Search Results (11,412)

Background: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the iduronate-2-sulfatase gene, leading to progressive multisystem involvement. Although international management guidelines exist, challenges in their implementation across different healthcare systems remain insufficiently addressed. This study aimed to establish a national expert consensus in Türkiye on the treatment and management of MPS II, aligning local practice with international standards. Methods: A modified Delphi methodology was conducted using two rounds of online surveys supported by three steering committee meetings. The process involved 10 experienced clinicians and a scientific committee of six professors. Based on international guidelines and country-specific clinical challenges, 72 consensus statements and 84 exploratory questions were developed. Statements achieving ≥ 80% agreement were accepted as consensus. Results: Consensus supported initiating enzyme replacement therapy (ERT) in both severe and attenuated MPS II, guided by functional and cognitive status. Severe cognitive impairment was not considered an exclusion criterion for ERT, given its somatic benefits. Experts agreed on continuing ERT into adulthood with individualized discontinuation decisions. Routine evaluations every 6–12 months, including respiratory, cardiac, and neurocognitive assessments, were recommended. Additional consensus areas included individualized premedication strategies, structured transition to adult care, selective home infusion, annual patient-reported outcome assessments, and the establishment of a national MPS II registry. Hematopoietic stem cell transplantation was not endorsed. Conclusions: This Delphi study demonstrates strong expert consensus on MPS II management in Türkiye, providing a practical framework to guide clinical practice, support alignment with international recommendations, and inform future policy and research priorities. Full article

Dengue fever, with a high proportion of asymptomatic infections, poses a major global public health challenge that traditional surveillance systems frequently underestimate. Wastewater-based epidemiology (WBE) has emerged as a promising approach to monitoring infectious diseases beyond enteric viruses. Dengue virus is shed in urine, feces, and saliva, providing a biological basis for wastewater detection alongside clinical surveillance. This systematic review and meta-analysis synthesize current evidence on dengue virus (DENV) detection in wastewater and evaluate methodological factors influencing detection success in WBE. A systematic literature search using selected databases and predetermined keywords, followed by eligibility screening, resulted in ten studies being included, covering community surveillance and experimental trials. DENV ribonucleic acids (RNA) were most consistently detected and enriched in wastewater solids, indicating this matrix as the most reliable for surveillance. Among concentration methods, ultrafiltration achieved the highest viral recovery efficiency, while reverse transcription digital polymerase chain reaction (RT-dPCR) demonstrated superior sensitivity and precision compared to those of reverse transcription quantitative polymerase chain reaction (RT-qPCR), particularly at low viral concentrations. Storage at −80 °C was critical for preserving RNA integrity. The meta-analysis yielded a pooled DENV positivity rate of 24% (95% CI: 20–28%) after exclusion of outliers. Overall, solid-phase analysis combined with RT-dPCR represents the most sensitive methodological approach across the included studies. Harmonized protocols are needed to support future translation of dengue WBE into community surveillance as current evidence mainly demonstrates methodological feasibility and provides a technical foundation for future public health integration. Therefore, further longitudinal and multi-site validation is required to establish its broader applicability for dengue surveillance. Full article

Background: Prefilled syringes (PFSs) are increasingly used for self- and assisted administration of high-value parenterals, yet design verification (DV) planning remains challenging due to overlapping drug, device, and combination product expectations, as well as limited harmonization of device components. To the best of our knowledge, there is no publication providing an end-to-end DV approach for developers. This work aims to provide a best-practice template for structuring and justifying DV programs for PFSs, with the explicit intent of improving transparency and offering practical clarity to development teams navigating regulatory and technical complexity. Methods: A risk-based DV approach is presented for an exemplary 1 mL long staked needle glass PFS intended for subcutaneous administration of a surrogate solution representative of a high-concentration biologic. The approach starts with the design inputs which were derived from intended use, user requirements, and the drug’s quality target product profile (QTPP), then translated into design outputs including Essential Drug Delivery Outputs (EDDOs). These outputs were proven by executing drug-independent and simulated drug-dependent DV tests using ISO- and pharmacopeia-aligned methods, including defined sampling, and real-time/accelerated aging. Results: A best-practice DV approach is presented, including test results across the evaluated functional, mechanical, and integrity endpoints. Conclusions: The presented approach provides a transferable DV template linking intended use to acceptance criteria, sample size rationale, and test selection. As a best-practice contribution, it supports more consistent, defensible DV planning for PFSs and may reduce ambiguity in the interface between drug and device development expectations. Full article

