Category X medicines are those which have such a high risk of causing foetal harm that they are contraindicated in pregnancy. When used in reproductive age women, risk management strategies are warranted to reduce unintended pregnancy exposure. To identify documentation of pregnancy risk management strategies for Category X medicines across Australian medicine information sources. The TGA Prescribing Medicines in Pregnancy Database (PMPD) was searched to identify Category X medicines licensed for indications relevant to reproductive age women. For each Category X medicine included in this evaluation, regulatory documents (Product Information [PI] and Consumer Medicine Information [CMI]) and corresponding monographs/chapters in clinical resources (Australian Medicines Handbook [AMH] and Therapeutic Guidelines [TG]) were reviewed for boxed warnings relating to pregnancy risks, pregnancy testing and contraception recommendations, and formal pregnancy prevention programs. Thirty-nine Category X medicines were retrieved through the TGA PMPD, 19 of which met the inclusion criteria. Boxed warnings documenting pregnancy risks were present for 47% (9/19) of medicines. Pregnancy testing and contraception recommendations appeared in most PIs and CMIs (89%, 17/19), as well as in 15 of 17 (88%) medicines listed in the AMH, but were only present for one of 12 (8%) medicines listed in the TG. Structured pregnancy prevention programs exist for only 16% (3/19) of medicines. Pregnancy risk management strategies for Category X medicines are inconsistently employed across Australian medicine information sources. Improving the quality and consistency of pregnancy risk management strategies is necessary to avoid harms from inadvertent exposure during pregnancy.
Point-of-care testing (POCT) has expanded rapidly across healthcare systems, increasing both program scale and operational complexity. However, quantitative benchmarking data describing how POCT programs are structured and supported across institutions remain limited. We conducted a cross-sectional survey to characterize POCT program support, including program scope, staffing, operational practices, governance, and challenges. The survey was distributed electronically through professional networks, and 93 institutional responses were analyzed. Descriptive analyses were performed, and derived metrics, including sites per point-of-care testing coordinator (POCC), were used to evaluate the relationship between program scale and staffing. POCT programs demonstrated substantial variability in scale, with wide ranges in the number of testing sites and operator populations. Adoption spanned multiple test categories, and many institutions reported use of multiple platforms for the same assays. Training, competency assessment, and quality management activities were primarily supported by laboratory staff and POCCs, with documentation frequently partially electronic. Median POCC staffing increased with program size; however, sites per POCC also increased significantly across program scale tiers (Kruskal-Wallis P < 0.001). Governance structures and operational responsibilities varied across institutions, and common challenges included staffing limitations, training and compliance burden, multisite coordination, and IT/connectivity constraints. POCT programs are expanding in scale and complexity, but workforce capacity and governance structures have not scaled proportionally. This mismatch creates a cumulative and multiplicative operational burden. These findings provide benchmarking data to inform scalable staffing models, governance strategies, and infrastructure development for sustainable POCT program management.
