and guiding the direction of future research. The increasing scientific production reflects growing interest in DAA THA.

Background/aim: Class 1 human leukocyte antigen (HLA) ensures that cytotoxic T lymphocytes (CTLs) attack tumor cells. As part of tumor de-differentiation, the expression of HLA on the tumor cell surface may decrease, which can facilitate tumor growth. Therefore, reduced expression of HLA is generally negatively associated with overall survival (OS). The reverse is true for programmed cell death protein (PD-1) and programmed death ligand 1 (PD-L1). The presence of PD-1 and PD-L1 on the surface of cancer cells inhibits immune defense mechanisms against cancer cells. Therefore, one would expect that increased PD-1/PDL-1 expression would result in decreased 5-year survival. The aim of this study was to correlate the expression levels of HLA-A and HLA-B/C with the expression levels of PD-1 and PDL-1 to evaluate the reliability of their prediction of 5-year OS., Materials and Methods: This study retrospectively examined patients upon the start of a new therapy line for metastatic breast cancer (MBC). The pilot cohort fulfilling very demanding inclusion criteria consisted of 34 patients. The diagnostics were primarily carried out using RT-qPCR., Results: The expression of HLA-A, HLA-B/C, PD-1, and PD-L1 is not significantly associated with OS., Conclusion: This pilot study found no significant association between HLA-A, HLA-B/C, PD-1, or PD-L1 expression and OS in MBC, indicating limited prognostic value for these biomarkers in this cohort., (Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Objective: General hospitals care for more than 70% of hospitalized children nationally but face challenges in pediatric quality improvement (QI). Feasibility and organizational readiness to change assessments can help inform effective QI. Our objective was to assess readiness to implement pediatric QI interventions among a broad sample of general hospitals participating in the Simultaneously Implementing Pathways for Improving Asthma, Pneumonia, and Bronchiolitis Care for Hospitalized Children (SIP) study., Methods: We conducted a mixed-methods study. Data were collected via electronic surveys and qualitative interviews. Participants included multidisciplinary inpatient pediatric clinicians and QI leaders. Surveys used validated tools, including the Organizational Readiness to Implement Change (ORIC) and Feasibility of Intervention Measure (FIM). Interview guides developed using an implementation framework explored feasibility of implementing evidence-based practices. We analyzed data using descriptive statistics and thematic analysis., Results: A total of 424 participants from 15 hospitals were approached, and 186 (44%) completed the survey. ORIC and FIM scores were scaled 1 to 5, with higher scores indicating agreement. Response results did not differ based on clinician type or experience. Clinicians at community hospitals with pediatric beds reported greater readiness than nested children's hospitals (median ORIC 4.4 vs 4.0, P = 0.02). Interviewees' (n = 21) anticipated feasibility challenges included aligning practices across hospital care settings and obtaining information technology support for electronic medical record changes., Conclusions: In this mixed-methods study, we found high but variable readiness for pediatric QI and identified specific threats to feasibility. We also illustrated how such assessments can be used to support pediatric QI efforts in general hospitals., (Copyright © 2025 by the American Academy of Pediatrics.)