Over the past decade, veterinary forensic toxicology has gained increasing relevance due to the recognition of animal poisoning as a criminal, environmental, and public health concern. This review provides an updated overview on current perspectives in veterinary forensic toxicology, focusing on common toxicological scenarios, analytical innovations, and interpretative challenges. Intentional poisoning of companion animals, wildlife intoxication, and environmental contamination are discussed within a One Health framework. Mass spectrometry-based techniques, including targeted gas chromatography–tandem mass spectrometry (GC-MS/MS), liquid chromatography–tandem mass spectrometry (LC–MS/MS) and high-resolution mass spectrometry (HRMS) for non-targeted screening, and emerging ambient mass spectrometry approaches are highlighted as pivotal tools in modern forensic investigations. Major limitations related to post-mortem changes, species-specific toxicokinetic, and the lack of harmonized interpretative criteria are critically examined. The review also identified future priorities such as methodological standardization, expansion of toxicokinetic databases across species, detection of emerging contaminants, and strengthened international cooperation. Overall, veterinary forensic toxicology is an emerging discipline at the intersection of animal welfare, environmental conservation, and public health providing essential evidence for legal, regulatory, and investigative purposes. Full article

Rice plant height is a key indicator of crop growth and phenology, yet continuous daily estimation remains challenging under limited field observations. This study proposes an interpretable Bayesian LUT-based framework to estimate rice plant height from time-series, satellite-derived GCVI, and sparse in situ measurements. Daily plant height was estimated as a posterior-weighted ensemble of multiple LUT-derived heights, together with uncertainty reflecting ambiguity among plausible growth trajectories. Applied to rice paddies in Ryugasaki City, Japan, using Harmonized Landsat–Sentinel-2 data from the 2025 growing season, the method achieved and RMSE = 7.08 cm on the validation dataset, outperforming simple baseline approaches. The estimated daily height time series also enabled evaluation of the timing at which plant height reached 70 cm, revealing clear spatial variability among fields and an associated uncertainty of approximately 10 days. Although this threshold was discussed with reference to previous studies on L-band SAR sensitivity, the present study relied solely on optical observations. Overall, the proposed framework provides a data-efficient and explainable approach for daily, spatially explicit rice growth monitoring, while current limitations include the single-region, single-year LUT construction and the simplified statistical assumptions used in the Bayesian weighting framework. Full article

Muscle vulnerability occurs at both extremes of the human lifespan, although its biological significance differs substantially between developmental growth and late-life decline. During childhood and adolescence, insufficient muscle accretion reflects disruption of physiological anabolic trajectories driven by inadequate energy availability, inflammatory burden, endocrine imbalance, or disease-associated catabolism. In older adults, muscle deterioration is characterized by anabolic resistance, neuromuscular remodeling, chronic low-grade inflammation, and hormonal decline, culminating in sarcopenia and loss of functional independence. The absence of harmonized diagnostic frameworks across age groups limits direct translational extrapolation. A lifespan-informed perspective distinguishing growth-supportive from function-preserving nutritional approaches is, therefore, required. This narrative review examines how major classes of nutritional bioactive interact with molecular pathways regulating skeletal muscle homeostasis in fragile populations across the lifespan. The analysis encompasses energy adequacy, protein quantity and quality, amino acid-dependent anabolic signaling, vitamin D status, lipid-derived mediators, redox-modulating phytochemicals, and micronutrients supporting mitochondrial bioenergetics. In pediatric contexts, nutritional interventions primarily aim to restore anabolic permissiveness within a structurally intact growth environment. In aging individuals, strategies focus on mitigating anabolic resistance through optimized protein intake, correction of micronutrient insufficiencies, and integration with resistance exercise to preserve functional capacity. This narrative review emphasizes the need to distinguish mechanistic rationale from clinically validated interventions, as improvements in molecular pathways do not consistently translate into meaningful functional outcomes. Full article

