Search Results (2,477)

Purpose: Obesity, characterized by abnormal fat accumulation with comorbidities, continues to increase dramatically, particularly in the pediatric population. Identifying the environmental and genetic causes underlying the development of obesity during early childhood is crucial for establishing preventive and protective treatments for this complex disease. We aimed to investigate genetic variants related to non-syndromic early-onset childhood obesity. Methods: Whole-exome sequencing was performed in three independent consanguineous families with obesity, including three index cases and two additional affected siblings. Non-synonymous variants with minor allele frequency < 0.01 in all normal populations were filtered using the Genomize-SEQ Platform. Variant confirmations and familial segregations were analyzed by Sanger sequencing. Results: WES revealed a shared ATXN3 gene variant and two known variants of the SH2B1 and ADIPOQ genes, which were reported to be associated with obesity. Additionally, five heterozygous novel gene variants of the ANKK1, NEGR1, OGDH, ABCB1, and GSK3B genes were identified, which are predicted to cause excessive fat accumulation and disruption of energy balance in individuals. Conclusions: We suggest that the cumulative effects of all obesity-associated detected variants lead to the early-onset obesity phenotype observed in individuals. Hence, periodic follow-up and treatment opportunities are recommended for index cases, alongside the adoption of a more active lifestyle and healthy nutrition practices. Full article

This paper examines whether a residual structural state extracted from cross-asset downside-risk dependence contains incremental information for forecasting next-day market downside risk beyond a strong heterogeneous autoregressive (HAR) benchmark. The empirical analysis uses Binance intraday data from September 2019 to December 2025 and a fixed sample of 24 liquid cryptocurrencies obtained through explicit data-quality screening and sample diagnostics. The forecasting target is the log of an equal-weight cross-sectional downside-risk index constructed from strictly valid asset-level realized downside semivariance measures. The empirical design is deliberately conservative: the market sample is fixed ex ante, the target is evaluated against Bitcoin (BTC) and Ethereum (ETH) dominance diagnostics, and asset-level HAR-type models are estimated recursively to generate ex-ante one-step-ahead residuals, from which rolling residual-dependence matrices and structural signatures are constructed. The selected residual state contains four components: average residual correlation, Frobenius-type deformation, influence concentration, and influential-set turnover. The evidence supports three qualified conclusions. First, the full residual state attains the lowest average QLIKE loss relative to the HAR benchmark, although the corresponding Diebold–Mariano test under the primary QLIKE loss does not reject equal predictive accuracy at conventional levels. Complementary Clark–West evidence on the nested log-scale comparison supports incremental predictive content for the level-state and full-state augmentations. Second, the strongest forecasting evidence comes from the full state rather than from deformation-only specifications. Third, event-window diagnostics show that structural reorganization is most pronounced around stress-entry and extreme-risk episodes, supporting an onset-sensitive rather than a long-lead early-warning interpretation. Overall, the evidence supports a cautious and statistically qualified predictive conclusion: residual market structure may contain incremental information for short-horizon downside-risk forecasting in cryptocurrency markets, especially around stress onset, but the result should not be interpreted as a decisive primary-loss improvement or as evidence that deformation alone dominates a strong benchmark. Full article

Systemic lupus erythematosus (SLE) is a polygenic autoimmune disorder where genetic diversity drives significant clinical heterogeneity. This review summarizes the current understanding of the roles of genetic polymorphisms in immunological dysregulation, organ-specific manifestations and therapeutic response heterogeneity in individuals with SLE. The literature was obtained from PubMed, EBSCOhost, Web of Science and Scopus. The narrative review comprised 60 publications published within the last 12 years. The research consistently identifies the major histocompatibility complex (MHC) region as the most significant genetic risk factor for the onset of autoimmunity. Genetic variants in STAT4 and IRF5 exacerbate disease progression by facilitating chronic inflammation. These genetic factors are associated with various clinical outcomes, including renal and neuropsychiatric symptoms. Polymorphisms in HLA class II, TLR7 and FBN2 are notably linked to serious consequences, including lupus nephritis (LN). Progress in targeted therapy signifies a transition to personalized medicine with medications such as anifrolumab, litifilimab, iberdomide and Janus kinase (JAK) or Cyclin-Dependent Kinase (CDK) inhibitors, demonstrating potential for targeting pathways associated with the interferon gene signature and STAT4 polymorphisms. Notwithstanding the problems presented by the heterogeneity of SLE, the identification of risk variations is anticipated to enhance predictive and therapeutic biomarkers, hence facilitating more precise and individualized disease management. Full article