Angus-based heifers (F0; n = 72; 14 to 15 mo; initial body weight [BW] = 380.4 ± 50.56 kg) were ranked by BW, bred via artificial insemination (AI) with female-sexed semen, and assigned to receive a basal diet (CON; n = 36) or the basal diet plus a vitamin and mineral supplement (VTM; n = 36) with the total mixed ration. Treatments were applied from breeding through calving, after which cow-calf pairs (n = 14 CON; n = 17 VTM) received a common diet. A subset of F1 heifers (n = 7 CON; n = 9 VTM) were bred via AI with female-sexed semen and evaluated from breeding through d 250 of gestation when pregnant heifers were slaughtered. Nutrient balance and energy metabolism were measured each trimester via apparent total tract digestibility and indirect calorimetry. Blood samples were collected each trimester and at harvest for hormone/metabolite analysis. Data were analyzed using the MIXED procedure of SAS with repeated measures where appropriate, with treatment, time, and interaction included as fixed effects and animal as the experimental unit. In F1 heifers, digestibility of dry matter, organic matter, neutral detergent fiber, acid detergent fiber, and N was not influenced by treatment (P ≥ 0.21) but decreased (P ≤ 0.03) as gestation advanced. Fecal energy (FE) losses, heat production (HP) as a percentage of gross energy intake, and retained energy (RE) were not affected by treatment (P ≥ 0.52); however, FE and HP increased (P ≤ 0.03) while RE decreased (P = 0.01) with advancing gestation. Circulating insulin concentration was greater (P < 0.01) in VTM heifers, whereas glucose decreased (P < 0.01) and non-esterified fatty acids and blood urea nitrogen increased (P ≤ 0.01) as gestation progressed. Body weight was greater (P < 0.01) in VTM heifers and at slaughter, VTM heifers tended (P ≤ 0.10) to have heavier carcasses and greater ribeye area than CON. The F1 CON heifers had heavier spleens relative to BW (P = 0.04) whereas other organs did not differ (P ≥ 0.17). In F2 fetuses, CON tended to have heavier reproductive tracts and spleens (P ≤ 0.10) with no other differences in organ weights (P ≥ 0.13), whereas VTM fetuses had greater (P = 0.01) blood glucose concentration. These results indicate that prenatal micronutrient supplementation programs growth and metabolic function across generations, with minimal effects on organ mass. Advancing gestation reduced efficiency of energy and nitrogen use, reflecting nutrient partitioning shifts supporting fetal growth. This experiment explored how supplementing beef heifers with vitamins and minerals during pregnancy affects metabolic outcomes and development across two subsequent generations. Heifers (F0) were fed either a forage-based basal diet (CON) or the same diet plus the addition of a vitamin and mineral supplement (VTM), beginning at breeding and continuing through calving. Their female calves (F1) were evaluated through puberty, breeding, and gestation. Across gestation, all F1 heifers had reduced nutrient digestibility and energy retention, as well as increased markers of fat mobilization and protein breakdown. Heifers born to supplemented dams were heavier through 23 months of age, tended to have heavier carcasses with larger ribeye area, and had greater circulating insulin and insulin-like growth factor I. Fetuses (F2) were evaluated at slaughter at d 250 of gestation and those from supplemented granddams (F0) had greater blood glucose concentrations. While these metabolic improvements in the fetus were observed, differences in organ mass were minimal. These results highlight the potential long-term impacts of gestational supplementation to improve cow-calf productivity and underscore the importance of strategically feeding pregnant heifers to meet micronutrient demands throughout pregnancy.
Significant variability exists in the current literature of bracing research and outcome reporting, highlighting the need to standardize study design and reporting practices to ensure cross-study consistency and comparability. The purpose of this study is to develop updated consensus-based recommendations for designing, reporting, and publishing bracing research in pediatric patients with idiopathic scoliosis. An anonymous Delphi process and a final in-person meeting using the nominal group technique (NGT) established consensus-based guidelines among a multidisciplinary group of bracing experts. Three consecutive, anonymous Delphi rounds were administered to 30 multidisciplinary bracing experts invited to participate in this study. An 80% agreement threshold was set throughout the survey process and final in-person meeting. Items that did not reach consensus were refined to incorporate feedback and redistributed in subsequent rounds to improve consensus. Items that met consensus across all the rounds were simplified to remove redundant items to develop the final list of guidelines. Of the 30 experts invited to participate, response rates were 24 (80%), 25 (83%), and 23 (77%) across survey rounds and 22 participants in the final, in-person meeting. Expert consensus was reached on 121 items across 6 domains which were refined and consolidated into a final 28-item summary of consensus-based guidelines for research in bracing idiopathic scoliosis (Fig. 1). Detailed, consensus-based research guidelines for bracing treatment in patients with idiopathic scoliosis were successfully developed. It must be acknowledged that these best practice guidelines are for research purposes only and are not clinical recommendations.
