Search Results (5,201)

Background/Objectives: Despite widespread antiretroviral therapy (ART) use, whether the expected transition from AIDS-defining to non-AIDS-defining cancers has occurred in settings with persistent late HIV presentation remains unclear. We examined long-term cancer patterns, determinants, and survival outcomes in a large HIV cohort. Methods: This retrospective, single-center cohort included 1419 people living with HIV followed between 2006 and 2024. Patients who developed malignancy were classified as AIDS-defining cancers (ADC) or non-AIDS-defining cancers (NADC). Immuno-virological parameters were assessed at HIV and cancer diagnosis. Survival was analyzed using Kaplan–Meier methods, and predictors of mortality were evaluated using Cox proportional hazards regression. Determinants of ADC development were assessed using multivariable logistic regression. Temporal changes were evaluated by trend analysis. Results: Sixty-six patients (4.6%) developed malignancy (31 ADC, 35 NADC). Late HIV presentation was common, with 72.7% having CD4+ T-lymphocyte counts < 350 cells/mm³ at cancer diagnosis, particularly among ADC cases. Most ADCs (93.5%) occurred within 24 months of HIV diagnosis. Overall survival did not differ between ADC and NADC groups (log-rank p = 0.14). Although mortality declined after 2015, temporal changes in ADC and NADC proportions did not reach statistical significance (p = 0.14). In Cox regression analysis, viral suppression before death or last follow-up was independently associated with lower mortality risk (HR 0.12; 95% CI 0.05–0.31). Lower CD4+ T-lymphocyte counts were associated with ADC development, and a CD4+ T-lymphocyte threshold of 295 cells/mm³ showed good discriminative performance (AUC = 0.83), although this cutoff should be interpreted cautiously due to the lack of external validation. Conclusions: In this long-term cohort from Türkiye, a clear epidemiological transition from ADC to NADC could not be demonstrated. The cancer spectrum remained strongly influenced by late HIV presentation and advanced immunodeficiency. Sustained viral suppression was independently associated with lower mortality risk, supporting the importance of early HIV diagnosis, timely ART initiation, and sustained virological control. Full article

The rapid expansion of molecular point-of-care (POC) diagnostics into decentralized settings, including emergency departments, retail pharmacies, and home environments, has shifted the burden of diagnostic performance from laboratory professionals to heterogeneous, often non-expert users. While traditional evaluation frameworks focus on analytical and clinical validity, they often overlook the impact of human-system interactions on real-world reliability. This review introduces the concept of Operational Validity: the ability of a diagnostic system to preserve its intended performance when operated by intended users within the constraints of real-world workflows and environments. To establish a rigorous foundation for this concept, this study provides a critical comparative analysis contrasting Operational Validity against traditional clinical evaluation dimensions (analytical validity, clinical validity, and clinical utility) and post-market metrics. While existing literature outlines isolated usability principles, the significance of this study lies in its synthesis of these fragmented concepts into a formalized, lifecycle-based “Operational Validity” framework that explicitly maps the causal mechanisms connecting initial user interaction directly to downstream clinical outcomes. By synthesizing international standards (IEC 62366-1) alongside the newly finalized May 2026 U.S. Food and Drug Administration (FDA) guidance on the Content of Human Factors Information in Medical Device Marketing Submissions, we examine how human factors engineering (HFE) and usability engineering serve as the methodological foundation for operational validity. We analyze the specific complexities of molecular workflows, identify key parameters of use-related failure modes in pre-analytical and interpretation stages, and detail the mandatory role of iterative formative and final summative usability testing in mitigating these risks. Finally, we propose a lifecycle-based approach to HFE that integrates design, simulated-use validation, and post-market surveillance. Establishing operational validity is essential to ensure that the high analytical sensitivity of molecular POC platforms translates into consistent clinical utility across the full spectrum of decentralized care. Full article

Since January 2023, the Russian Federation has implemented expanded neonatal screening for 36 hereditary disorders, which has changed the diagnostic algorithm for hyperphenylalaninemia/phenylketonuria (HPA/PKU) by introducing tandem mass spectrometry (MS/MS) on the second day of life, followed by confirmatory biochemical and molecular testing in newborns at risk. We analyzed 1247 newborns aged 5–15 days with elevated phenylalanine levels (≥120 µmol/L) and a phenylalanine to tyrosine ratio of at least 1 detected during the first stage of screening using MS/MS. At the reference center, newborns underwent repeat biochemical testing and stepwise molecular analysis of HPA-associated genes. Two pathogenic variants in HPA-associated genes were identified in 538 newborns, including 534 newborns with biallelic pathogenic variants in PAH and 4 with BH4-deficient forms (PTS, QDPR). The incidence of molecularly confirmed HPA was 1:4518 newborns (95% CI: 1:4152–1:4925). The PAH variant spectrum was dominated by p.Arg408Trp (c.1222C>T) (33.4%). Genotype-based analysis indicated that 73 newborns (13.7%) were likely responsive to cofactor therapy, whereas 222 (41.6%) were potentially responsive. These findings define the molecular epidemiology of HPA in Russia and support early genetic stratification for diagnosis and treatment. Full article

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted and repetitive behaviors, and sensory processing abnormalities, including food selectivity. Due to the lack of effective causal therapies, alternative approaches such as dietary interventions are increasingly being explored. This study aimed to assess the impact of dietary factors on the nutritional status of children with ASD. Methods: A total of 103 children (75 with ASD and 28 controls) were included. Nutritional status was assessed using biochemical markers and standardized anthropometric measurements. Associations between nutritional status and dietary factors, particularly elimination diets implemented either on medical indications or in the absence of clinical justification, were analyzed. Results: ASD diagnosis was independently associated with lower height SDS (Standard Deviation Score). Food selectivity was significantly associated with growth patterns: children with food selectivity showed a higher prevalence of short stature compared with the control group (15.2% vs. 0%, p = 0.033). Children following elimination diets had significantly lower BMI SDS compared with those without dietary restrictions (−0.35 [−1.29 to 0.05] vs. −0.22 [−0.78 to 1.14], p = 0.046), although only 11.1% had medical indications for such interventions. Among non-supplemented participants, vitamin D deficiency was significantly more prevalent in the ASD group (84.6% vs. 33.3%, p < 0.001). Conclusions: Elimination diets were the only dietary factor associated with a clinically relevant reduction in BMI SDS in children with ASD. Food selectivity alone was not associated with impaired nutritional status. Most elimination diets were implemented without confirmed medical indications. These findings highlight the importance of evidence-based dietary management and routine vitamin D supplementation in this population. Full article

Background: Renal vasculitis encompasses a heterogeneous spectrum of disorders where vascular inflammation leads to organ dysfunction. Given that renal involvement is the primary determinant of long-term morbidity, timely diagnosis and intervention are paramount. This review aims to synthesize recent pathogenic insights and evaluate how these mechanistic breakthroughs are reshaping current diagnostic and therapeutic paradigms. Methods: A narrative review of the literature was performed to analyze the pathophysiology, diagnosis, and management of pediatric renal vasculitis. The analysis synthesizes current clinical guidelines and recent trial data, highlighting the transition toward biomarker-driven precision medicine for refined disease assessment and management. Results: Diagnosis remains multimodal, necessitating the integration of clinical, laboratory, and histopathological data. In ANCA-associated vasculitis (AAV), recent evidence has challenged the traditional “pauci-immune” concept. Management of pediatric IgA vasculitis utilizes a risk-stratified approach, whereas cryoglobulinemic vasculitis requires targeted trigger elimination. Across all pediatric syndromes, there is a shift toward minimizing corticosteroid exposure and utilizing individualized frameworks. Conclusions: Despite substantial progress in targeted biological therapies and reduced corticosteroid burden, the long-term morbidity of pediatric renal vasculitis remains substantial. Outcomes are dictated by a synergy of disease-specific and patient-specific factors. Addressing persistent unmet needs in the field requires further refinement of individualized management protocols and the continued validation of dynamic biomarkers, alongside the implementation of pediatric-specific guidelines and age-appropriate outcome measures. Full article