The preparation for next-generation Earth Observation missions, such as the European Space Agency’s (ESA) Copernicus Hyperspectral Imaging Mission for the Environment (CHIME) and Land Surface Temperature Monitoring (LSTM), requires robust pre-launch proxy datasets. Because current simulation methodologies frequently rely on isolated, platform-specific approaches, this study proposes a comprehensive, unified multisensor framework capable of dynamically generating operationally realistic CHIME and LSTM datasets from diverse airborne and satellite sources. Three distinct processing pipelines were established. For hyperspectral data simulation, precursor satellite imagery (PRISMA and EnMAP) and high-resolution airborne measurements (HySpex) were harmonized to CHIME’s 30 m specifications utilizing Spectral Response Function (SRF) adjustments, Point Spread Function (PSF) spatial resampling, and 6S atmospheric radiative transfer modeling. For thermal data simulation, archive Landsat 8/9 and ASTER imagery were transformed into LSTM’s target 50 m, 5-band configuration using a synergistic two-step approach: a physics-based Spectral Super-Resolution (SSR) module followed by an AI-driven Spatial Super-Resolution (SpSR) transformer network. Evaluated across highly diverse inland, coastal, and riverine testbeds in Italy, the simulated products demonstrated high spectral, spatial, and radiometric fidelity. While inherently constrained by the native spectral ranges of the input sensors and by the current lack of absolute on-orbit mission data for validation, the downscaled images closely reproduced complex thermal patterns and water-quality gradients. Ultimately, this scalable framework provides the remote sensing community with early access to representative datasets and mission performance assessments, while accelerating pre-launch algorithm development and testing for environmental monitoring applications—particularly those focused on water discharges. Full article

Electric vehicles (EVs) have fundamentally changed the noise, vibration, and harshness (NVH) landscape of automotive powertrains. In the absence of masking internal-combustion-engine noise, harmonic components such as gear whine, electric-motor orders, and inverter-related tones become more perceptible and more critical to vehicle refinement. This review synthesizes the current state of the art in harmonic NVH engineering for electric drivetrains, focusing on the interactions between gear geometry, manufacturing variability, electromechanical coupling, structural transfer, and human sound perception. Classical mechanisms of gear-mesh excitation are revisited together with emerging EV-specific challenges, including long-wavelength flank deviations, ghost orders, lightweight housing dynamics, and psychoacoustic sound-quality requirements. The review further examines recent progress in predictive and data-driven approaches, including machine-learning-based gear-noise modeling, digital-twin concepts, and virtual NVH assessment workflows. Overall, the literature shows that harmonic NVH engineering in EVs is evolving from a conventional gear-noise problem into a multidisciplinary system-level task integrating gear dynamics, manufacturing science, structural acoustics, electric-drive control, psychoacoustics, and data-driven optimization. This review provides a structured synthesis of these developments and identifies key research gaps and future directions for the next generation of refined electric drivetrains. Full article

Objectives: This study aimed to establish local Diagnostic Reference Levels (DRLs) for adult computed tomography (CT) across Emirates Health Services (EHS) hospitals in the United Arab Emirates. Methods: A retrospective multicenter survey included 1257 adult patients from seven EHS hospitals who underwent six routine CT protocols: head without contrast (n = 375), chest without contrast (n = 403), chest with contrast (n = 50), abdomen–pelvis without contrast (n = 204), abdomen–pelvis with contrast (n = 164), and chest–abdomen–pelvis (n = 61). Only single-phase, standard-range examinations were included. Examinations with major protocol deviations, extended scan ranges, or manual exposure overrides were excluded. CTDIvol and DLP were extracted from DICOM dose reports and reviewed against protocol definitions and scanner dose documentation. Local DRLs were defined as the 75th percentile of the dose distribution for each protocol, and median values were reported as achievable dose indicators. Results: Inter-hospital variability was observed across all protocols, particularly for abdomen–pelvis and chest–abdomen–pelvis examinations. The proposed DLP-based local DRLs (mGy·cm) were: head without contrast, 1179.6; chest without contrast, 425.0; chest with contrast, 1238.0; abdomen–pelvis without contrast, 637.2; abdomen–pelvis with contrast, 1269.9; and chest–abdomen–pelvis, 1411.5. Median values indicated achievable doses below the 75th percentile for all protocols. Compared with selected international studies, abdomen–pelvis doses were broadly comparable, whereas head and chest doses were somewhat higher. Conclusions: This study provides a coordinated multicenter baseline for adult CT local DRLs across EHS hospitals. The findings support protocol harmonization, scan-length optimization, targeted staff training, and integration with dose-monitoring systems to strengthen CT dose optimization and patient safety and to inform future updates of UAE national DRLs. Full article