Objective: Current knowledge surrounding the diagnosis and mechanisms that result in immune checkpoint inhibitor-associated diabetes (ICI-DM) remain to be fully defined. We present clinical vignettes of patients that have presented to our hospital to illustrate the heterogenous clinical profiles that patients with ICI-DM can experience. We also provide an update on ICI-DM, focusing on current and future perspectives and emerging therapies. Methods: We performed a retrospective review of the electronic records of five ICI-DM patients who presented to St. Vincent’s Hospital Melbourne between 2020 and 2024, with patients identified from the hospital endocrinology and oncology databases. We also performed a literature review via a PubMed search using the keywords “checkpoint inhibitors” and “diabetes” between the years 2015 and 2025 to allow us to collate a descriptive review on ICI-DM. Results: Our cases show some heterogeneity in presentation, with biochemical evidence of diabetic ketoacidosis (DKA) in 4/5 patients, presentation 18–253 days (median 47 days) from ICI commencement, HbA1c 59–78 mmol/mol (median 66 mmol/mol), and c-peptide 0.06–0.77 pmol/mL (median 0.09 pmol/mL). Islet autoantibodies were present in 4/5 cases and high-risk HLA alleles identified in 1/2 tested patients. The findings from our descriptive review support a similar heterogeneity in ICI-DM presentations. Inconsistent diagnostic criteria for ICI-DM were noted with low c-peptide being the most common biochemical presentation. Pancreatic volume is emerging as a useful predictive marker of ICI-DM development. We found no reports of the reversal of ICI-DM with immunosuppression in humans, although recent preclinical studies suggest that this approach is feasible. Conclusions: Diagnostic criteria should include new-onset hyperglycaemia with low paired c-peptide, and may be supported with T1DM-associated autoantibodies and evidence of pancreatic atrophy on imaging. Further research is needed in the realm of predicting ICI-DM and considering the role of immunosuppression as a treatment modality. Full article

The buckling and post-buckling responses of carbon fibre-reinforced polymer (CFRP) structures are strongly affected by geometric imperfections, boundary conditions, and material nonlinearities, making their reliable numerical prediction challenging. This work presents an integrated experimental–numerical investigation of a stiffened CFRP panel subjected to compressive loading, with the aim of improving model validation in instability regimes. The experimental campaign combines full-field measurements obtained through digital image correlation with local strain data from strain gauges, adopting a back-to-back configuration to capture the strain reversal associated with global buckling. The experimental results are compared with nonlinear finite element simulations incorporating intralaminar damage based on Hashin’s failure criteria. A good agreement between the numerical and experimental results is observed in the pre-buckling and early post-buckling regimes. However, increasing discrepancies arise at higher load levels, mainly due to manufacturing imperfections and uncertainties in boundary conditions, which influence the onset and evolution of localized deformation. Statistical indicators are employed to quantitatively assess the correlation between the experimental and numerical responses. The analysis focuses on the key response parameters, including the load–displacement behaviour, out-of-plane displacements, strain evolution, and damage initiation, enabling a comprehensive comparison of experimental and numerical results. The results demonstrate the effectiveness of combining full-field and point-wise measurements for validating numerical models of composite structures. Furthermore, the study highlights the limitations of idealized modelling assumptions and provides insights into the sensitivity of CFRP structures to imperfections in post-buckling and failure regimes. Full article

