Semaglutide is recognised for its superior effects on glycaemic control and weight management. However, the clinical outcomes following semaglutide discontinuation are not well established. This study aimed to evaluate the clinical and metabolic consequences of such switch. This was a retrospective cohort study utilising a non-interventional, single-arm, before-and-after design. This study included 120 patients with type 2 diabetes who discontinued semaglutide and transitioned to alternative regimens. Key metabolic parameters, such as body weight, glycated haemoglobin, fasting and postprandial glucose and lipid profiles, were extracted from medical records at baseline and at 6 months post-switch. Across the entire cohort, no significant changes were observed in any metabolic parameter between baseline and the follow-up, suggesting short-term metabolic stability. However, subgroup analyses revealed notable trends: patients switched to dulaglutide and liraglutide tended to exhibit deteriorating glycaemic control and body weight gain. In contrast, the basal insulin group showed relatively stable body weight. The trends of weight regain and worsening glycaemic control following transition to less potent glucagon-like peptide-1 receptor agonists are consistent with semaglutide’s superior metabolic efficacy. Nonetheless, the study’s limited statistical power and short duration may obscure subtle but clinically meaningful changes. These findings suggest that long-term alternative regimens may not fully sustain the metabolic benefits achieved with semaglutide.

Let $(X,\chi,k)$ be a triple consisting of a smooth, compact hyperbolic Riemann surface $X$ of genus $g$, and an $m$ dimensional unitary multiplier system $\chi$ of admissible weight $k$. Our first result establishes an analogue of the prime geodesic theorem for the weighted prime geodesic counting function associated to $(X,\chi,k)$. The error term we obtain is explicit with effectively computable constants which depend solely on the genus of $X$, the dimension of $\chi$, the length of shortest geodesic on $X$ and the smallest non-zero eigenvalues of the weighted Laplacian $\Delta_{2k}$ as well that of the scalar Laplacian $\Delta_{0}$. Our second result studies the asymptotic behavior of the spectral determinant $\det\Delta_{2k_n}$ for a sequence $(X_{n}, \chi_{n}, k_{n})$ for which the genus of $X_n$ tends to infinity. Under reasonably general circumstances, namely the existence of a weak spectral gap, a uniform discreteness of the underlying Fuchsian group, and a type of non-accumulation of bounded geodesics, we prove that $\log\det\Delta_{2k_n}/\mathrm{vol}(X_{n})$ converges to a constant $C_{\alpha}$ which depends only on $\alpha=\lim_{n\to\infty} k_n$. Our result is deterministic and is compatible with the three well-studied probabilistic models, namely Weil-Petersson, Brooks-Makover, and random covers model.

Multimodal large language models (MLLMs) increasingly support high-stakes decision making by combining complementary information from images and text. While existing explainability methods identify influential image regions or text tokens, they cannot answer a fundamental question: which modality drives a prediction? Consequently, a model may produce the correct output while relying on the wrong source of evidence, masking shortcut learning and unsafe reasoning. We formulate modality attribution as a complementary explainability objective for multimodal foundation models and propose Counterfactual Modality Attribution (CMA), the first framework for quantifying modality-level contributions in MLLMs. CMA generates image-only, text-only, and joint multimodal counterfactuals using coupled diffusion priors and converts them into principled modality attribution scores through a cooperative game-theoretic formulation based on Shapley values. We evaluate CMA on controlled synthetic benchmarks with known ground-truth modality reliance and on a real-world multimodal clinical dataset. CMA correctly identifies the decision-driving modality in 98% of controlled cases and consistently outperforms baselines, revealing failures of cross-modal reasoning that remain invisible to predictive accuracy alone. Our results establish modality attribution as a complementary dimension of explainability beyond feature attribution, providing a principled framework for auditing multimodal foundation models in safety-critical applications.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C-related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C-attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C-attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