Background: This study explores the relationship between inflammation and longevity in a high-incidence focus of amyotrophic lateral sclerosis (ALS) in post-WWII Guam. Characteristics of this focus include the sudden appearance of the disease in high numbers and the unusually long lifespan (without medical interventions) seen in some cases. We used bio-banked specimens to evaluate the relationship between serum immunoregulators and survival time., Methods: We evaluated sera from 69 Guam ALS cases collected within 2 years of symptom onset by NIH researchers from 1950 to 1983 for 11 immunoregulators via ELISA (CRP, eotaxin-1, RANTES, IL-6, IL-8, IL-10, IFN-γ, IP-10, MCP-1, MCP-2 and TARC). Factor analysis identified two factors responsible for ~68% of the variation in the data. We estimated Cox proportional hazards models to identify immunoregulators associated with time to death., Results: Each 10-unit increase in factor 2 cytokines (MCP-2 and TARC) was associated with a 38% increase in the risk of death (HR: 1.38; 95% CI: 1.19, 1.65; p: 0.00)., Discussion: Like sporadic ALS cases worldwide, inflammation is associated with a shortened lifespan in Guamanian ALS; more specifically, our findings suggest serum levels of MCP-2 and TARC at onset may predict disease duration. Further investigation is needed to determine the role of these immunoregulators in disease prognosis and as targets for diagnostic and therapeutic interventions., (© 2025 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Purpose To evaluate the ability of MR elastography (MRE) to noninvasively quantify tissue biomechanics and determine the added diagnostic value of biomechanics for predicting response throughout neoadjuvant chemotherapy (NAC). Materials and Methods In this prospective study (between September 2020 and August 2023; registration no. NCT03238144), participants with breast cancer scheduled to undergo NAC underwent five MRE scans at different time points alongside clinical dynamic contrast-enhanced MRI (DCE MRI). Regions of interest were drawn over the tumor region for the first two scans, while for the post-NAC scan, the initial pre-NAC tumor footprint was used. Biomechanics, specifically tumor stiffness and phase angle within these regions of interest, were quantified as well as the corresponding ratios relative to before NAC (tumor-stiffness ratio and phase-angle ratio, respectively). Postsurgical pathologic analysis was used to determine complete and partial responders. Furthermore, a repeatability analysis was performed for 18 participants. Results Datasets of 41 female participants (mean age, 47 years ± 12.5 [SD]) were included in this analysis. The tumor-stiffness ratio following NAC decreased significantly for complete responders and increased for partial responders (0.76 ± 0.16 and 1.14 ± 0.24, respectively; P < .001). The phase-angle ratio after the first cycle of the first NAC regimen compared with before NAC predicted pathologic response (1.23 ± 0.31 vs 0.91 ± 0.34; P < .001). Combining the tumor stiffness ratio with DCE MRI improved specificity compared with DCE MRI alone (96% vs 44%) while maintaining the high sensitivity of DCE MRI (94%). Repeatability analysis showed excellent agreement for elasticity (repeatability coefficient, 8.3%) and phase angle (repeatability coefficient, 5%). Conclusion MRE-derived phase-angle ratio and tumor stiffness ratio were associated with pathologic complete response in participants with breast cancer undergoing NAC, and a combined DCE MRI plus MRE approach significantly enhanced specificity for identification of complete responders after NAC, while maintaining high sensitivity. Keywords: Breast Cancer, MR Elastography, Neoadjuvant Chemotherapy, Dynamic Contrast-enhanced MRI Supplemental material is available for this article. Clinical trials registration no. NCT03238144 Published under a CC BY 4.0 license.

Vision impairment is common among older adults and affects dementia screening assessments, which include visually presented items. We developed and validated a version of the Montreal Cognitive Assessment (MoCA) for people with vision impairment that includes all the cognitive domains included in the standard MoCA. Visual components of the MoCA were adapted by developing alternative spoken forms. We used both individual item analysis and item substitution to identify the optimal set of alternative items for inclusion in the Montreal Cognitive Assessment for People With Vision Impairment (MoCA-VI) in place of the original items to maximize sensitivity and specificity for dementia. We evaluated the performance and reliability of the final tool, including adjustments for demographic factors. One hundred twenty-eight participants with vision impairment (presenting distance visual acuity worse than 6/12), 79 cognitively healthy and 49 with dementia, completed the adapted MoCA. An additional 86 participants with normal vision completed the standard MoCA and alternative items to assess score equivalence and independence from vision impairment. Twenty-six participants were retested 2-4 weeks after initial testing. With the optimal item set, the final MoCA-VI had an area under the curve of 0.96 (95% CI [0.93, 0.99]). At a cut point of 24 points or less, sensitivity was 95.9%, with a specificity of 92.4%. The intraclass correlation for test-retest reliability was 0.84 (95% CI [0.81, 0.96]). The MoCA-VI is a specific and reliable test for possible dementia among adults with vision impairment. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function 1,2 . As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma 3 , the most common embryonal brain tumour in children 4 . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST 5 . However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3-neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions., Competing Interests: Competing interests: B.B.L. is a co-founder, shareholder and member of the scientific advisory board of Light Horse Therapeutics. N.Z. is one of the scientific cofounders and a shareholder of SEED Therapeutics. N.Z. serves as a member of the scientific advisory board of Synthex, Molecular Glue Lab and Differentiated Therapeutics with financial interests. R.M. is a scientific advisory board member and equity holder of Regenacy Pharmaceuticals. R.M. and N.C.P. are inventors on patent applications related to the CoraFluor TR-FRET probes used in this work. P.A.C. is a co-founder of Acylin Therapeutics and a consultant for Abbvie regarding p300 acetyltransferase inhibitors. The remaining authors declare no competing interests., (© 2025. The Author(s).)

UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal 1 . By co-opting KBTBD4, a substrate receptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1-CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition 2,3 . However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3-neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST-HDAC1/2-KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader., Competing Interests: Competing interests: B.B.L. is a cofounder, shareholder and member of the scientific advisory board of Light Horse Therapeutics. N.Z. is one of the scientific cofounders and a shareholder of SEED Therapeutics. N.Z. serves as a member of the scientific advisory board of Synthex, Molecular Glue Labs and Differentiated Therapeutics with financial interests. R.M. and N.C.P. are listed as inventors on patent applications related to the CoraFluor TR-FRET probes used in this work. P.A.C. is a co-founder of Acylin Therapeutics and a consultant for Abbvie regarding p300 acetyltransferase inhibitors. L.B.-P. is a founder, consultant and holds privately held equity in Scorpion Therapeutics. R.M. is a scientific advisory board member and equity holder of Regenacy Pharmaceuticals. S.A.C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, Seer and PrognomIQ. The other authors declare no competing interests., (© 2025. The Author(s).)