Understanding the effects of light on the body at different times of the 24 h solar day is a topic of increasing interest. In this paper, we use a mathematical model from the literature to simulate what would be expected of the human circadian clock on different light schedules. We first reproduce an influential experiment which found eBooks, when compared to a paper book, delayed sleep by roughly 10 min and melatonin onset by 1.5 h. The model is able to match the delay in sleep onset but struggles to reproduce the melatonin phase delay. However, certain initial conditions and parameters are capable of phase shifts consistent with the original study’s magnitude, suggesting that the original study’s finding may have been influenced by the pre-study entrainment or variability among the participants. We next simulate the same protocol under higher daytime light levels (increasing baseline illumination from 90 to 500 lux) and find that brighter daytime exposure reduces both sleep onset latency and the variability in phase delay attributable to evening eBook light. Finally, we explore how the timing of a bright light pulse during the day changes outcomes, such as sleep onset and circadian amplitude, and how these effects interact with light during the other hours of the 24 h day. Together, these modeling results suggest robust daytime light exposure confers resilience against the circadian-disruptive effects of evening light, generating testable predictions regarding the timing and intensity of beneficial light interventions for maintaining circadian alignment. Full article

Rheumatoid arthritis (RA) has traditionally been managed after the onset of clinically apparent synovitis; however, accumulating evidence indicates that disease-related immune abnormalities precede clinical diagnosis by several years. This preclinical phase is characterized by systemic autoimmunity, early musculoskeletal symptoms, and subclinical inflammation in genetically and environmentally susceptible individuals. In this review, we summarize current concepts regarding the pathogenesis, risk stratification, and therapeutic interception of preclinical RA. Particular attention is given to the mucosal origin hypothesis and to the roles of immunosenescence, peripheral helper T cells, and fibroblast-like synoviocytes in early disease evolution. Recent advances in clinical, serological, and imaging-based risk stratification have improved the identification of individuals at high risk of progression to clinical RA, and emerging intervention trials have shown that selected therapies may delay disease onset or reduce early inflammatory burden. Although complete prevention of RA has not yet been achieved, these findings support a paradigm shift from the treatment of established RA toward earlier, risk-adapted intervention before irreversible joint damage occurs. Future efforts should focus on refining predictive biomarkers, optimizing the timing and intensity of intervention, and establishing safe, individualized preventive strategies. Full article

Background and Objectives: Early identification of patients at risk for severe forms of acute cholangitis (AC) is crucial for guiding prompt therapeutic interventions. In addition to traditional biomarkers such as C-reactive protein (CRP), newer indices like the neutrophil-to-lymphocyte ratio (NLR) are cost-effective and easy-to-use diagnostic tools. In the context of limited evidence from Eastern European populations, this study aimed to compare the performance of NLR and CRP in identifying organ dysfunction-based severe presentation of acute cholangitis according to a modified TG18-derived classification. Materials and Methods: We conducted a retrospective study including patients admitted to Colentina Clinical Hospital between January 2021 and September 2025. Demographic, clinical, and laboratory data were collected from medical records, with a focus on admission inflammatory biomarkers: NLR and CRP. Symptom onset-to-presentation time was not recorded. Patients were stratified by disease severity according to a modified organ dysfunction-based severity classification, and comparative statistical analysis, including Receiver Operating Characteristic (ROC) curve analysis, was performed to assess the diagnostic performance and optimal cut-off values of both biomarkers for severe clinical presentation. Results: A total of 364 patients were included, with a median age of 68 years (IQR: 60–78), and a slight female predominance (55.5%). Of these, 231 were classified as non-severe and 133 as severe. Both CRP and NLR were significantly higher in severe cases (p = 0.042 and p = 0.018, respectively. Despite statistical significance, CRP showed limited discriminatory ability, whereas NLR showed only a marginal numerical advantage. ROC analysis showed poor discriminatory ability for both CRP (AUC = 0.564, 95% CI 0.503–0.624, p = 0.042) and NLR (AUC = 0.574, 95% CI 0.513–0.635, p = 0.018) in predicting severe AC incidence. The difference between AUCs was minimal (ΔAUC = 0.010, 95% CI −0.062 to 0.082, p = 0.78, DeLong test). Conclusions: Both CRP and NLR showed limited discriminatory performance in identifying organ dysfunction-based severe presentation of acute cholangitis. The small, non-significant difference between the two markers does not support a meaningful comparative advantage, and neither biomarker appears suitable for reliable early risk stratification on its own. Full article