The present study established a chloroplast genomic foundation for Verbenaceae phylogenetics and reveals natural selection as the primary force that governs codon usage evolution. Species within Verbenaceae family hold considerable medicinal, economic, and ornamental value, and play critical roles in maintaining ecosystem biodiversity. Despite these multifaceted applications, comprehensive studies on their chloroplast genome characteristics, codon usage patterns, and evolutionary dynamics remain limited. Here, we sequenced and assembled the complete chloroplast genomes of Verbena bonariensis, Glandularia tenera, and Verbena officinalis, and conducted comparative analyses with eight additional Verbenaceae species. All 11 species exhibited the typical quadripartite structure, with genome lengths ranging from 149,869 to 155,079 bp and GC contents varying between 38.23% and 39.25%. Collinearity analysis revealed highly conserved synteny across species. Phylogenetic reconstruction supported a close evolutionary affinity between Verbena and Glandularia. Codon usage bias analysis indicated a preference for A/U-ending codons, with each species exhibiting 29-30 codons with RSCU > 1. Effective number of codons (ENC) analysis suggested weak codon usage bias across all species. Simple sequence repeat (SSR) analysis identified 46-80 SSRs per species, predominantly mononucleotide repeats, primarily located in noncoding regions. ENC-GC3s, parity rule 2 (PR2), and neutrality analyses collectively indicated that natural selection is the predominant force shaping codon usage patterns. Selection pressure analysis further revealed pervasive strong purifying selection (Ka/Ks < 0.5) across most genes. Together, our findings provide an important genomic foundation for phylogenetic reconstruction, molecular evolution, and genetic resource utilization within Verbenaceae.
Inflammatory diseases represent a major global health burden, and current therapies frequently fail to achieve sustained control of inflammation or prevent progressive tissue damage. Cortistatin (CST), an endogenous neuropeptide structurally related to somatostatin, has emerged as a multifunctional regulator of neuroimmune and immunometabolic pathways. This scoping review was conducted in accordance with PRISMA-ScR guidelines and maps and synthesizes preclinical evidence on the biological roles and therapeutic potential of CST across experimental disease models. A comprehensive literature search identified 31 preclinical studies published between 2006 and 2025 that evaluated CST administration or cortistatin deficiency. Despite substantial heterogeneity in disease models, including neurodegenerative, autoimmune, cardiovascular, fibrotic, and musculoskeletal conditions, CST consistently demonstrated protective effects. Across studies, CST reduced pro-inflammatory cytokine production, attenuated tissue damage, and improved functional outcomes and survival. Mechanistically, CST modulated key inflammatory pathways such as NF-κB signaling and NLRP3 inflammasome activation, suppressed Th1 and Th17 responses, and promoted regulatory T cell expansion through interactions with somatostatin receptors, GHSR1a, and MrgX2. Emerging translational strategies, including peptide analogues, protease-activated prodrugs, and nanoparticle-based delivery systems, have improved pharmacokinetic stability and therapeutic efficacy in experimental models. Collectively, these findings establish cortistatin as a consistent endogenous regulator of neuroimmune responses across diverse experimental conditions, highlighting its potential as a promising therapeutic target for immunomodulation in complex inflammatory diseases.