Objectives: We aimed to descriptively evaluate the feasibility and clinical utility of TowardPi BO (4K ultra-HD microscope integrated with a 400 kHz swept-source intraoperative optical coherence tomography (SS-iOCT) system) in managing various ophthalmic surgical conditions in a real-world setting. Methods: We analyzed surgical videos and data from 123 consecutive cases that underwent elective surgery with the assistance of this SS-iOCT system at Beijing Tongren Hospital between 2 September 2025 and 10 February 2026. Cases were included when the iOCT provided critical, real-time information that directly influenced surgical decision-making or technique modification. Cases were excluded if iOCT served only routine confirmatory or educational purposes without altering the surgical plan. Results: A total of 72 surgical cases were included, comprising 7 intraocular lens implantations with ciliary sulcus fixation, 19 macular holes, 3 cases of macular hole retinal detachment (MHRD), 4 cases of macular schisis with or without foveal detachment (MSRD), 12 cases of submacular hemorrhage, 20 cases of rhegmatogenous retinal detachment (RRD), and 7 intraocular mass lesions. The 400 kHz SS-iOCT significantly aided in surgical visualization, guided real-time decision-making, and prompted modifications in surgical techniques. Conclusions: To our knowledge, this is the first real-world study to evaluate the application of a 400 kHz SS-iOCT system across a wide spectrum of ophthalmic conditions, including its novel use in intraocular tumors. From routine to complex surgical cases, SS-iOCT enhances surgical precision and facilitates real-time decision-making, ultimately contributing to improved surgical outcomes. Full article

Temperature-dependent luminescence of Pr³⁺-doped materials was investigated using both conventional luminescence intensity ratio (LIR) and principal component analysis (PCA)-based thermometry. Three host matrices with distinct structural properties, LiLaP₄O₁₂, YNbO₄, and Y₂O₃, were selected to evaluate the influence of crystal structure on thermometric performance. Temperature-resolved emission spectra recorded over the 103–523 K (−170 to 250 °C) range were analyzed using both approaches, with the first principal component (PC₁) serving as a thermometric parameter in the PCA. The results show that crystal symmetry and site multiplicity strongly influence the temperature-dependent spectral evolution and, consequently, the thermometric response. LiLaP₄O₁₂ exhibits stable and well-defined spectral evolution, resulting in balanced thermometric accuracy and resolution. YNbO₄ shows enhanced sensitivity to temperature variations due to increased spectral complexity and stronger crystal-field effects, leading to improved resolution but increased calibration uncertainty. In contrast, Y₂O₃ exhibits reduced thermometric performance due to overlapping emissions from multiple crystallographically inequivalent sites with distinct thermal responses. Compared to LIR, PCA provides improved thermometric figures of merit, particularly in systems with complex and strongly overlapping emission bands, demonstrating the potential of full-spectrum analysis in luminescence thermometry. Full article

Ticks are widely distributed in China and can carry and transmit a variety of pathogens that potential to cause serious impacts on public health and the economy. Little is known about the broader spectrum of Coxiella-like endosymbiont (CLE) in ticks under natural conditions in China. The aim of this study was to detect, analyze, and characterize phylogenetically CLE found in ticks in Hebei Province, China. A total of 947 ticks collected from Hebei Province were identified as Haemaphysalis longicornis based on morphological characteristics and cytochrome c oxidase gene PCR analysis of extracted DNA. Subsequently, DNA was analyzed via PCR for the IS1111 gene (frequently associated with Coxiella burnetii), and the amplified DNA was then sequenced and analyzed phylogenetically using a set of primers targeting the 16S rRNA, groEL, and rpoB genes. A total of 8.24% (78/947) of ticks from the Chengde, Baoding, and Cangzhou regions were positive in the IS1111 PCR. Phylogenetic analysis using the 16S rRNA, groEL, and rpoB genes revealed the presence of CLE in Ha. longicornis ticks from these regions and the formation of two distinct clades, suggesting horizontal gene transfer events. Our results strengthen the growing evidence that CLE, not Coxiella burnetii, is ubiquitously associated with ticks across diverse geographic locations—a distinction critical for accurately interpreting tick microbiome surveys and avoiding false assumptions of zoonotic risk. Full article