Background/Objectives: The rapid expansion of New Approach Methodologies (NAMs) is transforming oral biopharmaceutics by offering mechanistically rich, human-relevant tools that can reduce reliance on animal testing while improving translational confidence. Regulatory agencies, including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), are increasingly open to NAM-generated evidence, provided that methods are fit-for-purpose and scientifically justified. This review synthesizes current advances and evaluates how NAMs can be integrated across drug-development stages to enhance the prediction of oral absorption, formulation performance, and regulatory decision-making. Methods: A comprehensive literature review was conducted across classical and emerging methodologies, including in vitro permeability and solubility models, organoids, organ-on-a-chip (OoC) systems, machine learning frameworks, and mechanistic approaches such as the physiologically based pharmacokinetic (PBPK) and biopharmaceutics (PBBM) models. Emphasis was placed on physiological relevance, predictive performance, validation status, and regulatory applicability. Results: Classical tools remain essential for the Biopharmaceutics Classification System (BCS)-based biowaivers and risk-based assessments, yet they often lack physiological fidelity. NAMs provide enhanced representation of intestinal architecture, hydrodynamics, transporter activity, and metabolism. Organoids and microphysiological systems generate high-quality permeability and metabolic data, while computational NAMs enable scalable prediction of ADME properties and formulation behavior. When integrated into PBPK/PBBM models, these methods have great potential in predicting in vivo performance in humans. Evidence demonstrates that NAMs can refine, reduce, and, in specific contexts, replace animal studies without compromising scientific rigor. Conclusions: NAMs complement, rather than displace, classical biopharmaceutic tools, enabling a more mechanistic, human-centered, and ethically responsible framework for drug development. Their effective implementation will depend on continued validation, standardization, and regulatory harmonization as the field transitions toward fully NAM-supported biopharmaceutical assessment. Full article

Background/Objectives: The cochlea and vestibular organs develop concurrently during embryogenesis and share anatomical and functional pathways. As a result, congenital factors affecting the vestibulocochlear system may impair both hearing and vestibular function. Despite this, the relationship between congenital bilateral sensorineural hearing loss (SNHL) and vestibular dysfunction remains insufficiently defined. This study evaluated vestibular function in patients with congenital bilateral SNHL and investigated the association between hearing loss severity and vestibular function. Methods: A total of 202 participants aged 7–31 years were enrolled, including 102 patients with congenital bilateral SNHL and 100 healthy controls. Vestibular function was assessed using videonystagmography (VNG) during sinusoidal harmonic acceleration (SHA) rotational testing and caloric testing performed according to the Fitzgerald–Hallpike protocol, as well as with the video head impulse test (vHIT). Statistical analyses compared vestibular parameters between groups and assessed correlations with hearing loss severity. Results: Patients with congenital bilateral SNHL exhibited significantly lower vestibulo-ocular reflex (VOR) values in the SHA test compared to controls. Greater hearing loss severity was associated with lower VOR gain values. No statistically significant differences were observed between groups in caloric test results or vHIT VOR gain values. However, corrective saccades during vHIT were identified exclusively in patients with hearing loss and occurred in approximately 15% of cases. Furthermore, the age of independent walking was significantly delayed in the study group compared to controls. Conclusions: Congenital bilateral SNHL is associated with vestibular dysfunction, as evidenced by abnormal SHA test results and the presence of corrective saccades in vHIT. These patients may also experience delayed motor development. These findings suggest that vestibular dysfunction may be present in patients with congenital sensorineural hearing loss and may have functional implications. Full article