Vagus nerve stimulation (VNS) is a neuromodulatory intervention with antiinflammatory and autonomic regulatory properties. Although its clinical applications have primarily been explored in neurological disorders, its potential role in pulmonary and respiratory outcomes across preclinical and clinical settings remains incompletely characterized and dispersed across different study domains. This scoping review aimed to map the available evidence on the effects of VNS on the pulmonary and respiratory systems, with particular emphasis on inflammatory and autonomic mechanisms. This scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Three reviewers systematically searched PubMed, Web of Science, and the Cochrane Library for studies published between January 2020 and February 2026. Original preclinical and clinical studies investigating invasive or noninvasive VNS and reporting pulmonary, respiratory physiology, autonomic, or inflammatory outcomes were included. A total of 159 records were identified, of which 12 studies met the inclusion criteria. The evidence base was predominantly preclinical. In animal studies, invasive cervical VNS was frequently associated with reductions in pulmonary inflammation, histopathological lung injury, and proinflammatory cytokine expression. Clinical studies were limited and heterogeneous, but generally indicated variable modulation of autonomic function, including changes in parasympathetic activity, as well as heterogeneous effects on systemic inflammatory markers and limited respiratory outcomes. Current evidence suggests that VNS may modulate pulmonary inflammatory responses in preclinical models. However, clinical evidence remains limited and heterogeneous, particularly regarding autonomic and respiratory outcomes. Well-designed clinical trials using standardized stimulation protocols and predefined respiratory end points are needed to clarify its therapeutic potential in respiratory disorders.
Diabetes prevalence is increasing in Thailand, creating growing demands on the health system. Understanding the spatial distribution of diabetes risk and its association with socioeconomic and healthcare system factors among the diabetes risk population is critical for designing targeted prevention and intervention strategies. We examined the distribution of diabetes risk groups across provinces in Thailand with reference to the spatial association between economic, social and public health service factors based on data from the Ministry of Public Health's Health Data Center (HDC) for the year 2021. The dataset included 22,491,934 individuals across the 76 provinces as well as social, economic and public health services. The methods included Local Indicators of Spatial Association (LISA), Ordinary Least Squares (OLS), Spatial Lag Model (SLM) and Spatial Error Model (SEM). Explanatory variables included average night-time light intensity, average monthly income, hospital-to-population ratio and proportion of the population with health insurance. Major clusters of High-High (HH) diabetes risk were identified by LISA mainly located in the North of Thailand. In all models, the direction and significance of the associations were consistent (p<0.001 for all variables investigated and p<0.01). R2=0.47. The SLM gave the best fit, capturing spatial spill-over effects. Higher night-time light intensity (coefficient = -85.70, p<0.05) and higher monthly income (coefficient = -0.079, p<0.001) were negatively associated with diabetes risk. These inverse relationships implied that greater urbanization and higher socio-economic standing may protect against diabetes risk, possibly through improved access to health infrastructure, improved health education and preventive services. Conversely, the higher hospital-to-population ratios (coefficient = 572.28, p<0.001) and the larger proportions of Civil Servant Medical Benefits Scheme (CSMBS) coverage (coefficient = 226.46, p<0.001) the higher diabetes risk. These counterintuitive findings likely reflect reverse causation, in which provinces with higher disease burden or poor health attract more resources of health care and have increased insurance coverage, a pattern consistent with healthcare service distribution responding to existing health needs rather than preventing occurrence of disease.
Type 2 diabetes mellitus (T2DM) increases susceptibility to sepsis-associated acute kidney injury (SA-AKI). While guidelines support chronic sodium-glucose cotransporter 2 (SGLT2) inhibitor use in T2DM, their efficacy and optimal intervention timing in acute sepsis remain unclear. We hypothesized that this efficacy is timing-dependent. To test this, we utilized a T2DM mouse model subjected to graded lipopolysaccharide (LPS) challenges as a clinically relevant surrogate for sepsis. Notably, to precisely capture the longitudinal and dynamic trajectory of renal function, we incorporated continuous real-time transcutaneous glomerular filtration rate (tGFR) monitoring. We evaluated the SGLT2 inhibitor dapagliflozin (DAPA) across three regimens representing distinct clinical scenarios: preventive (pre-LPS only, modeling prior chronic use), therapeutic (initiated post-LPS, modeling de novo intensive care initiation), and whole-course (continuous administration, modeling treatment continuation). Following LPS challenge, T2DM exacerbated renal dysfunction across all doses and impaired endogenous functional recovery. High-resolution real-time tGFR tracking and subsequent biomarker analyses revealed that the renoprotective effect of DAPA was dependent on the timing of intervention. In moderate endotoxemia, both therapeutic and whole-course regimens were superior to the preventive regimen. Compared to preventive administration alone, initiating or continuing treatment during the acute insult (therapeutic and whole-course regimens) more effectively preserved early glomerular filtration rate (GFR) trajectories, attenuated the rise in tubular injury markers, and promoted histological repair. Supported by dynamic renal function monitoring, this study demonstrates that DAPA provides significant renoprotection in a preclinical T2DM model of endotoxemia-associated acute kidney injury. This efficacy is closely associated with the timing of intervention, with greater protective effects observed when treatment is initiated during or maintained after the acute endotoxemic challenge. These preclinical findings suggest that intervention timing could be a key determinant of SGLT2 inhibitor efficacy, providing a scientific rationale for evaluating the prompt initiation or continuation of this therapy in diabetic patients presenting with acute sepsis.