We present SPECTRE, a new equilibrium code based on the Multi-Region relaxed MHD model for robustly calculating 3D equilibria with general magnetic topology, allowing for flux surfaces, magnetic islands, and chaos. The code builds on a previous MRxMHD solver, SPEC, but performs significantly better thanks to a new formulation of force, the use of a stable trust-region-based least squares minimization scheme, as well as several additional features. SPECTRE is verified through application to configurations with known equilibrium solutions, in vacuum and with finite beta, both in the fixed boundary and the free boundary mode. Notably, these include vacuum equilibria of a quasi-axisymmetric (QA) device in fixed-boundary mode, and of W7-X in the free-boundary mode, along with a classical stellarator finite-beta free-boundary case. Finally, the solver is applied to a modern optimized finite-beta quasi-isodynamic (QI) configuration, where we demonstrate calculation of a strongly-shaped equilibrium with a core island which is in agreement with a HINT calculation.

Immunohistochemistry (IHC) is central to precision oncology in advanced non-small cell lung cancer (NSCLC), although its predictive value and the need for molecular confirmation differ across biomarkers. This narrative review aimed to summarize the clinical utility, validated assays, scoring systems, diagnostic performance, and testing algorithms for predictive IHC biomarkers in NSCLC. Recent guidelines, regulatory documents, and selected analytical and clinical studies were reviewed for programmed death-ligand 1 (PD-L1), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), mesenchymal-epithelial transition factor receptor (c-Met), B-Raf proto-oncogene serine/threonine kinase V600E (BRAF V600E), pan-tropomyosin receptor kinase (pan-TRK), human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor (EGFR). PD-L1 and ALK are established IHC-based predictive assays, although PD-L1 interpretation remains assay-, platform-, and cutoff-specific. VENTANA ALK D5F3 and VENTANA MET SP44 RxDx are clinically validated companion diagnostics, whereas HER2 IHC score 3+ may support eligibility for trastuzumab deruxtecan in the tumor-agnostic setting. ROS1, BRAF V600E, pan-TRK, and non-companion-diagnostic c-Met or HER2 assays are best used for screening or triage and generally require molecular confirmation. EGFR mutation-specific IHC is not recommended because of insufficient diagnostic performance. Overall, IHC enables rapid, tissue-sparing biomarker assessment but should be integrated with broad genomic and transcriptomic next-generation sequencing (NGS), particularly when alteration-specific findings are negative, equivocal, or discordant.

AIM To determine the frequency of congenital muscular torticollis (CMT), identify associated risk factors and assess common associated neonatal conditions. METHODS This retrospective study reviewed medical records of newborns diagnosed with CMT at the Clinic for Gynaecology and Obstetrics, University Clinical Centre Tuzla, from 1 January 2019 to 31 December 2023. Data on maternal, pregnancy, delivery, neonatal and physiotherapy-related variables were analysed. RESULTS During the five-year period, 16,899 newborns were delivered, of whom 141 (0.83%) were diagnosed with CMT. CMT was most frequent among newborns of primiparous mothers (94; 66.7%) and after vaginal delivery (78; 55.3%). Most newborns had an Apgar score ≥8 (108; 76.6%) and were born at ≥37 weeks of gestation (130; 92.2%). CMT was slightly more common in female newborns (73; 51.8%) and was more often right-sided (88; 62.4%). Complete recovery was reported among all newborns with available physiotherapy follow-up data. CONCLUSION The frequency of CMT over the five-year period was 0.83%. Early diagnosis and timely initiation of physical therapy were associated with complete recovery among newborns with available follow-up data.