We evaluated global radiotherapy practices in the management of early-stage (AJCC/UICC 8th edition stages I-II) glottic cancer (ESGC). A cross-sectional online survey was conducted in March 2025 across centers worldwide. Data was collected on clinical practices, including staging, CT simulation, target volumes delineation, organs-at-risk contouring, radiotherapy techniques, dose and fractionation schedules, treatment delivery techniques, and image guidance practices. A total of 181 responses were received, primarily from Asia (41.4%) and Europe (24.3%). Most respondents were from non-academic public centers (44.2%), with multidisciplinary team involvement reported by 84.5%. Head and neck CT scan was the most used staging modality (80.1%). Intensity-Modulated Radiation Therapy was the most common planning technique (82.9%). Hypofractionated radiotherapy schedules predominated for T1 (84%) and T2 (72.4%) disease. T1a was typically treated with whole-larynx target volume (72.4%). Use of ipsilateral involved vocal cord irradiation varied by geographical region (p = 0.015), being most common in North America (44.8%) and Europe (38.6%). Accelerated fractionation for T2 also differed significantly (p < 0.001), with the highest use reported in North America (41.4%). Daily Cone-Beam Computed Tomography was acquired by (58.2%). In total, 70% of respondents expressed interest in the results of a future phase III randomized trial comparing stereotactic body radiation therapy to conventional radiotherapy. Significant global variations in radiotherapy practices for ESGC were observed, likely reflecting disparities in access and differences in institutional protocols. The development and implementation of standardized, evidence-based global guidelines are essential to harmonize care, minimize toxicity, and improve outcomes for patients with ESGC. Full article

We simulate the generation of multiple harmonics up to the sixth order extending into vacuum ultraviolet. The harmonics are generated by χ⁽ⁿ⁾:χ^(m) cascades, containing second- or third-order perturbative nonlinear processes. We identify three additional phase-matching conditions beyond standard phase matching, namely when only the first step or only the second step of the cascades are phase-matched and when the non-phase-matched second or third harmonic produces quasi-phase matching for higher-order harmonics, causing an essential enhancement of the harmonic signals. Full article

Metal–organic frameworks (MOFs) are porous hybrid nanomaterials assembled from metal ions or clusters and organic ligands. Owing to their tunable structures, versatile compositions, and exceptional payload capacities, MOF-based systems have attracted increasing interest in drug delivery and theranostics. Yet, despite rapid progress in efficacy-focused studies, translational evaluation remains limited by incomplete evidence on safety, in vivo fate (pharmacokinetics), and degradation. This review examines MOF nanomedicines through a three-element evidence-chain framework and a four-level material evaluation and substantiation (MES) grading system to relate commonly reported endpoints to development-relevant questions. Major degradation patterns across representative MOF families are summarized, and the influence of surface engineering on safety, in vivo fate, and degradation is discussed. Representative studies are re-examined to illustrate how evidence gaps in these dimensions may affect translational interpretation. Key priorities for the field include dose standardization, quantitative in vivo evaluation, harmonized degradation assays, long-term and repeat-dose studies, and more consistent formulation reporting. By integrating these issues into a unified evidence-chain framework, this review aims to support a more comparable, interpretable, and development-relevant evaluation of MOF nanomedicine research. Full article

Circulating tumor DNA (ctDNA) has many potential applications in the management of cancer, including detection, monitoring, and treatment response assessment. This study evaluates pre-treatment ctDNA detection in a single-institution pan-cancer cohort using a highly sensitive tumor-informed ctDNA assay. Participant samples were collected at the University Health Network across six study cohorts. A total of 273 patients with stage II-IV cancers spanning 16 tumor types were analyzed using a personalized tumor-informed assay (RaDaR^®). Harmonized methods were employed to mitigate the impact of variables known to influence ctDNA detection and its quantification. Pre-treatment ctDNA was detected in 83% of participants (226/273) across all stages and cancer types. Detection rates varied by clinical characteristics, including cancer type and stage; ctDNA was detected in 100% of stage IV metastatic recurrent high-grade serous ovarian cancer (HGSOC) patients (n = 8/8) and 54% of stage IV melanoma patients (n = 6/11). The median estimated variant allele fraction (eVAF) across all patients with a positive ctDNA result was 0.25% (range: 0.000029–37.7%), varied by tumor type and increased with cancer stage. A total of 11% of positive samples (24/226) had an eVAF of <0.01%. This pan-cancer ctDNA analysis using a highly sensitive assay reveals high detection rates overall, including ~10% at low levels (<0.01% eVAF), offering a reference for future clinical ctDNA applications and furthering our understanding of factors influencing ctDNA measurements. Full article