Background: Although the relationship between cervical carotid tortuosity and cardiovascular risk in patients with Loeys-Dietz syndrome has been studied, it is unclear whether cervical carotid tortuosity influences the risk of neurovascular events., Methods: This is a single-institution retrospective cohort study. Cervical carotid tortuosity and morphology were assessed in patients with Loeys-Dietz syndrome who underwent baseline computed tomography/magnetic resonance imaging of the cervical and cerebral arteries from 2010 to 2022. The primary end point was a composite of adverse neurovascular events (multiple vessel cervical artery dissection, ischemic stroke, intracerebral hemorrhage, and any neurovascular intervention) at 5- and 10-year follow-ups. Independent risk factors were identified using univariate and multivariate logistic regression analyses. Single-variable predictors of 5- and 10-year outcomes were analyzed via receiver operating curve analyses. Cutoff values were determined per the Youden J index. Stratification analyses were performed for ages <60 and ≥60 years., Results: Of 105 eligible participants, 63 were included (mean age, 40±17 years; 52% female). During a mean follow-up of 8.7±4.1 years, 23 (37%) developed an adverse neurovascular event. Five-year follow-up was achieved in 86% and 10-year follow-up in 48%. Carotid total absolute curvature (TAC; P =0.008), coiling morphology ( P =0.012), and TGFBR1/2 genetic variant ( P =0.037) were independently associated with 5-year events. Stratification analyses revealed that the age group <60 years was more vulnerable to high TAC (unadjusted odds ratio, 7.2 [95% CI, 2.0-25.4]; P =0.002). Baseline TAC was the only independent predictor of adverse events at 5 years (area under the curve, 0.84; P <0.001) and 10 years (area under the curve, 0.75; P =0.007) in this age group. An optimal threshold for predicting neurovascular events was TAC ≥16.5. None were predictive in the age group ≥60 years., Conclusions: Cervical carotid tortuosity is associated with a long-term increased risk of neurovascular events in Loeys-Dietz syndrome. Angiographic findings of high-risk features such as increased TAC and coiling morphology may help to identify neurovascular vulnerability noninvasively at an early stage., Competing Interests: Dr Braverman serves on the Professional Advisory Board and Board of Directors for the Marfan Foundation. Dr Osbun provides consulting services for Medtronic, MicroVention, Penumbra, Stryker Corporation, and Terumo. The other authors report no conflicts.

Nodular gill disease (NGD) is a serious proliferative gill condition that affects farmed salmonids, particularly in Europe. While the cause of NGD remains unknown (and maybe multifactorial), various amoebae are often isolated from the gills of affected fish and can in some cases be seen associated with lesions by histopathology. The present study aimed to quantify the abundance of different amoeba species directly from the gills of rainbow trout affected by NGD and healthy controls. An 18S rRNA amplicon metagenomic approach was employed to profile the diversity and abundance of micro-eukaryotes (including amoebae) while suppressing the amplification of host DNA using a salmonid-specific C3 spacer blocking primer. The 18S rRNA metagenomics approach identified a diversity of micro-eukaryotes on the gills of rainbow trout, including the phylum's Amoebozoa, Diatomea, Platyhelminthes and Ciliophora. Rainbow trout clinically affected by NGD had a significantly higher abundance of a specific sequence (zOTU2) classified as Vannella sp. compared to healthy controls. A quantitative PCR assay was then developed and validated which accurately quantified the abundance of this Vannella sp. sequence from a NGD outbreak in a Swiss rainbow trout farm. Additional PCR and Sanger sequencing analysis of the zOTU2 sequence demonstrated that this sequence is most likely derived from Vannella mustalahtiana. Our study highlights the potential role of Vannella mustalahtiana in NGD in Switzerland and further describes a specific and validated diagnostic PCR assay for accurate detection of this Vannella species., (© 2024 The Author(s). Journal of Fish Diseases published by John Wiley & Sons Ltd.)

Objectives: To define the natural distensibility of the human ureter and evaluate the impact of other possibly favourable factors on ureteric distensibility., Patients and Methods: A total of 101 patients undergoing ureteroscopic stone removal or percutaneous nephrolithotomy underwent ureteric sizing using sequential passage of 37-cm urethral dilators in 2-F increments while attached to a unique force sensor. Insertion forces were limited to 6 N. After 6 N was attained, an appropriately sized ureteric access sheath was passed. At the conclusion of each procedure, Post-Ureteroscopic Lesion Scale score was determined., Results: Urethral dilators were passed in 61% of patients at ≤14 F; 39% of patients accepted urethral dilators of ≥16 F. The mean dilator size was 14 F. Multivariate logistic regression analysis revealed that preprocedural ureteric stenting and antibiotic use favoured passage of 16-F dilators (odds ratio [OR] 5.16, 95% confidence interval [CI] 1.70-15.62 [P = 0.004] and OR 5.15, 95% CI 1.743-15.243 [P = 0.003], respectively). Neither tamsulosin nor prior urinary tract infection had an impact on ureteric size (OR 0.765, 95% CI 0.281-2.084 [P = 0.601], OR 1.049, 95% CI 0.269-4.089 [P = 0.945], respectively)., Conclusion: Using continuous insertion force monitoring and a 6-N threshold, the majority of unstented adult human ureters within our patient population safely accommodated a 14-F dilator. Safe passage of a 16-F dilator at the 6-N threshold was more likely among patients with a preexisting indwelling ureteric stent or patients who were treated with antibiotics within a week of the procedure., (© 2024 BJU International.)

Acquired resistance to first-line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all-atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild-type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue-residue and residue-solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery., (© 2024 Wiley Periodicals LLC.)

Purpose: Deep convolutional neural networks (CNN) hold promise for assisting the interpretation of dopamine transporter (DAT)-SPECT. For improved communication of uncertainty to the user it is crucial to reliably discriminate certain from inconclusive cases that might be misclassified by strict application of a predefined decision threshold on the CNN output. This study tested two methods to incorporate existing label uncertainty during the training to improve the utility of the CNN sigmoid output for this task., Methods: Three datasets were used retrospectively: a "development" dataset (n = 1740) for CNN training, validation and testing, two independent out-of-distribution datasets (n = 640, 645) for testing only. In the development dataset, binary classification based on visual inspection was performed carefully by three well-trained readers. A ResNet-18 architecture was trained for binary classification of DAT-SPECT using either a randomly selected vote ("random vote training", RVT), the proportion of "reduced" votes ( "average vote training", AVT) or the majority vote (MVT) across the three readers as reference standard. Balanced accuracy was computed separately for "inconclusive" sigmoid outputs (within a predefined interval around the 0.5 decision threshold) and for "certain" (non-inconclusive) sigmoid outputs., Results: The proportion of "inconclusive" test cases that had to be accepted to achieve a given balanced accuracy in the "certain" test case was lower with RVT and AVT than with MVT in all datasets (e.g., 1.9% and 1.2% versus 2.8% for 98% balanced accuracy in "certain" test cases from the development dataset). In addition, RVT and AVT resulted in slightly higher balanced accuracy in all test cases independent of their certainty (97.3% and 97.5% versus 97.0% in the development dataset)., Conclusion: Making between-readers-discrepancy known to CNN during the training improves the utility of their sigmoid output to discriminate certain from inconclusive cases that might be misclassified by the CNN when the predefined decision threshold is strictly applied. This does not compromise on overall accuracy., Competing Interests: Declarations. Ethics approval and consent to participate: Waiver of informed consent for the retrospective analysis of the clinical samples (development dataset, MPH dataset) was obtained from the ethics review board of the general medical council of the state of Hamburg, Germany. All procedures performed in this study were in accordance with the ethical standards of the ethics review board of the general medical council of the state of Hamburg, Germany, and with the 1964 Helsinki declaration and its later amendments. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Purpose: This study examined the impact of venlafaxine and bupropion on the detection of nigrostriatal degeneration by dopamine transporter (DAT)-SPECT., Methods: 43 patients (70.7 ± 8.6y, 44% female) with [ 123 I]FP-CIT-SPECT under venlafaxine (n = 26, 37.5-225 mg/d), bupropion (n = 16, 150 or 300 mg/d) or both (n = 1) were included retrospectively. The striatal specific [ 123 I]FP-CIT binding ratio (SBR), its left-right asymmetry and the putamen-to-caudate ratio were transformed to z-scores and submitted to a cluster analysis for data-driven categorization., Results: Two clusters were identified. The first cluster (37% cases) showed a Parkinson's disease (PD)-like pattern: median striatal SBR/asymmetry/putamen-to-caudate z-score -4.5/4.9/-3.8. The second cluster (63%) showed symmetric reduction with normal intra-striatal gradient: median striatal SBR/asymmetry/putamen-to-caudate z-score -2.7/0.4/0.2. Patients with follow-up clinical reference diagnoses of neurodegenerative (n = 8) and non-neurodegenerative (n = 16) parkinsonism fell exclusively into the former or the latter cluster, respectively (p < 0.001)., Conclusion: Venlafaxine and bupropion cause uniform reduction of the striatal [ 123 I]FP-CIT SBR that can be distinguished from PD-like reductions., Competing Interests: Declarations. Ethics approval: Waiver of informed consent for the retrospective analysis of anonymized data was obtained from the ethics review board of the general medical council of the state of Hamburg, Germany. All procedures performed in this study were in accordance with the ethical standards of the ethics review board of the general medical council of the state of Hamburg, Germany, and with the 1964 Helsinki declaration and its later amendments. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Plecomacrolides, such as concanamycins and bafilomycins, are potent and specific inhibitors of vacuolar-type ATPase. Concanamycins are 18-membered macrolides with promising therapeutic potential against multiple diseases, including viral infection, osteoporosis, and cancer. Due to the complexity of their total synthesis, the production of concanamycins is only achieved through microbial fermentation. However, the low titers of concanamycin A and its analogs in the native producing strains are a significant bottleneck for scale-up, robust structure-activity relationship studies, and drug development. To address this challenge, we designed a library of engineered Streptomyces strains for the overproduction of concanamycin A-C by combining the overexpression of target regulatory genes with the optimization of fermentation media. Integration of two endogenous regulators from the concanamycin biosynthetic gene cluster (cms) and one heterologous regulatory gene from the bafilomycin biosynthetic gene cluster significantly increased production of concanamycin A and its less abundant analog concanamycin B in Streptomyces eitanensis. The highest titers reported to date were observed in the engineered S. eitanensis DHS10676, which produced over 900 mg/L of concanamycin A and 300 mg/L of concanamycin B. Heterologous overexpression of the identified target regulatory genes across a panel of Streptomyces spp. harboring a putative concanamycin biosynthetic gene cluster confirmed its identity, and significantly improved concanamycin A production in all tested strains. Strain engineering, optimization of fermentation, and extraction purification protocols enabled swift access to these structurally complex plecomacrolides for semi-synthetic medicinal chemistry-based approaches. Together, this work established a platform for robust overproduction of concanamycin analogs across species., Competing Interests: Declaration of competing interests The authors have no competing interests to declare., (Copyright © 2024 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

Unconventional spin-orbit torques arising from electric-field-generated spin currents in anisotropic materials have promising potential for spintronic applications, including for perpendicular magnetic switching in high-density memory applications. Here, all the independent elements of the spin torque conductivity tensor allowed by bulk crystal symmetries for the tetragonal conductor IrO 2 are determined via measurements of conventional (in-plane) anti-damping torques for IrO 2 thin films in the high-symmetry (001) and (100) orientations. It is then tested whether rotational transformations of this same tensor can predict both the conventional and unconventional anti-damping torques for IrO 2 thin films in the lower-symmetry (101), (110), and (111) orientations, finding good agreement. The results confirm that spin-orbit torques from all these orientations are consistent with the bulk symmetries of IrO 2 , and show how simple measurements of conventional torques from high-symmetry orientations of anisotropic thin films can provide an accurate prediction of the unconventional torques from lower-symmetry orientations., (© 2025 Wiley‐VCH GmbH.)

Associations between mental health, diet, and risk of Alzheimer's disease highlight the need to investigate whether dietary patterns moderate the relationship between symptoms of depression and anxiety, and neurodegeneration-related blood-based biomarkers. Cognitively unimpaired participants (n = 89) were included from the Australian Imaging, Biomarkers and Lifestyle study (mean age 75.37; 44 % male). Participants provided dietary, depressive and anxiety symptom data, and had measurement of blood-based biomarkers. Dietary pattern scores (Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension diet (DASH), and Western diet) were generated. Moderation and simple slope analyses were employed. In males with mean and below mean MeDi adherence, depressive symptoms were associated with higher neurofilament light (NfL) levels. In Apolipoprotein E ε4 non-carriers with lower than mean and mean MeDi adherence, depressive symptoms were associated with higher NfL and Aβ40 levels. No associations were observed between DASH and Western diets and neurodegeneration-related biomarkers. MeDi adherence is potentially a moderator of the relationship between depressive symptoms and neurodegeneration-related blood-based biomarkers, with sex- and genotype-specific approaches important to consider within this relationship., (Copyright © 2025. Published by Elsevier Inc.)

Pulmonary hypertension (PH) is a general term used to describe high blood pressure in the lungs from any cause. Pulmonary arterial hypertension (PAH) is a progressive, and fatal disease that causes the walls of the pulmonary arteries to tighten and stiffen. One of the major characteristics of PAH is the hyperproliferation and resistance to apoptosis of vascular cells, which trigger excessive pulmonary vascular remodeling and vasoconstriction. The death-associated protein DAP-kinase (DAPK) is a tumor suppressor and Ser/Thr protein kinase, which was previously shown to regulate the hypoxia inducible factor (HIF)-1α. Against this background, we now show that DAPK1 regulates human pulmonary arterial smooth muscle cell (hPASMC) proliferation and energy metabolism in a HIF-dependent manner. DAPK1 expression is downregulated in pulmonary vessels and PASMCs of human and experimental PH lungs. Reduced expression of DAPK1 in hypoxia and non-hypoxia PAH-PASMCs correlates with increased expression of HIF-1/2α. RNA interference-mediated depletion of DAPK1 leads to fundamental metabolic changes, including a significantly decreased rate of oxidative phosphorylation associated with enhanced expression of both HIF-1α and HIF-2α and glycolytic enzymes, as hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and an integrator between the glycolysis and citric acid cycle, pyruvate dehydrogenase kinase 1 (PDK1). DAPK1 ablation in healthy donor hPASMCs leads to an increase in proliferation, while its overexpression provides the opposite effects. Together our data indicate that DAPK1 serves as a new inhibitor of the pro-proliferative and glycolytic phenotype of PH in PASMCs acting via HIF-signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Its angular representation on the retina does not solely determine the perceived size of an object. Instead, contextual information is interpreted. We investigated the levels of processing at which this interpretation occurs. Combining three experimental paradigms, we explored whether masked and more implicitly coded objects are already size-rescaled. We induced object size rescaling using a modified variant of the Ebbinghaus illusion. In this variant, six dots altered the size of a central stimulus and served as inducers generating Object-Substitution Masking (OSM). Participants reported the average size of multiple circles using the size-averaging paradigm, allowing us to test the contribution of masked and non-masked central target circles. Our Ebbinghaus illusion variant altered perceived stimulus size and showed robust masking via OSM. Furthermore, size-averaging was sensitive enough to detect perceived size changes in the magnitude of the ones induced by the Ebbinghaus illusion. Finally, combining all three paradigms, we observed that masked and non-masked stimuli contributed to size averaging in a size-rescaled manner. In a control experiment testing the general effects of Ebbinghaus inducers, we observed a contrast-like effect on size averaging. Large inducers decreased the perceived average size, while small inducers increased it. In summary, our experiments indicate that context integration, induced by the Ebbinghaus illusion, alters size representations at an early stage. These modified size representations are independent of whether a target is recognisable. Moreover, perceived average size appears to be coded relative to surrounding perceptual groups., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: There is a need for a noninvasive, affordable, sensitive, and specific biomarker to diagnose early acute rejection, to negate the need for frequent biopsies. Dd-cfDNA is a powerful adjunct yet there is limited data on the ethnic differences in its values. There is anecdotal evidence that dd-cfDNA values at rejection may be higher in Black as compared to non-Black recipients. This study aims to add to this literature while defining such variability and comparing it to previously validated cutoffs for dd-cfDNA of 0.5% or 1%., Design: This was a single-center retrospective observational study of patients who underwent graft biopsies with a preceding, paired, dd-cfDNA value. Recipients were separated into White, Black, and Hispanic racial and ethnic groups, and dd-cfDNA values at rejection versus nonrejection were compared., Results: With 0.5% and 1% cutoffs, false negative rates for rejection were 13% and 22%, respectively. The false positive rate was 38.4%. 12.2% of Black recipients, 11.8% of Hispanic recipients, and 44% of White recipients had rejection with a negative AlloSure ® . Values >0.5% corresponded to histologic rejection in 61.5% of Black, 66.7% of White, and 56.3% of Hispanic recipients. Antibody-mediated rejection occurred in 65.5% of rejection cases in Black recipients, while exhibiting the lowest rate of T-cell-mediated rejection. Dd-cfDNA values gave an accurate diagnosis of rejection in 52.8% of recipients with AMR versus 19.3% in TCMR., Conclusion: This study demonstrated that dd-cfDNA was applicable to Black recipients with a robust ability to detect antibody-mediated rejection, as compared to White and Hispanic recipients., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr Olaitan previously received honoraria for presentations and advisory board activities and study grants from CareDx.

Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for preclinical trials. Comprehensive data on this tumour type are scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma (OMM) to determine whether the common canine disease could inform the rare human equivalent. Using a human and canine primary OMM cohort of treatment-naive archival tissue, alongside clinicopathological data, we obtained transcriptomic, immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species and linked our findings to immunohistochemical, microbiome, and clinical data. Human and dog OMM stratified into two distinctive transcriptional groups, which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4-high and MET-high and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools that distinguish between transcriptomic subgroups. We found that OMM had conserved transcriptomic subtypes and biological similarity between human and canine OMM, with significant implications for patient classification, treatment, and clinical trial design. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Purpose To develop a practical, easily implementable risk stratification model based on preoperative contrast-enhanced CT (CECT) nodal features to predict the probability of pathologic extranodal extension (pENE) in patients with oropharyngeal squamous cell carcinoma (OPSCC). Materials and Methods Preoperative CECT studies in consecutive patients with OPSCC who underwent surgical resection between October 2012 and October 2020 were examined by four neuroradiologists, blinded to the pathologic outcome, for imaging features of pENE. The pathology report was queried for the presence of pENE. Decision tree analysis with cost-complexity pruning was performed to identify a clinically pragmatic model to predict pENE. Results A total of 162 patients (median age, 60 years [IQR, 54-67 years]; 134 male, 28 female) with 208 dissected heminecks were included. The primary OPSCC site for most patients was tonsil (67%, 109 of 162) or base of tongue (31%, 50 of 162). Most patients had early-stage disease (American Joint Committee on Cancer Staging Manual eighth edition category T0-T2, 93% [151 of 162]; N0-N1, 90% [145 of 162]). Pathologically confirmed pENE was reported in 28% (45 of 162) of patients. CECT features that were significantly associated with pENE on univariable analysis included size, necrosis, spiculation, perinodal stranding, and infiltration of adjacent structures. Decision tree analysis identified a predictive model including spiculation or irregular margins, matted nodes, and infiltration of adjacent structures. The model had a sensitivity of 41% (19 of 46) and specificity of 96% (157 of 162) for predicting pENE. Conclusion The developed model for predicting pENE using preoperative CECT features is practical and had high specificity in patients with OPSCC. Further prospective study is warranted to determine impact on clinical management and outcomes. Keywords: Head/Neck, CT, Radiation Therapy/Oncology, Neoplasms-Primary, Oncology, Decision Analysis, Observer Performance Supplemental material is available for this article. © RSNA, 2025.

Cellular and gene therapy (CGT) products have emerged as a popular approach in regenerative medicine, showing promise in treating various pancreatic and liver diseases in numerous clinical trials. Before these therapies can be tested in human clinical trials, it is essential to evaluate their safety and efficacy in relevant animal models. Such preclinical testing is often required to obtain regulatory approval for investigational new drugs. However, there is a lack of detailed guidance on selecting appropriate animal models for CGT therapies targeting specific pancreatic and liver conditions, such as pancreatitis and chronic liver diseases. In this review, the gastrointestinal committee for the International Society for Cell and Gene Therapy provides a summary of current recommendations for animal species and disease model selection, as outlined by the US Food and Drug Administration, with references to EU EMA and Japan PMDA. We discuss a range of small and large animal models, as well as humanized models, that are suitable for preclinical testing of CGT products aimed at treating pancreatic and liver diseases. For each model, we cover the associated pathophysiology, commonly used metrics for assessing disease status, the pros and limitations of the models, and the relevance of these models to human conditions. We also summarize the use and application of humanized mouse and other animal models in evaluating the safety and efficacy of CGT products. This review aims to provide comprehensive guidance for selecting appropriate animal species and models to help bridge the gap between the preclinical research and clinical trials using CGT therapies for specific pancreatic and liver diseases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2025. Published by Elsevier Inc.)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. A critical aspect of AD pathology is represented by oxidative stress, which significantly contributes to neuronal damage and death. Microglia and astrocytes, the primary glial cells in the brain, are crucial for managing oxidative stress and supporting neuronal function. Carnosine is an endogenous dipeptide possessing a multimodal mechanism of action that includes antioxidant, anti-inflammatory, and anti-aggregant activities. The present study investigated the effects of Aβ1-42 oligomers (oAβ), small aggregates associated with the neurodegeneration observed in AD, on primary rat mixed glia cultures composed of both microglia and astrocytes, focusing on the ability of these detrimental species to induce oxidative stress. We assessed intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels as markers of oxidative stress. Exposure to oAβ significantly elevated both ROS and NO intracellular levels compared to control cells. However, this effect was completely inhibited by the pre-treatment of mixed cultures with carnosine, resulting in ROS and NO levels similar to those observed in untreated (control) cells. Single-cell analysis of cellular responses to oAβ revealed heterogeneous ROS production, resulting in two distinct clusters of cells, one of which was very responsive to the treatment. The presence of carnosine counteracted the overproduction of ROS, also leading to a single, homogeneous cluster, similar to that observed in the case of control cells. Interestingly, unlike ROS response, single-cell analysis of NO production did not show any distinct clusters. Overall, our findings demonstrated the ability of carnosine to mitigate Aβ-induced oxidative stress in mixed glia cells, by rescuing ROS and NO intracellular levels, as well as to normalize the heterogeneous response to the treatment measured in terms of clusters' formation. The present study suggests a therapeutic potential of carnosine in pathologies characterized by oxidative stress including AD., Competing Interests: Declaration of 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., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: In patients with spontaneous intracranial hypotension (SIH), microsurgical repair is recommended in Type 1 (ventral) dural leaks, when conservative measures fail. However, there is lacking consensus on the optimal surgical technique for permanent and safe closure of ventral leaks., Methods: We performed a retrospective analysis of surgically treated SIH patients with Type 1 leaks at our institution between 2013 and 2023. Patients were analyzed according to the type of surgical technique: (1) Microsurgical suture vs (2) extradural and intradural patching (sealing technique). End points were resolution of spinal longitudinal epidural cerebrospinal fluid collection (SLEC), change in brain SIH-Score (Bern-Score), headache resolution after 3 months, surgery time, complications, and reoperation rates., Results: In total, 85 (66% women) patients with consecutive SIH (mean age 47 ± 11 years) underwent transdural microsurgical repair. The leak was sutured in 53 (62%) patients (suture group) and patch-sealed in 32 (38%) patients (sealing group). We found no significant difference in the rates of residual SLEC and resolution of headache between suture and sealing groups (13% vs 22%, P = .238 and 89% vs 94%, P = .508). No changes were found in the postoperative Bern-Score between suture and sealing groups (1.4 [±1.6] vs 1.7 [±2.1] P = 1). Mean surgery time was significantly shorter in the sealing group than in the suture group (139 ± 48 vs 169 ± 51 minutes; P = .007). Ten patients of the suture and 3 of the sealing group had a complication (23% vs 9%, P = .212), whereas 6 patients of the suture and 2 patients of the sealing group required reoperation (11% vs 6%, P = .438)., Conclusion: Microsurgical suturing and patch-sealing of ventral dural leaks in patients with SIH are equally effective. Sealing alone is a significantly faster technique, requiring less spinal cord manipulation and may therefore minimize the risk of surgical complications., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Congress of Neurological Surgeons.)

Introduction: We performed a retrospective analysis of patients with multiple myeloma (MM) receiving palliative radiotherapy (RT) and assessed factors associated with local control, with a focus on dose/fractionation and cytogenetics., Materials and Methods: We included patients who received palliative RT for MM at our institution. Cytogenetics were collected via fluorescence in situ hybridization. Follow-up imaging was used to assess local control., Results: A total of 239 patients with 362 treated lesions were included. Eighty-six (36.0%) patients had high-risk cytogenetics. Most lesions received 20 Gray (Gy) in 5 fractions (131, 36.2%), 8 Gy in 1 fraction (93, 25.7%), or 30 Gy in 10 fractions (48, 13.3%). At a median follow-up of 4.3 years, 4-year local progression was 13.4% (95% confidence interval [CI]: 10.3-17.5). No cytogenetic abnormalities were correlated with local progression, nor were double- and triple-hit status. There was a nonsignificant trend toward association between number of treated lesions and local progression (HR for >3 vs. 1: 2.43 [95% CI: 0.88-6.74], P = .059). Among patients with >3 treated lesions, equivalent dose in 2 Gy fractions ≥20 Gy reduced progression (HR: 0.05 [95% CI: 0.01-0.23], P = .0001)., Conclusion: In this large study of patients with MM, modern palliative RT achieved excellent rates of long-term local control. Although there was no dose-response observed in the overall cohort, patients with high volume symptomatic disease may benefit from EQD2 ≥20 Gy. High-risk cytogenetics did not appear to influence radioresponsiveness, and standard radiation doses appear to be effective for all MM patients regardless of cytogenetics., Competing Interests: Disclosure 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 article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide. Locoregional nodal involvement by OSCC is commonly encountered. Current conventional and functional imaging modalities have limited diagnostic accuracy in nodal assessment, particularly in head and neck cancer. Thus, definitive management of head and neck malignancies customarily addresses the locoregional nodes along with the primary malignancy. However, OSCC, particularly tongue cancer, shows erratic lymphatic drainage and thus commonly requires extensive bilateral neck dissection, leading to significant morbidity. Cancer integrin imaging with 68 Ga-trivehexin PET-CT can offer highly specific result and thus has the potential for effective tailored management., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Nowadays, consent to use donor bodies for medical education and research is obtained from the body donors and their families before the donation. Recently, the International Federation of Associations of Anatomists (IFAA) published guidelines that could restrict the appearance of cadaveric images in commercial anatomical resources such as textbooks and other educational products. These guidelines state that the donor must expressly consent to using such images for this purpose. Cadaveric photos and drawings made from dissections of cadavers have been used in anatomy textbooks and atlases for hundreds of years. They are invaluable for anatomy students and clinical/surgical practitioners. The IFAA guidelines should not restrict the use of those older books; to do so would infringe the rights of those seeking knowledge from these resources. As the images in such textbooks and atlases are anonymized and are used for teaching and research, and the donors and their families are informed about this before the donation, we believe no additional consent is needed. It is impossible to separate educational from "commercial" usage entirely in any situation, e.g., publications from publishers and the use of cadavers in medical schools. Therefore, our best efforts to avoid unethical use of cadaveric images by following traditional consent processes are still needed so that more people will reap the benefits from them. As senior textbook/atlas authors/editors from over 10 countries, we believe that using cadaveric images in anatomy textbooks is appropriate, and no additional consent should be necessary. Such usage falls within the good faith of professionals using these invaluable gifts., (© 2025 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)