Public-sector sustainability and climate reporting increasingly address environmental exposure, governance, and financial effects, yet existing frameworks do not adequately disclose preparedness for low-probability, high-impact systemic risks whose probabilities, timing, thresholds, and transmission channels remain deeply uncertain. This article develops a Public-Sector Resilience Reporting Standard (PSRRS) as a pre-standard architecture for government preparedness disclosure. The design has three bounded objectives: diagnose cross-framework disclosure gaps, translate these gaps into a theoretically grounded capability-to-disclosure architecture, and demonstrate its analytical use through an illustrative Florida application and two hazard-neutral stress tests. The documentary corpus includes international sustainability and public-sector reporting standards, ISO and UNDRR resilience and continuity instruments, three Florida resilience documents, and peer-reviewed literature on resilience governance, decision-making under deep uncertainty, critical infrastructure interdependency, catastrophic uncertainty, climate-risk disclosure, public finance, climate-risk pricing, local-government credit risk, investor attention, and ransomware service disruption. A structured interpretive coding protocol classifies each framework as explicit, partial, or not explicit across nine disclosure dimensions; a codebook appendix identifies the assessment criteria, the a priori and inductively refined dimensions, and the validation boundaries. Florida is not treated as a basis for statistical or jurisdictional generalization. Instead, it illustrates how a comparatively developed resilience architecture may disclose statutory continuity, critical-asset data, project ranking, and output metrics while leaving systemic dependencies, adaptive triggers, long-horizon fiscal exposure, residual service risk, distributional effects, and assurance mechanisms insufficiently visible in the reviewed reporting corpus. AMOC and case-grounded cyber-fiscal stress tests show how the PSRRS shifts reporting from hazard inventories and funded projects toward auditable evidence of institutional capacity, adaptive readiness, and public-value protection. The article specifies mandatory, recommended, and optional clauses, evidence requirements, indicator examples, a disclosure index, a sample report structure, and a three-tier pilot conformity model. The contribution is conceptual and operational, but not yet a validated formal standard; cross-jurisdictional piloting, inter-rater coding, cost testing, assurance testing, and stakeholder consultation are identified as the next stage of standardization.

We present the design, construction, and first plasma experiments of Polaris, a new small-scale stellarator experiment (major radius R ~ 0.4 m) located at the Swiss Plasma Center. Polaris consists of a relatively large vacuum vessel (~0.5 m^3) predominantly made of glass windows and inside which different sets of magnetic coils can be installed. A first modular coil configuration has been designed with six identical, circular, water-cooled copper coils toroidally arranged in an optimal way so that they generate a large volume of magnetic surfaces and rotational transform in vacuum (iota ~ 0.3). The total current in each coil goes up to ~ 5 kA, producing a magnetic field on-axis of B ~ 0.03 T. An RF antenna specifically designed to operate in vacuum delivers up to 2.5 kW of power to produce plasma via inductive coupling and electron-impact ionization. We present the engineering solutions adopted for the design of Polaris and illustrate the great experimental flexibility it enables. Time-averaged values and fluctuations of plasma density, electron temperature, and floating potential are measured at various toroidal locations, providing insights into the plasma equilibrium, electrostatic turbulence, and associated transport. The glass vacuum chamber of Polaris additionally provides unprecedented optical access to the entire plasma volume. With its original, flexible design, Polaris is a'stellarator fish-tank', allowing interchangeable coil sets and exploration of various magnetic configurations. Furthermore, its low-temperature, low-density, high-neutral-pressure plasmas are relevant to stellarator edge physics, making Polaris a first-of-kind testbed for the fundamental investigation of stellarator edge-relevant physics.

Background Abdominal obesity in young adults may reflect a biologically active metabolic phenotype, even before full metabolic syndrome develops. However, how endocrine, adipokine, insulin-resistance, and fibrinolysis-related biomarkers vary across early metabolic phenotypes remains incompletely understood. This study examined whether selected circulating biomarkers differ among normal-weight controls, young adults with abdominal obesity, and those with metabolic syndrome. Methods This cross-sectional secondary biomarker analysis included 175 young adults aged 19–21 years who were classified according to International Diabetes Federation criteria as controls (n = 106), abdominal obesity (n = 37), or metabolic syndrome (n = 32). Fasting insulin, HOMA-IR, cortisol, 25-hydroxyvitamin D, leptin, adiponectin, the adiponectin/leptin ratio (A/L ratio), ghrelin, and plasminogen activator inhibitor-1 (PAI-1) were analyzed. Between-group differences were assessed using nonparametric tests, ordered trends were evaluated across the phenotype gradient, sensitivity analyses were adjusted for sex, smoking status, and physical activity, and penalized logistic regression was used to explore biomarker associations with abdominal obesity and metabolic syndrome. Results Insulin, HOMA-IR, cortisol, leptin, and PAI-1 showed positive ordered phenotype-related patterns, whereas ghrelin, adiponectin, and the A/L ratio showed negative ordered patterns. Vitamin D concentrations were lower in the abdominal obesity and metabolic syndrome groups than in controls. The strongest between-group effects were observed for PAI-1, cortisol, ghrelin, adiponectin, and the A/L ratio. Overall group effects remained significant after adjustment and false discovery rate correction. In mutually adjusted penalized models, the A/L ratio remained associated with abdominal obesity, whereas PAI-1 remained associated with metabolic syndrome. Conclusion Young adults with abdominal obesity showed measurable endocrine, adipokine, insulin-resistance, and fibrinolysis-related alterations, including those who did not meet criteria for metabolic syndrome. The A/L ratio and PAI-1 may provide complementary information, with the A/L ratio more closely associated with abdominal obesity and PAI-1 more closely associated with metabolic syndrome in exploratory models. These findings support further evaluation of phenotype-based biomarker profiling for characterizing early cardiometabolic dysregulation in young adults and should be confirmed in larger, sex-balanced cohorts.

Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women, whereas heart failure with reduced ejection fraction (HFrEF) predominates in men. Despite these well-established epidemiological differences, sex-specific alterations in vascular function in heart failure (HF) remain poorly characterised. This systematic review, using a narrative synthesis approach, evaluated sex-related differences in vascular function in individuals with HF. The review was prospectively registered with PROSPERO (CRD42024617745). MEDLINE and CINAHL were searched from inception to 26th November 2024 for studies reporting sex-stratified measures of arterial stiffness among individuals with HF. Nine studies met the eligibility criteria for inclusion (n = 2820; men: n = 1390, women: n = 1430). Of the included studies, 78% were characterised as HFpEF. Compared with men, women exhibited a higher pulsatile arterial load and lower arterial compliance. Representative findings from individual studies showed that women exhibited a higher augmentation index (28.9 ± 13.7% vs 21.7 ± 11.9%, p < 0.001) and augmentation pressure (19.1 ± 12.4 vs 13.7 ± 10.1 mmHg, p = 0.003). Body mass index (BMI) showed variable relationships with arterial stiffness indices, including positive associations with pulse wave velocity (r = 0.24, p < 0.01), central pulse pressure (r = 0.33, p < 0.001), and augmentation index (r = 0.23, p = 0.01), but an inverse relationship was found with cardio-ankle vascular index (r = −0.204, p < 0.001). Importantly, sex differences in HFpEF remained significant after adjustment for BMI. Women with HF exhibit higher pulsatile arterial load and reduced arterial compliance compared with men, which remain after adjustment for BMI. Sex-specific vascular dysfunction contributes to HF pathophysiology and supports the need for sex-informed assessment.

Background/Objectives: DNA-based identification of degraded human remains represents a major challenge in forensic science, particularly in cases involving burned, fragmented, or commingled bodies. Advances in forensic genetics have expanded the analytical capabilities for such samples; however, the effectiveness of different approaches and their integration within Disaster Victim Identification (DVI) workflows remain heterogeneous. This systematic review aims to critically evaluate current evidence on DNA-based identification of degraded remains, focusing on methodological strategies, emerging genomic technologies, and DVI applications, while integrating laboratory evidence and operational forensic practice into a structured analytical framework. Methods: A systematic literature search was conducted in Scopus and Web of Science from database inception to 5 June 2026, following PRISMA 2020 guidelines. Eligible studies included original research addressing DNA analysis of degraded, thermally altered, or highly compromised human remains in forensic or DVI contexts. After a multistep screening process involving title/abstract and full-text evaluation, 37 studies were included. Data were extracted and organized into three thematic categories: (i) core DNA analysis, (ii) advanced molecular technologies, and (iii) DVI case applications. Results: The findings demonstrate that DNA recovery from degraded remains is influenced by thermal exposure, tissue type, and sampling strategy. Teeth and dense cortical bone consistently provide higher DNA yield. While autosomal STR profiling remains the primary analytical approach, its limitations in highly degraded samples are mitigated through the complementary use of mitochondrial DNA (mtDNA), Y-chromosome STRs (Y-STRs), and SNP markers, together with advanced sequencing technologies such as massively parallel sequencing (MPS). Emerging technologies, including rapid DNA systems and predictive models based on macroscopic indicators, significantly enhance efficiency and success rates. DVI studies report identification rates exceeding 90–95% when multidisciplinary and structured workflows are applied. The evidence further supports a flexible triage-based analytical strategy, in which marker selection is guided by tissue preservation and degradation level. Conclusions: DNA-based identification of degraded human remains has evolved into an adaptive, multi-level forensic process. Successful outcomes rely on the integration of optimized sampling, hierarchical genetic analysis, and coordinated DVI strategies. The findings support a triage-based framework that links tissue selection, degradation assessment, and analytical methodology to maximize identification success. Future developments should focus on predictive models, advanced genomic tools, and standardized workflows to further improve identification in challenging forensic scenarios.

Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (AlloHCT). Conditioning with chemotherapy and radiation enables donor engraftment but causes tissue injury that upregulates the alarmin interleukin-33 (IL-33) in fibroblastic reticular cells (FRCs) in secondary lymphoid organs (SLO) and tissue stromal cells. While mechanisms releasing IL-33 from nuclear sequestration remain elusive, free IL-33 directly activates donor CD4+ T cells to promote Th1 differentiation and expansion. Early IL-33 blockade limits GVHD initiation, yet the role of local IL-33 in sustaining alloimmunity remains unclear. We used preclinical models to define how IL-33 signaling to donor T cells within SLO versus the gastrointestinal tract (GIT) stroma controls active GVHD and graft-versus-lymphoma (GVL) responses. BALB/c recipients received B6 T cell—depleted bone marrow, A20 lymphomas, and T cells from donors with inducible ST2 (IL-33R) deletion to control IL-33 signaling during GVHD and GVL. To identify stromal functions, B6 recipients lacking IL-33 in FRCs (CCL19-Cre×Il33fl/fl) or gut epithelium (Vil-Cre×Il33fl/fl) were transplanted with BALB/c T cells and bone marrow. T cell—dependent IL-33 release was tested using GzmB⁻/⁻, St2+/+, and St2⁻/⁻ T cells. Late ST2 deletion resolved GVHD without compromising GVL. IL-33 signaling increased Foxp3 levels and reduced T-bet expression in donor CD4+ T cells, while sustaining TCF-1. Unexpectedly, loss of FRC-derived IL-33 exacerbated GVHD, whereas gut epithelial IL-33 deletion was protective. IL-33 induced GzmB, and GzmB⁻/⁻ T cells displayed impaired activation and expansion. Early SLO-derived IL-33 establishes effector programming that influences later tissue responses. IL-33+ stroma—T-cell crosstalk programs donor CD4+ T-cell fate and shapes local alloimmunity during GVHD. IL-33—stroma feedback is a key signal to alloreactive T cells during GVHD. NIH/NIAID F30AI147437, NIH T32 CA082084, NIH/NHLBI R01HL122489, NIH/NIAID R21AI121981, NIH/NIAID R56AI13927 Transplantation Immunology (TRAN)