Background: Risk stratification of patients with asymptomatic aortic stenosis (AS) remains challenging, as symptom-based assessment may underestimate disease severity. Exercise stress echocardiography (ESE) provides a comprehensive evaluation of valvular, ventricular, and cardiopulmonary responses under physiological stress and may improve prognostic assessment. Methods: A systematic review was conducted according to PRISMA guidelines to evaluate the prognostic value of ESE in asymptomatic moderate and severe AS. Electronic databases (PubMed, Scopus, and EMBASE) were searched from inception to March 2026. Studies were included if they assessed adult patients with asymptomatic moderate or severe AS undergoing exercise-based stress echocardiography and reported clinical outcomes. Studies using exclusively pharmacological stress or lacking outcome data were excluded. Data were extracted and synthesized qualitatively. Continuous variables were summarized as weighted medians and interquartile ranges. Results: A total of 11 studies were included, encompassing a heterogeneous population of patients with moderate-to-severe and severe AS. During follow-up, a substantial proportion of patients experienced adverse events, including symptom onset, aortic valve replacement, or death. Across studies, exercise-derived parameters consistently showed strong prognostic value. In particular, exercise-induced increases in mean transvalvular gradient, an elevated E/e’ ratio, the development of pulmonary hypertension, and reduced functional capacity emerged as the most reproducible predictors of adverse outcomes. Notably, thresholds such as an increase in mean transvalvular gradient ≥ 18–20 mmHg, peak exercise E/e’ ≥ 15, and systolic pulmonary artery pressure ≥ 60 mmHg were consistently associated with a higher risk across multiple studies. Myocardial deformation parameters and biomarkers such as exercise-induced BNP further contributed to risk stratification in selected studies. In contrast, resting parameters alone were less consistently predictive. Conclusions: ESE provides incremental prognostic information in asymptomatic moderate and severe AS by unmasking subclinical hemodynamic and myocardial abnormalities. The integration of stress-derived parameters, including reproducible threshold values, into clinical assessment may improve risk stratification and support more individualized management strategies. Further studies are needed to validate these cut-offs and define their role in guiding clinical decision-making. Full article

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition with high morbidity among survivors. Emerging evidence suggests that acute biochemical hypothalamic–pituitary axis disturbances, resulting from disruption of neuroendocrine regulation, are an underrecognized complication in the acute phase of aSAH. However, its correlation with clinical severity remains insufficiently explored. To investigate whether clinical severity of aSAH predicts acute biochemical pituitary-axis abnormalities and identify which hormonal axes are most affected in the acute phase. A prospective observational study was conducted at The National Institute of Neurology and Neurovascular Diseases, Bucharest (October 2024–March 2025) on 38 patients confirmed aSAH admitted within 48 h of symptom onset, of which 20 patients were included. Hormonal panels assessing adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), and antidiuretic hormone (ADH) were obtained prior to surgical intervention. Clinical severity was evaluated using the Glasgow Coma Scale (GCS), the Hunt and Hess (HH) scale, and the Modified Fisher Scale. Correlations between hormonal deficiencies and severity scores were analyzed using the Spearman correlation. Biochemical abnormality of the ACTH axis was most prevalent (75%), followed by ADH (50%) and TSH (40%), while GH deficiency was rare (5%). ACTH-axis biochemical abnormality correlated significantly with lower GCS (ρ = −0.61, p = 0.004) and higher HH scores (ρ = 0.59, p = 0.006). Multiple-axis abnormalities demonstrated the strongest correlations with all severity metrics (GCS: ρ = −0.68, p = 0.001; HH: ρ = 0.72, p < 0.001; Fisher: ρ = 0.57, p = 0.009). Greater clinical severity in aSAH is associated with a higher prevalence of acute biochemical endocrine abnormalities, particularly involving the ACTH axis and multiple hormonal pathways. These findings are exploratory and hypothesis-generating. Early hormonal assessment in patients with severe aSAH may help identify individuals at risk for acute endocrine abnormality, but validation in larger prospective studies is required before influencing clinical practice. Full article

The squat is a fundamental multi-joint movement widely studied in strength training and biomechanics. While numerous experimental and computational studies have examined squat kinematics and joint loading, the mechanisms governing how squat technique adapts to increasing external load remain insufficiently understood. In particular, inverse-dynamics-based approaches often overlook explicit constraints imposed by limited joint moment capacity. This study presents a computational framework for predicting load-dependent adaptations of squat posture. The human body was represented as a multi-segment rigid-body system, with joints modeled as nonlinear rotational elements with bounded moment capacity. A reference squat trajectory was first generated kinematically, and a constrained optimization procedure was then applied at each motion frame to determine a mechanically admissible posture under increasing barbell load. The results show that higher loads lead to systematic posture adaptations, including increased torso inclination and redistribution of rotational demand from the knee toward the hip joint. For the highest load, peak torso pitch increased from 30° to over 40°, while joint utilization exceeded unity, indicating the onset of yielding. These findings identify joint moment capacity as a key constraint governing squat technique and demonstrate the potential of the proposed framework for predictive biomechanical analysis. Full article

Camellia japonica is a widely cultivated woody ornamental plant. However, current studies mostly focus on the onset of flowering, neglecting the overall flowering time distribution patterns of the blooming process. In this study, we used uniform 5-year-old potted cuttings of C. japonica ‘Jinjiang Mudan’ to evaluate six candidate distribution models, including normal, log-normal, skew-normal, gamma, Weibull, and exponential, to model flowering time distribution. These candidates were compared to obtain an optimal distribution model using three-fold cross-validation, six evaluation indicators, and three goodness-of-fit tests in the control. The optimal distribution model was used to compare and analyze the different effects of the control, shading, and exogenous hormone treatments. The results showed that the skew-normal distribution model emerged as the most suitable distribution model among the six candidates and captured the flowering time distribution characteristics effectively in all treatments. Shading treatments were found to delay and extend the flowering period, with moderate treatments (50% and 70% shading) demonstrating better performance, extending the flowering period by approximately 40%. In terms of exogenous hormone treatments, BG (a mixture of the 6-BA and GA₃) concentrations could prolong and delay the flowering period. Lower concentrations (100 and 250 mg L⁻¹) of 6-BA and GA₃ were effective in extending the flowering period, with BA250 exhibiting the most pronounced effect, delaying flowering onset by approximately 12% and extending the flowering period by approximately 17%. Considering that this study is based on single-location and single-season trials, these findings provide a valuable methodological resource for quantifying and predicting flowering time distribution in C. japonica, other ornamentals, and crops. Full article

Background/Objectives: Nivolumab plus ipilimumab (IO–IO) provides durable clinical benefit in metastatic renal cell carcinoma (mRCC), yet long-term real-world data focusing on progression-free and treatment-free (PF–TF) survival remain limited. This study aimed to evaluate the long-term outcomes of IO–IO with a particular focus on the frequency and clinical characteristics of PF–TF. Methods: We retrospectively analyzed 63 patients with mRCC treated with first-line IO–IO across eight institutions with a minimum potential follow-up of five years. Progression-free survival (PFS), PFS2, and overall survival (OS) were assessed. PF–TF was defined as absence of disease progression and any cancer-directed therapy at the five-year landmark. Clinical and treatment-related factors were compared between patients with and without PF–TF. Results: The median PFS, PFS2, and OS were 7.5 (95% confidence interval [CI], 5.1–13.3), 26.2 (95% CI, 13.6–46.6), and 47.4 months (95% CI, 29.3–not reached), respectively. At 5 years, 11 patients (17%) achieved PF–TF. Baseline characteristics, IMDC risk classification, and peripheral blood biomarkers were not predictive of PF–TF. PF–TF was associated with the absence of bone metastases, presence of lymph node metastases, and occurrence of immune-related adverse events (irAEs), as well as the delayed onset of irAEs. No PF–TF patients required corticosteroid pulse therapy, and durable PF–TF was observed even after early treatment discontinuation due to adverse events. Conclusions: IO–IO demonstrated sustained long-term efficacy in real-world practice, with a subset achieving durable PF–TF. These findings highlight IO–IO as a strategy capable of providing long-term disease control with reduced treatment burden in selected patients with mRCC. Full article

Aims: This study aimed to examine the association between three-year changes in body mass index (BMI) and the risk of new-onset or progressive diabetic kidney disease (DKD) among people with type 2 diabetes and a normal BMI at baseline. Methods: A total of 416 people with type 2 diabetes (T2DM) and a normal BMI were enrolled from the Chongqing Diabetes Registry (CDR, NCT03692884) cohort and were followed for incident DKD until 2025. The change in BMI at the three-year follow-up was classified as follows: stable BMI (<5% change), decreased BMI (≥5% reduction), and increased BMI (≥5% gain). Cox proportional hazards models were used to analyze the association between BMI change categories and DKD risk. Results: During a mean follow-up of 3.4 years, people with an increased BMI exhibited a significantly higher risk of DKD onset or progression compared with people with a stable BMI [HR = 1.67, 95%CI: 1.15–2.43, p = 0.007]. Each 1% increase in BMI was significantly associated with an increased risk of DKD onset or progression [HR = 1.05, 95%CI: 1.02–1.07, p < 0.001]. This association remained significant after multivariable adjustment. Time-dependent receiver operating characteristic (ROC) curves showed that the area under the curve (AUC) of this indicator reached 0.683–0.729 for the prediction of new-onset or progressive DKD risk over 3–5 years. In subgroup analyses, decreased BMI was associated with a lower risk of DKD among people aged <60 years [HR = 0.21; 95% CI: 0.04–0.96; p = 0.044]. Conclusions: A ≥5% increase in BMI in three years may be a risk factor for new-onset or progressive DKD among people with T2DM and normal BMI. Conversely, a ≥5% decrease in BMI may be associated with renal protection in non-elderly individuals within the population. Full article

Background: Cardiac involvement represents a major determinant of morbidity and mortality in patients with muscular dystrophies (MDs). Evidence supporting guideline-directed heart failure (HF) therapy in this population remains limited. We aimed to retrospectively assess the effectiveness and tolerability of sodium–glucose co-transporter 2 inhibitors (SGLT2i) in patients with MDs and a previous history of HFrEF, HFpEF and HFmrEF and/or echocardiographic evidence of an LVEF < 50% Methods: In this retrospective, single-center study, we enrolled consecutive patients with MD treated with empagliflozin or dapagliflozin between October 2021 and October 2024. Comprehensive clinical, laboratory, echocardiographic, and functional data were collected at a baseline (V1) and at follow-up (V3) visit to evaluate longitudinal changes. Results: Twenty-four patients (mean age 42 ± 16 years; 92% male) were included, with a median follow-up of 418 ± 104 days. SGLT2i therapy was well tolerated; one patient discontinued treatment due to a urinary tract infection. LVEF significantly improved from 41 ± 5% to 44 ± 6% (p = 0.005). FSS decreased from 36 to 30 (p < 0.001), indicating improved functional capacity. Background HF therapy was intensified over time, with increased prescription of mineralocorticoid receptor antagonists (21% vs. 52%; p = 0.039) and β-blockers (67% vs. 91%). The interval between MD diagnosis and cardiomyopathy onset independently predicted LVEF improvement (β = 0.17; p = 0.012). Conclusions: In patients with MDs and HF, SGLT2i therapy was safe and associated with a modest but significant improvement in LVEF, reduced fatigue, and enhanced prescription of guideline-directed HF therapy. These findings support the potential role of SGLT2i in this high-risk population and warrant confirmation in larger prospective studies. Full article