Primary pulmonary adenocarcinoma in dogs is rare, and effective systemic therapies remain limited. To evaluate the molecular basis of potential precision oncology approaches, hotspot mutations in HER2, BRAF, KRAS, and PIK3CA were analyzed in 20 surgically resected canine pulmonary adenocarcinomas and three canine pulmonary adenocarcinoma cell lines. HER2 V659E and BRAF V595E mutations were each detected in 3/20 cases (15%), while KRAS G12V was detected in 1/20 cases (5%). No PIK3CA hotspot mutations were identified. The BRAF V595E mutation was additionally detected in the AZACL2 cell line. Functional analysis demonstrated increased sensitivity of AZACL2 cells to the BRAF inhibitor dabrafenib and MEK inhibitors including trametinib, compared with BRAF wild-type cell lines. These findings support MAPK pathway dependency in BRAF-mutant canine pulmonary adenocarcinoma. The mutation spectrum was broadly consistent with previous reports, suggesting a conserved molecular landscape across geographic regions. Collectively, these data identify BRAF and HER2 alterations as clinically relevant candidates for molecular diagnostics and targeted therapy in canine pulmonary adenocarcinoma. Full article

Background: Non-pharmaceutical interventions during the COVID-19 pandemic altered respiratory pathogen circulation, and a bacterial rebound followed once restrictions were lifted. We describe pediatric pneumococcal respiratory infections and their bacterial co-detections in the immediate post-pandemic period. Methods: We retrospectively analyzed respiratory specimens from children aged 0–18 years tested with a multiplex real-time PCR panel (Allplex Respiratory Panel, Seegene, Seoul, South Korea; seven bacterial pathogens) restricted to this predefined bacterial spectrum at a tertiary pediatric hospital in Galați, Romania, during 2022 and 2023. A total of 2546 panels were performed in 2022 and 3250 in 2023, allowing pneumococcal positivity rates to be calculated. Proportions are reported with Wilson 95% confidence intervals; associations were tested with Pearson chi-square and Fisher exact tests in SPSS v.23. Results: Children with detected Streptococcus pneumoniae rose from 100 to 415, corresponding to a rise in pneumococcal positivity from 3.9% (100/2546) to 12.8% (415/3250). Among the positive children, pneumococcus–Haemophilus influenzae co-detection increased from 33.0% to 45.1% (odds ratio 1.63, 95% CI 1.02–2.61; p = 0.029), while pneumococcus alone fell from 60.0% to 50.1%. Boys, urban residence, and early childhood predominated, and community-acquired pneumonia diagnoses rose from 61 to 214. No profile–demographic association reached significance (panel–residence 2023, p = 0.063). Conclusions: A post-pandemic rise in pediatric pneumococcal detections and increasing H. influenzae co-detection were observed, supporting syndromic multiplex PCR in rapid pediatric diagnostics and antimicrobial stewardship. Full article

A recent generalized Bilal (G-Bilal) model demonstrates remarkable flexibility in capturing a wide spectrum of failure behaviors, including monotonic and non-monotonic (upside-down bathtub-shaped) hazard patterns, outperforming several existing models such as the Weibull, gamma, and exponential families. This paper develops several inferential frameworks for different G-Bilal parameters of life using samples gathered by improved Type-II adaptive progressive censoring. This enhanced design ensures optimal control of test duration while maintaining high inferential precision. Expressions for the model parameters, reliability, and hazard rate functions are derived, followed by the development of maximum likelihood (ML) and maximum product of spacing (MPS) estimators with their asymptotic confidence intervals using the observed Fisher information with the delta approach. Furthermore, Bayesian estimators and two associated credible intervals are proposed under independent gamma priors and computed through Markov iterations, with both ML and MPS posteriors considered. Extensive Monte Carlo experiments confirm the consistency, robustness, and precision of the proposed estimators, with Bayesian spacing-based methods exhibiting superior accuracy and coverage. The model’s practical potential is further verified through two real applications: one involving mechanical system lifetimes and another analyzing health insurance premium data, representing physical and actuarial domains, respectively. Using the introduced censoring, the proposed G-Bilal model outperforms all competing models in terms of goodness-of-fit and reliability estimates in both cases. The results underscore the G-Bilal model’s adaptability, computational stability, and empirical superiority, establishing it as a powerful tool for modern reliability and actuarial risk assessments. Full article

Background and Objectives: Temporomandibular disorders (TMDs) encompass a broad spectrum of functional and structural abnormalities of the temporomandibular joint (TMJ). Conventional diagnostic tools, although essential, often fail to capture the underlying biochemical mechanisms driving disease progression. Synovial fluid (SF), by virtue of its direct proximity to intra-articular tissues, represents an accessible biological matrix for identifying molecular signatures of inflammation, cartilage degradation, lubrication failure, oxidative stress, and angiogenic activation. The objective of this review is to synthesize current evidence on SF proteomics in TMD and evaluate its potential translational value in precision medicine. Materials and Methods: A narrative review of the literature was conducted on PubMed to identify human studies focused on SF proteomic and biochemical biomarkers in TMD. Eligible studies included original research articles assessing SF composition in relation to specific TMJ pathologies, diagnostic categories, or clinical phenotypes. Extracted data included study design, sample characteristics, analytic methodology, biomarkers investigated, and key findings. Google Gemini (Google LLC, Mountain View, CA, USA) was used as an AI-assisted tool to support language editing and manuscript writing during the preparation of this article. The use of this tool was limited to linguistic refinement; all scientific content, data interpretation, and conclusions were formulated and verified by the authors. Results: Across the analyzed studies, TMD phenotypes—particularly disc displacement with or without reduction (DDwR, DDwoR) and osteoarthritis (OA)—were characterized by consistent alterations in cytokines (IL-1β, IL-6, IL-8, TNF-α), extracellular matrix (ECM) components (aggrecan, glycosaminoglycans (GAGs), decorin, MMP-2, MMP-9), lubrication molecules (lubricin/PRG4), oxidative stress mediators (myeloperoxidase (MPO), nitric oxide (NO), glutathione peroxidase (GPX)), adipokines (chemerin, resistin, adiponectin), and angiogenic factors (vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2)). Recent liquid chromatography–tandem mass spectrometry (LC–MS/MS) analyses further revealed phenotype-specific protein clusters and pathways related to inflammation, ferroptosis, hypoxia signaling, and proteoglycan metabolism. Conclusions: Current evidence suggests that SF proteomics and multi-analyte biomarker profiling offer a promising, hypothesis-generating approach for understanding the biological mechanisms underlying TMD. The integration of proteomic, metabolic, and inflammatory markers holds future potential for diagnostic panel development; however, prospective clinical validation is still required before SF-based molecular profiling can be implemented as a precision medicine tool in TMJ disorders. Full article