Routine follow-up of lung cancer patients involves thoracic computed tomography (CT) scans every 3-6 months for 2 years and then annually up to 5 years. With increasing numbers of survivors, risk-stratified follow-up, tailoring surveillance to recurrence risk, may reduce unnecessary scans while maintaining high-quality follow-up. This study explored healthcare professionals' (HCPs) perceived barriers and facilitators to implement risk-stratified follow-up in lung cancer care. A qualitative study was performed, involving 14 semi-structured individual interviews with HCPs engaged in lung cancer care. Transcripts were analyzed using inductive thematic analysis, with codes subsequently organized according to the Grol and Wensing framework across six different levels: Innovation, Patient, Professional, Social context, Organization, and Economic and Political. Barriers and facilitators were identified across all levels. HCPs generally viewed risk-stratified follow-up as a promising approach to align care with individual patient risk. Facilitators included its personalized nature, potential to reduce unnecessary imaging, and improve follow-up efficiency. However, HCPs emphasized the need for robust evidence demonstrating safety, effectiveness, and resource optimization. Patient-level barriers included varying follow-up preferences and limited health literacy, while tailored communication was seen as a facilitator. Organizational barriers such as staffing shortages and unclear role delineation were frequently mentioned. Integration into care pathways and interprofessional collaboration were identified as facilitators to address these challenges. Concerns about reduced clinical autonomy and patient safety were also expressed. Financial constraints at the economic and political level were reported to potentially hinder implementation. HCPs are generally receptive to evidence-based risk-stratified follow-up. Successful implementation requires evidence of effectiveness, integration into care pathways, clear roles, and aligned reimbursement.
Cardio-oncology has emerged as a pivotal discipline aimed at preserving cardiovascular health in patients undergoing contemporary cancer therapies. Despite growing awareness of treatment-related cardiac injury, the evidence base supporting preventive strategies and standardized safety assessment remains fragmented. This review critically appraises randomized controlled trials evaluating pharmacological and non-pharmacological interventions for the prevention of cancer therapy-related cardiac dysfunction. In parallel, we examine how cardiovascular events are monitored, defined, and reported in major oncology trials, with particular emphasis on patient selection criteria and the use of structured surveillance protocols. Across drug classes repurposed from heart failure (HF) prevention and treatment, including neurohormonal antagonists, angiotensin receptor-neprilysin inhibition, lipid-lowering therapies, as well as exercise-based interventions, randomized evidence has demonstrated modest and inconsistent benefits. Reported effects are largely confined to subclinical alterations, such as changes in left ventricular systolic function, myocardial deformation parameters, or circulating cardiac biomarkers. By contrast, convincing reductions in clinically meaningful outcomes, including overt HF, treatment interruption, or cardiovascular mortality, remain limited. Concurrently, oncology trials frequently exhibit heterogeneous cardiovascular event definitions, incomplete safety reporting, and systematic exclusion of patients with pre-existing cardiac disease, thereby constraining external validity and obscuring the true burden of cardiotoxicity and competing cardiovascular risks. Advancing the field will require a paradigm shift toward individualized, risk-enriched prevention strategies anchored in clinically relevant endpoints. Broader inclusion of patients with stable cardiovascular comorbidities, managed under structured specialist supervision, alongside standardized frameworks for cardiovascular safety monitoring and reporting, is essential. Emerging artificial intelligence, as enabled tools applied to cardiac imaging, electrocardiography, and remote monitoring offer a promising opportunity to harmonize early detection of cardiotoxicity across trial sites and refine phenotyping of treatment-related cardiac injury. Integrating these elements into future trial design will be critical to ensure that therapeutic progress in oncology is not undermined by preventable cardiovascular harm.
Peer networks may influence early psychiatric vulnerability, both through direct exposure to peers' mental disorders and via peers' genetic predispositions. Clarifying these peer influences could inform preventive strategies aiming to improve adolescent mental health. To determine whether adolescents' exposure to peers' diagnosed mental disorders or genetic predispositions is associated with subsequent risk of mental disorders and whether these associations differ across disorders or peer network contexts. Nationwide register-based cohort study including Finnish residents born between 1985 and 2000. Cohort members were assigned to 4 peer network contexts: lower secondary school, upper secondary school, postal code area, and 1000-m square. Follow-up extended from age 17 years until first mental disorder diagnosis, emigration, death, or December 31, 2023. Study data were analyzed from October 2025 to March 2026. (1) Peers' family-based genetic risk scores (FGRS) for mental disorders, estimated from diagnoses in first- through fifth-degree relatives and (2) peers' own diagnoses of mental disorders. Time to an incident diagnosis of the disorder after age 17 years. Associations were estimated using Cox proportional hazards models adjusted for sex, birth year, proband FGRS, parental education and income level, and peer network size. Of 604 819 cohort members (mean [SD] age, 17 [0] years; 303 967 male [50.3%]), 234 117 received a mental disorder diagnosis over a median (IQR) follow-up of 11.7 (7.5-16.5) years. Peer FGRS was associated with subsequent risk of the same disorder across disorders and peer networks, with the greatest associations for externalizing disorders in upper secondary school (hazard ratio [HR], 1.34; 95% CI, 1.29-1.38). In contrast, peer diagnoses showed the strongest associations for internalizing disorders in upper secondary school (HR, 1.17; 95% CI, 1.15-1.18). Cross-disorder associations were also observed, with peer FGRS for externalizing disorders associated with proband internalizing outcomes, and vice versa. However, whereas peer internalizing diagnoses were associated with both proband internalizing and externalizing outcomes, associations between peer externalizing diagnoses and proband internalizing outcomes were substantially weaker than those with proband externalizing outcomes. Findings of this cohort study suggest that peer environments, particularly in upper secondary school settings, are associated with mental health trajectories. More research is needed to elucidate the mechanisms underlying these findings.
The Survey of Reading Strategies (SORS) is widely used to assess English-as-a-second-language (ESL) students' metacognitive regulation of reading across three strategy dimensions (Global, Problem-Solving, Support), yet this three-factor structure has rarely undergone confirmatory validation. This study introduces HiLoLev, a theory-driven two-factor measurement reconceptualisation that distinguishes higher-level integrative/monitoring strategies from lower-level decoding/support strategies. Using confirmatory factor analysis (CFA) on data from 554 Swedish upper-secondary ESL students, legacy three-factor specifications (oblique, higher-order) were contrasted with the proposed theory-driven HiLoLev model based on SORS items. The original structures showed poor fit with high interfactor correlations and substantial cross-loadings; by contrast, an 11-item HiLoLev model fit well (RMSEA = 0.051, SRMR = 0.045) and offered clearer interpretability. While the full SORS remains pedagogically useful, its subscales should not be assumed to represent stable latent constructs for inferential analyses. For research applications (e.g., regression models, mediation analyses, or group comparisons), confirm the structure in-sample via CFA or consider using the 11-item HiLoLev model as a compact, cognitively grounded latent specification of SORS items.
Intensive swine production stressors induce stress responses that compromise welfare and health, positioning behavior as a critical welfare indicator. Although antibiotics traditionally improve performance, antimicrobial resistance concerns have driven the search for alternatives. This systematic review evaluated the influence of zootechnical additives, used as alternatives to antibiotic growth promoters (AGP), on pig behavior. Following the PICO framework (pigs, antimicrobial alternatives, AGP, behavioral responses), three databases (Scopus, PubMed, Web of Science) were searched. Out of 1,893 identified articles, seven met the inclusion criteria, highlighting the scarcity of standardized behavioral research in this field. Extracted variables included biting frequency, posture (lying/standing/sitting), exploration, agonistic behavior, object interaction, reactivity, stereotypies, and vocalizations. The limited study number and heterogeneous assessment methods restricted direct comparisons between additives. While organic acids showed non-significant effects, probiotics improved exploration and activity in weaned piglets, improved human-animal relationships in sows, and reduced stress reactivity in offspring. L-glutamine increased standing time and novel object exploration in weaned piglets. Regarding phytogenics, Moringa oleifera reduced belly nosing, while Passiflora incarnata decreased aggression and biting in weaned piglets. In conclusion, feed additives can positively modulate pigs behavioral responses; however, these findings stem from limited data and require cautious interpretation. These findings highlight the potential of specific feed additives to mitigate stress-related behaviors in pigs, while emphasizing the urgent need for standardized ethological protocols to strengthen behavioral evidence across production phases.
Methylphenidate may reduce suicide risk among patients with attention-deficit hyperactivity disorder. Several studies have noted that the association between methylphenidate use and suicidality is weakening. Data were collected from Taiwan's National Health Insurance Research Database to assess the association between methylphenidate exposure and suicide attempt risk across two exposure periods (main analysis: 2001-2002; duplication analysis: 2004-2005). We compared suicide attempt risk between patients who initiated methylphenidate treatment and those with no recorded psychiatric treatment or methylphenidate exposure during the same period. In both the main and duplication analyses, patients receiving methylphenidate exhibited a higher subsequent risk of suicide attempts than unexposed individuals. A duration-response pattern was observed in both cohorts: the hazard ratio of suicide attempts declined with longer cumulative methylphenidate use, from 1.60/1.84 for < 30 days to 1.45/1.65 for ≥ 180 days. Because hazard ratios were closely aligned across 2001-2002 and 2004-2005, the association of methylphenidate with reduced suicide attempt risk did not appear to decrease over time. Longer use of methylphenidate was associated with a lower risk of subsequent suicide attempts among patients in Taiwan receiving methylphenidate. The beneficial effect of methylphenidate on suicide risk remained consistent over time.
Quantitative polymerase chain reaction (qPCR) is an indispensable tool in clinical biochemistry laboratories for gene expression and copy number variation (CNV) analyses. However, the interpretation of qPCR data including normalization, rigorous statistical testing, and professional visualization typically requires advanced bioinformatics expertise. This study aimed to develop a user-friendly, web-based platform that integrates robust statistical frameworks and quality control modules for streamlined and standardized qPCR data evaluation. GeneQuantify is freely accessible at https://GeneQuantify.streamlit.app/ and its source code is openly available at https://github.com/burhanettiny/GeneQuantify (GPL-3.0 license). GeneQuantify, a web-based application developed using Python and Streamlit, allows for the input of target and reference gene Cq values via manual entry or direct import from spreadsheet software or standardized RDML/RDES file formats. The platform automatically calculates ΔCq, ΔΔCq, and relative expression levels using the 2^(-ΔΔCq) method. Integrated features include multi-reference gene normalization (geNorm), automated outlier detection (Grubbs' test or Interquartile Range), and amplification efficiency correction (Pfaffl model). ΔCt values are subjected to normality (Shapiro-Wilk) and variance homogeneity (Levene's) testing to ensure statistical validity. The platform features an automated statistical decision pipeline (Shapiro-Wilk → Levene → t/Welch/Mann-Whitney/ANOVA/Kruskal-Wallis) with Bonferroni and Benjamini-Hochberg FDR corrections. A six-language interface (Turkish, English, German, French, Spanish, and Arabic) ensures international accessibility. Platform accuracy was validated against manual Excel-based calculations across seven predefined test scenarios, yielding consistent results in all cases. GeneQuantify provides a highly accessible, integrated qPCR analysis environment that consolidates automated calculations, quality control, statistical decision-making, and visualization. By aligning with MIQE guidelines and offering RQ-based automated statistical selection, the platform enhances reproducibility, transparency, and workflow efficiency in molecular research, clinical biochemistry, and educational settings.
Periodontitis is a chronic inflammatory disease affecting more than 1 billion people worldwide and leading to irreversible alveolar bone loss. Although salivary biomarkers are potentially non-invasive diagnostic targets, the longitudinal changes in osteocalcin (a marker of bone turnover) following periodontal therapy have been poorly described across levels of disease progression. In this prospective longitudinal study, a new multimodal method combining salivary biomarker analysis and Cone-Beam Computed Tomography (CBCT) was employed. A total of 100 patients (25 systemically healthy controls and 75 patients with periodontitis, stratified into Stages I, II, or III according to the World Workshop 2017 classification) received non-surgical periodontal therapy (NSPT). Salivary osteocalcin and clinical parameters (PPD, CAL, PI) were evaluated at baseline, 3 months, and 6 months. The sample size was estimated by G*Power software to achieve reliable power (> 90%) for detecting clinically important correlations. Baseline salivary osteocalcin levels showed a stage-dependent increase, with Stage III patients exhibiting concentrations 4.7-fold higher than those of healthy controls (28.5 ± 4.1 vs. 6.1 ± 1.9 ng/mL; p < 0.001). Temporal trajectory analysis revealed that the greatest therapeutic effect occurred within the first three months post-NSPT, with Stage III patients showing a 30.5% reduction in osteocalcin by six months. Strong correlations were observed between osteocalcin and CAL (r = 0.88, p < 0.001), with treatment-induced changes in osteocalcin significantly predicting clinical improvement (r = 0.75, p < 0.001). Salivary osteocalcin may be a valid, non-invasive biomarker of the metabolism of the periodontal bone. Early post-treatment red detection offers an important therapeutic window to optimize follow-up intervals based on treatment, and it can be incorporated into the personalized periodontal care workflow.
Checkpoint inhibitors, a class of immunotherapeutic agents, have transformed the oncology landscape by targeting immune checkpoints - regulatory pathways that modulate immune cell activity. By inhibiting proteins such as programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), these agents enhance the immune response against cancer cells. However, their efficacy comes at the cost of a range of immune-related adverse events (irAEs), including autoimmune reactions such as colitis, hepatitis, and endocrinopathies, which can range in severity from mild to life-threatening. We present the case of a 76-year-old man with cholangiocarcinoma on durvalumab, a PD-L1 inhibitor, who presented to the emergency department with shortness of breath, cough, and weakness. Workup led to the diagnosis of immune-related myasthenia gravis and a non-ST-elevation myocardial infarction (NSTEMI), the latter believed to be secondary to durvalumab-induced myocarditis. Initial treatment with intravenous immunoglobulin (IVIG) produced brief, partial symptomatic improvement but failed to resolve respiratory weakness or other bulbar manifestations. His condition deteriorated rapidly, progressing to respiratory failure within weeks of onset. