Search Results (1,263)

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a transformative therapy for obesity and type 2 diabetes (T2D) in pediatric populations. This review synthesizes current evidence on efficacy, safety, and knowledge gaps in children and adolescents. Methods: A structured review of randomized controlled trials, extension studies, and mechanistic investigations evaluating GLP-1RAs in pediatric obesity and T2D was conducted. Outcomes of interest included body weight, BMI, body composition, glycemic control, and adverse events. Results: In adolescents, liraglutide and semaglutide consistently produce clinically meaningful reductions in BMI, body weight, and waist circumference, with modest improvements in systolic blood pressure and minimal effects on lipid levels or HbA1c. A newer trial in children 6 to <12 years showed liraglutide reduced BMI compared with placebo, with GI events consistent with prior safety profiles. Weight loss tends to include both fat and lean components; rapid weight loss may impair muscle strength or bone density if resistance exercise and adequate protein intake are not ensured. Risks include micronutrient gaps, misuse, and uncertain long-term effects on growth and puberty. These important considerations remain largely unaddressed in pediatric studies, and adult data can’t be directly extrapolated to children due to developmental, hormonal, and physiological differences. Conclusions: GLP-1 RAs are a promising adjunct to lifestyle therapy for pediatric obesity, but pediatric-specific protocols are needed to safeguard musculoskeletal health, ensure nutritional adequacy, and minimize misuse. Critical gaps remain in pediatric pharmacokinetics, dosing strategies, and long-term developmental safety. Further research is essential to develop evidence-based guidelines for safe and effective pediatric anti-obesity therapy. Full article

Background/Objectives: Optimal timing to initiate renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI) remains uncertain. This study evaluated the impact of early RRT initiation (<24 h after severe AKI diagnosis) on renal recovery and mortality in intensive care unit (ICU) patients. Methods: This prospective cohort included 119 patients with dialysis-requiring AKI admitted to two ICUs between December 2022 and December 2024. Patients were categorized according to RRT initiation timing (early < 24 h or delayed >24 h). Mortality (at 20, 30, and 76 days) and renal recovery (at 3, 10, and 30 days) were assessed using Kaplan–Meier curves and a log-rank test. Moreover, multivariate logistic regression was performed to identify factors associated with renal recovery. Results: Early RRT was initiated in 39 (32.8%) patients, and delayed RRT was initiated in 80 (67.2%). The early group had higher clinical severity (SOFA: 10 vs. 7; p = 0.016). Mortality did not differ between the groups (log-rank p = 0.396, 0.742, and 0.932 at 20, 30, and 76 days, respectively). However, early renal recovery (within 3 days) was more frequent in the early group (51.3% vs. 27.5%; p = 0.010), and early RRT was an independent predictor of this outcome (OR 3.26; 95% CI: 1.37–7.75 p = 0.008). Conclusions: Early RRT did not reduce mortality but was associated with improved early renal recovery in critically ill patients with AKI. Full article

Floods are among the most destructive natural hazards, with damages expected to intensify under climate change and socio-economic pressures. Effective reservoir operation remains a critical yet challenging strategy for mitigating downstream impacts, as operators must navigate nonlinear system dynamics, uncertain inflow forecasts, and trade-offs between competing objectives. This study proposes a novel end-to-end data-driven framework that integrates process-based hydraulic simulations, a Transformer-based surrogate model for flood damage prediction, and reinforcement learning (RL) for reservoir gate operation optimization. The framework is demonstrated using the Coralville Reservoir (Iowa, USA) and two major historical flood events (2008 and 2013). Hydraulic and impact simulations with HEC-RAS and HEC-FIA were used to generate training data, enabling the development of a Transformer model that accurately predicts time-varying flood damages. This surrogate is coupled with a Transformer-enhanced Deep Q-Network (DQN) to derive adaptive gate operation strategies. Results show that the RL-derived optimal policy reduces both peak and time-integrated damages compared to expert and zero-opening benchmarks, while maintaining smooth and feasible operations. Comparative analysis with a genetic algorithm (GA) highlights the robustness of the RL framework, particularly its ability to generalize across uncertain inflows and varying initial storage conditions. Importantly, the adaptive RL policy trained on perturbed synthetic inflows transferred effectively to the hydrologically distinct 2013 event, and fine-tuning achieved near-identical performance to the event-specific optimal policy. These findings highlight the capability of the proposed framework to provide adaptive, transferable, and computationally efficient tools for flood-resilient reservoir operation. Full article

Background/Objectives: Sudden unexpected postnatal collapse (SUPC) is a rare but catastrophic event affecting apparently healthy neonates during the first days of life. Therapeutic hypothermia has been increasingly applied in this setting due to pathophysiological overlap with hypoxic–ischemic encephalopathy, but its effectiveness remains uncertain. The aim of this review is to systematically identify, appraise, and synthesize the evidence on therapeutic hypothermia for SUPC. Methods: We searched MEDLINE, Scopus, Embase, Web of Science, and Cochrane up to February 2025. Eligible studies included term or near-term infants with SUPC within seven days of life who underwent therapeutic hypothermia. Data were extracted on demographics, collapse circumstances, therapeutic hypothermia protocol, mortality, seizures, neuroimaging, and neurodevelopment. Results: Thirteen studies were included, encompassing 70 infants. Most events occurred within two hours of life, during skin-to-skin or breastfeeding, and were strongly associated with primiparity. Therapeutic hypothermia was typically initiated within six hours of collapse, using whole-body cooling at 33–34 °C for 72 h. Mortality was approximately 10% (widely ranging from 0 to 50%). Seizures were frequent (70–90%), and MRI abnormalities were reported in about half of cases. Approximately half of survivors demonstrated normal neurodevelopment at one year. Study quality was low to moderate, and risk of bias substantial. Conclusions: Therapeutic hypothermia is feasible in SUPC and survival with favorable outcomes has been documented, but the certainty of evidence is very low. Given recurrent risk factors such as primiparity and early skin-to-skin/breastfeeding, enhanced vigilance and preventive strategies are essential. Therapeutic hypothermia should be considered case by case, ideally within specialized centers and supported by registries. Full article

Collaborative filtering (CF) continues to be a fundamental approach in recommendation systems for providing users with personalized suggestions. However, such kind of recommender systems are prone to performance issues when faced with noisy, inconsistent, or deliberately manipulated user ratings. Although Generative Adversarial Networks (GANs) offer promising solutions to capture complex user-item interactions in these CF situations, many existing GAN-based methods assume uniform reliability across all ratings, reducing their effectiveness under uncertain conditions. To overcome this challenge, this paper presents DST-AttentiveGAN to introduce a confidence-aware adversarial framework specifically designed to denoise inconsistent ratings in collaborative filtering scenarios. The proposed approach employs Dempster-Shafer Theory (DST) to compute confidence scores by aggregating diverse behavioral indicators, such as item popularity, user activity, and rating variance. These scores guide both components of the GAN architecture in which the generator incorporates a cross-attention mechanism to highlight trustworthy features, while the discriminator uses DST-based confidence to evaluate the credibility of input ratings. Training is carried out using a stabilized Wasserstein GAN objective that promotes both robustness and convergence efficiency. Experimental results in three benchmark data sets show that DST-AttentiveGAN consistently surpasses conventional GAN-based models, delivering more accurate and reliable recommendations under conditions of uncertainty. Full article

Background and Objectives: Breast lesions of uncertain malignant potential identified on biopsy, known as “B3 lesions,” constitute a significant portion of diagnoses in numerous published studies. These lesions are associated with a variable risk of coinciding malignant tumors, and current guidelines recommend complete excision, which can occasionally lead to an upgrade in the resection specimen. However, alternative, less invasive treatment strategies, such as clinical follow-up, may be considered. In this study, we retrospectively analyzed diagnostic biopsies from our institution to determine the upgrade rate of each B3 lesion subgroup to breast malignancy following complete excision. Materials and Methods: All breast biopsies conducted at our institution from 1 January 2018 to 30 November 2022 and classified as B3 lesions were included in this study. The lesions were categorized into groups and subgroups based on their growth pattern and histopathological features. To determine the upgrade rate to ductal carcinoma in situ (DCIS) or invasive breast cancer (IBC) for each B3 lesion subgroup, we assessed the histological concordance between the biopsy and the resection specimen. Results: During the study period, 10,531 biopsies were performed, of which 1045 (9.93%) were classified as B3 lesions. Among these, 795 (76.08%) were subsequently resected, either through surgical procedures (98.32%) or using the Vacuum-Assisted Excision technique (1.68%). Histological examination revealed that 89 (11.19%) of the resected B3 lesions were upgraded to breast malignancy, with 59 cases (7.42%) progressing to DCIS, 22 cases (2.76%) to IBC, and 8 cases (1.01%) to borderline or malignant phyllodes tumor. The upgrade rate varied among histopathological subgroups, being lowest in complex sclerosing lesions without atypia (4.95%, 95% CI: 2.5–8.7%) and highest in intraductal papillomas with atypia (58.82%; 95% CI: 32.9–81.6%). Conclusions: Statistically significant differences were observed between B3 lesion subgroups, with a higher risk of upgrade in lesions exhibiting atypia. As our understanding of B3 lesions evolves, there is potential to implement therapeutic strategies tailored to the specific risk associated with each subgroup. This approach could allow for less invasive management options, such as clinical or radiological follow-up, thereby sparing patients from unnecessary invasive procedures when appropriate. Full article

Background/Objectives: Coagulopathy is a common complication of liver cirrhosis, partly due to impaired synthesis of vitamin K-dependent coagulation factors. Despite its frequent use, the efficacy of vitamin K in this setting remains uncertain. This study aimed to evaluate the effect of vitamin K administration on coagulation parameters in patients with cirrhosis. Methods: We performed a retrospective study of 122 cirrhotic patients hospitalized between 2020 and 2024, who received vitamin K for coagulopathy correction. Coagulation and liver function parameters were monitored over time. Results: An early and progressive improvement in INR values was observed, in a subset of patients, following vitamin K administration. INR values across time points were strongly correlated, while only weak associations were observed with bilirubin levels. These findings support a selective therapeutic effect, rather than universal efficacy. Discussion: Despite current guidelines discouraging routine vitamin K use in cirrhosis, our findings suggest that selected patients—particularly those with reversible deficiency—may benefit from supplementation. The observed decrease in INR values supports a targeted, context-based approach rather than empirical management. Conclusions: However, due to the retrospective design and absence of a control group, the observed improvements cannot be conclusively attributed to vitamin K administration. Vitamin K may improve coagulation in cirrhotic patients with reversible deficiency, but its efficacy is not universal. Its use should be individualized and guided by clinical and biochemical context, as part of a broader treatment strategy. Full article

Background/Objectives: C-reactive protein (CRP) is widely used as a marker of perioperative inflammation, but its predictive value for cardiac surgical outcomes remains uncertain. Obstructive sleep apnea (OSA), a prevalent and underrecognized comorbidity, may independently contribute to postoperative complications through non-inflammatory mechanisms. This study aimed to reevaluate the prognostic role of CRP and determine the clinical impact of OSA severity on postoperative recovery, focusing on new-onset atrial fibrillation (AF), prolonged intubation time, and postoperative CPAP/AIRVO use as indicators of respiratory burden. Methods: In this prospective cohort of 142 elective cardiac surgery patients, preoperative polysomnography and serial CRP measurements were obtained. Multivariable regression, mediation analysis, and propensity score matching (PSM) were performed to evaluate associations between OSA severity, CRP, and perioperative outcomes (AF, intubation time, CPAP/AIRVO use). Results: OSA severity independently predicted prolonged intubation (β = 1.74, p = 0.0019) and new-onset AF (β = 0.85, p = 0.004), even after excluding patients with preexisting arrhythmia. CRP showed poor discriminatory power as a standalone biomarker (AUC for IOT > 14 h = 0.445) and did not mediate OSA–outcome associations. However, CRP > 2.1 mg/dL doubled the odds of moderate-to-severe OSA (OR = 2.05, p = 0.041). A composite score integrating AHI, BMI, and postoperative CRP strongly correlated with postoperative respiratory support (p < 0.0001). Conclusions: OSA exerts a stronger and more consistent influence on perioperative outcomes than CRP, challenging reliance on CRP for risk stratification. Incorporating objective OSA screening and spirometry into preoperative assessment may enhance perioperative risk prediction and guide personalized management strategies. Full article

This paper addresses the critical multiple-uncertainty challenge in laser link acquisition for space gravitational wave detection missions—a key bottleneck where spacecraft attitude alignment for laser link establishment is perturbed by inherent random disturbances in such missions, while also needing to balance ultra-high attitude precision, fuel efficiency, and compliance with engineering constraints. To tackle this, a convex optimization-based attitude control strategy integrating covariance control and free terminal time optimization is proposed. Specifically, a stochastic attitude dynamics model is first established to explicitly incorporate the aforementioned random disturbances. Subsequently, an objective function is designed to simultaneously minimize terminal state error and fuel consumption, with three key constraints (covariance constraints, pointing constraints, and torque saturation constraints) integrated into the convex optimization framework. Furthermore, to resolve non-convex terms in chance constraints, this study employs a hierarchical convexification method that combines Schur’s complementary theorem, second-order cone relaxation, and Taylor expansion techniques. This approach ensures lossless relaxation, renders the optimization problem computationally tractable without sacrificing solution accuracy, and overcomes the shortcomings of traditional convexification methods in handling chance constraints. Finally, numerical simulations demonstrate that the proposed method adheres to engineering constraints while maintaining spacecraft attitude errors below 1 μrad under environmental uncertainties. This study provides a convex optimization solution for laser link acquisition in space gravitational wave detection missions considering uncertainty conditions, and its framework can be extended to the optimal design of other stochastically uncertain systems. Full article

Background/Objectives: The medial longitudinal arch (MLA) is initially masked by a fat pad that makes the foot appear flat. In preschool age, this fat pad resorbs, and the arch becomes more defined. The exact age at which the arch attains its final form remains uncertain due to high inter-individual variability and differing assessment methods, which complicates the distinction between physiological development and potential abnormalities. Moreover, commonly used classification terms such as “flat” or “normal” do not adequately reflect the developmental progression and may be misleading in young children. This study aimed to describe the MLA developmental patterns and propose an adjusted classification terminology to improve clinical differentiation between feet undergoing normal developmental changes and cases requiring intervention. Methods: The present study employs both cross-sectional (285 children aged 4.00–8.99 years) and longitudinal (50 children measured annually between ages 4–6) designs. Foot dimensions were assessed using standard anthropometry, and the MLA was assessed via podograms using the Chippaux–Smirak index (CSI). To better reflect the developmental nature of the MLA, the arch was categorized as “formed” and “unformed”. Cross-sectional data were analyzed with ANOVA and visualized using LOESS regression, longitudinal data with linear mixed models, and relationships between CSI and foot dimensions with Spearman’s correlation. Results: MLA development showed significant changes up to age 6, with the most pronounced changes occurring between ages 4 and 5 and slowing thereafter. Children with an unformed arch at age 4 exhibited a steeper developmental trajectory than those with an already advanced arch form. Correlations between arch shape and foot dimensions were statistically significant but weak. No significant between-sex differences were observed. Conclusions: The timing of the most pronounced phase of medial longitudinal arch (MLA) development varies between individuals and is typically completed by 6 years of age, with no sex-dependent differences. Age 6 therefore represents a practical milestone for reliable clinical assessment, since earlier classifications risk misinterpreting normal developmental variation as pathology. Full article

The challenge of optimally controlling energy storage systems under uncertainty conditions, whether due to uncertain storage device dynamics or load signal variability, is well established. Recent research works tackle this problem using two primary approaches: optimal control methods, such as stochastic dynamic programming, and data-driven techniques. This work’s objective is to quantify the inherent trade-offs between these methodologies and identify their respective strengths and weaknesses across different scenarios. We evaluate the degradation of performance, measured by increased operational costs, when a reinforcement learning policy is adopted instead of an optimal control policy, such as dynamic programming, Pontryagin’s minimum principle, or the Shortest-Path method. Our study examines three increasingly intricate use cases: ideal storage units, storage units with losses, and lossy storage units integrated with transmission line losses. For each scenario, we compare the performance of a representative optimal control technique against a reinforcement learning approach, seeking to establish broader comparative insights. Full article

Background/Objectives: PRAME (Preferentially Expressed Antigen in Melanoma) is a promising immunohistochemical marker for distinguishing melanoma from benign melanocytic lesions, though optimal thresholds remain uncertain. This study evaluated PRAME expression in melanocytic lesions and compared diagnostic accuracy using two thresholds. Methods: We retrospectively assessed PRAME expression in 145 melanocytic lesions diagnosed between 2016 and 2021 at Istanbul Training and Research Hospital: 52 melanomas, 27 dysplastic nevi, 23 Spitz nevi, 15 compound nevi, 23 blue nevi, and 5 congenital nevi. Immunohistochemical staining (PRAME EP461, Cell Marque) was scored semi-quantitatively based on nuclear positivity: 0 (negative), 1 (1–24%), 2 (25–49%), 3 (50–74%), and 4 (≥75%). Diagnostic accuracy was evaluated at 50% and 75% thresholds. Results: PRAME expression at both thresholds was significantly higher in melanomas than nevi (p < 0.05). Sensitivity and specificity were 92.3% and 96.8% at 50%, and 82.7% and 98.9% at 75%. Lowering the threshold to 50% improved sensitivity with minimal specificity loss, particularly differentiating melanoma from dysplastic, compound, and blue nevi. Occasional positivity was observed in Spitz and dysplastic nevi; one melanoma was PRAME-negative. Conclusions: PRAME is an effective marker for melanoma diagnosis. A 50% threshold optimizes sensitivity while preserving specificity; however, histopathological evaluation remains the gold standard, and PRAME should be used only as an adjunct to avoid potential overdiagnosis, particularly in borderline lesions. Full article

Introduction: Juvenile myasthenia gravis (JMG) is a rare autoimmune disorder with a variable clinical course and limited pediatric-specific treatment guidelines. Objective clinical scales, such as the Quantitative Myasthenia Gravis (QMG) Score and the Pediatric Myasthenia Gravis Quality of Life 15 (PM-QOL15), may support individualized management, but their role in routine practice remains underexplored. Methods: We retrospectively reviewed 10 seropositive JMG patients followed at a single tertiary neuromuscular clinic between 2014 and 2024. All patients underwent a systematic assessment with QMG at each visit, while PM-QOL15 was administered at the final visit. Clinical data, comorbidities, antibody status, treatment modalities, and outcomes were analyzed. Associations between treatment strategies, comorbidities, and scale scores were explored using appropriate statistical methods. Results: Seven patients (70%) underwent thymectomy, resulting in a reduction in mean QMG scores from 7.7 to 2.4, though residual relapses were observed. Chronic intravenous immunoglobulin (IVIG) therapy, administered to 70% of patients, did not significantly reduce relapse rates or steroid exposure and was associated with higher QMG scores in the second year, suggesting use in more severe phenotypes rather than therapeutic efficacy. Prolonged corticosteroid therapy did not improve remission time or relapse frequency and was complicated by major adverse effects in two patients. Timing of azathioprine initiation showed no significant correlation with relapse frequency. PM-QOL15 correlated strongly with mean QMG (r = 0.88, p < 0.001), reflecting cumulative disease burden. Patients with comorbidities required longer stabilization, although differences were not statistically significant. Conclusions: The routine integration of QMG and PM-QOL15 into follow-up may facilitate the earlier recognition of subclinical deterioration, provide objective measures of treatment response, and guide personalized management in JMG. Thymectomy showed benefit in selected patients, while the long-term roles of IVIG and corticosteroids remain uncertain. Larger multicenter prospective studies are warranted to confirm these findings and refine evidence-based strategies for pediatric JMG. Full article

Background/Objectives: CDH1 gene is widely studied, as pathogenic variants are involved in diffuse gastric cancers and lobular breast cancers. CDH1 genotype contributes to the management of clinical practice recommendations for cancer prevention. We proposed a qualitative and quantitative description of CDH1 alternative splicing profile on lymphoblastoid cell lines (LCLs). The aim of this description was to allow a comprehensive interpretation of the effect of variants of uncertain significance (VUS) on CDH1 splicing. Methods: We studied, using RNAseq, the splicing profile of 22 LCLs (untreated and treated with puromycin) with no pathogenic variant on CDH1 and evaluated the effect on CDH1 splicing of four VUS. Results: We highlighted a total of eleven alternative splicing events including four junctions starting from intron 2, defining novel isoforms of CDH1. We also identified an isoform causing the skip of exon 11 and leading to a disruption of the reading frame with high levels of expression on negative CDH1 control LCLs, confirmed by ddPCR. Splicing RNAseq results for CDH1 VUS: c.1008+1G>A and c.1936+5G>A showed complex splicing patterns but allowed their classification as pathogenic. We studied CDH1 VUS exon 4 to exon 11 duplication with RNA analysis combined with Bionano optical genome mapping. Depending on alternative splicing of proximal and distal exons 11 within the duplication, we identified four distinct transcripts, leading to truncated proteins, classifying the duplication as pathogenic. Conclusions:CDH1 has a complex alternative splicing profile characterized by a dynamic splicing of intron 2 making CDH1 a good candidate for a study using long-read RNAseq. Full article

Background/Objectives: Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and dementia. The comparative prognostic value of MRI-based neuroimaging markers and genetic risk factors such as the APOE ε4 allele for cognitive outcomes remains uncertain. The objectives of this study were to estimate the pooled prevalence of cognitive impairment in CSVD, evaluate the associations of key neuroimaging markers (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes) and APOE ε4 with cognitive outcomes, and assess their diagnostic performance. Methods: This study included a systematic review and meta-analysis in accordance with PRISMA and MOOSE guidelines, searching five databases (2005–2025). Eligible studies included adults with CSVD and MRI-visible markers reporting cognitive outcomes (mild cognitive impairment [MCI], global cognitive impairment [GCI], all-cause dementia [ACD], vascular dementia [VaD], and Alzheimer’s disease [AD]). Thirty-nine studies comprising 18,425 participants were included. Pooled prevalence and associations were estimated using random-effects models, and diagnostic accuracy was evaluated. Certainty of evidence was assessed using the GRADE framework. Results: The pooled prevalence of GCI in CSVD was 57% (95% CI: 51–62%), while MCI prevalence was 46% (95% CI: 42–51%). WMHs were strongly associated with VaD (OR 10.35, 95% CI: 7.32–14.64), lacunes with ACD (OR 3.18, 95% CI: 1.24–8.20), and CMBs with AD (OR 1.52, 95% CI: 1.04–2.24). APOE ε4 carriage increased the risk of GCI (OR 1.80, 95% CI: 1.41–2.29). Across markers, diagnostic sensitivity was low, specificity was moderate-to-high, and AUROC values were modest. GRADE certainty ranged from low to moderate, with the highest confidence for WMHs and VaD. Conclusions: CSVD-related MRI markers and APOE ε4 are significantly associated with both early and late cognitive outcomes, supporting the integrated vascular–neurodegenerative continuum. The limited diagnostic sensitivity and variable certainty of evidence highlight the need for harmonized definitions, lesion quantification, and multimodal imaging–genetic approaches to improve early detection and risk stratification of CSVD-related cognitive impairment. Full article