Background: Prolonged intermittent fasting is associated with metabolic and immune adaptation; however, the extent to which transcriptional immune responses translate into systemic inflammatory changes, and how these processes relate to autophagy, senescence-associated signaling, and inflammasome regulation, remains incompletely understood. Methods: This study represents a secondary integrative analysis of a previously characterized cohort of healthy young men undergoing Ramadan fasting. Longitudinal data across four time points (T1–T4) were re-analyzed, integrating targeted mRNA profiling of autophagy-, senescence-, and inflammasome-related genes with circulating cytokines and clinical parameters. Baseline-stratified regression and exploratory clustering were applied to assess inter-individual variability. Results: Fasting was associated with modest reductions in body weight (−1.78 ± 1.44 kg, FDR < 0.001) and BMI (−0.56 ± 0.47 kg/m², FDR < 0.001), without hemodynamic instability. Autophagy-related transcripts (ULK1, ATG5) were upregulated, while senescence markers showed divergent regulation (p53↑, p21↓). Inflammasome-related genes (NLRP3, IL1B) increased at the transcriptional level; however, circulating IL-1β and IL-6 remained stable and TNFα decreased (FDR < 0.001), indicating dissociation between transcriptional priming and systemic cytokine output. ΔNLRP3 was inversely associated with baseline expression (β = −1.88, R² = 0.31, p = 0.0056), suggesting baseline-dependent transcriptional responsiveness. Responses followed a continuous spectrum rather than discrete subtypes. Conclusions: Prolonged intermittent fasting is associated with coordinated immunometabolic remodeling characterized by transcriptional changes in autophagy-, senescence-, and inflammasome-related pathways, without systemic inflammatory escalation. Inflammasome-related responses appear baseline-dependent, suggesting graded immunological responsiveness rather than a uniform activation. These findings are hypothesis-generating and support the interpretation of fasting as a graded immunometabolic modulator rather than a uniform pro-inflammatory stimulus within the limitations of a secondary exploratory analysis. Full article

Background/Objectives: Opportunistic infections remain clinically important after kidney transplantation and may contribute to morbidity and graft dysfunction in pediatric recipients. Data regarding their timing, spectrum and clinical course in children remain limited. Methods: We retrospectively reviewed pediatric kidney transplant recipients followed at a single tertiary center between 2014 and 2024. Demographic and clinical characteristics, infection type, timing after transplantation, management and outcomes were recorded. Infection incidence was assessed at the patient level, whereas pathogen distribution and timing were analyzed per infection episode. Results: Twenty-seven pediatric kidney transplant recipients were included, with a mean follow-up of 5.6 years. Ten patients (37.0%) developed at least one clinically significant opportunistic infection, and one patient experienced two distinct episodes, resulting in 11 infection events. BK virus was the most frequent pathogen, followed by fungal infections and cytomegalovirus (CMV). Five episodes (45.5%) occurred within the first post-transplant year, whereas six (54.5%) occurred later during follow-up. Late infections included CMV, fungal infections, BK virus and West Nile virus. Most infections resolved after targeted management without persistent graft impairment; however, one patient developed biopsy-confirmed BK virus-associated nephropathy with sustained graft dysfunction. No infection-related mortality was observed. Conclusions: Clinically significant opportunistic infections occurred both early and late after pediatric kidney transplantation, with more than half of all infectious episodes developing beyond the first post-transplant year. Although overall outcomes were favorable, BK virus-associated nephropathy remained clinically relevant because of its impact on graft function. Full article

Introduction: Conjunctival and eyelid lesions encompass a broad spectrum of conditions, ranging from benign entities to malignant neoplasms, and may significantly impact ocular health and quality of life. Their occurrence is influenced by environmental exposure, demographic characteristics, and access to healthcare services. In public health settings, delayed diagnosis and limited access to specialized care may contribute to disease progression. Objective: To characterize the clinical and epidemiological profile of conjunctival and eyelid lesions in patients treated at a referral ophthalmology service within the Brazilian Unified Health System (SUS). Methods: This retrospective observational study reviewed medical records of patients diagnosed with conjunctival and/or eyelid lesions during ophthalmologic screening campaigns. Clinical and demographic variables were analyzed using descriptive statistics to assess prevalence and distribution patterns. Results: A total of 66 patients were included. Conjunctival involvement predominated (78.8%), with the nasal region being the most frequently affected location (62.1%). Pterygium was the most prevalent diagnosis (31.8%), followed by racial melanosis (15.2%) and melanocytic nevus (12.1%). No statistically significant differences were observed according to sex or lesion laterality. However, a significant association was identified between lesion type and anatomical location. Conclusions: Conjunctival and eyelid lesions in this population were predominantly benign and associated with demographic and environmental factors. These findings highlight the importance of structured screening strategies and early diagnosis to improve clinical outcomes and support public health policies aimed at reducing the burden of ocular disease within the SUS. Full article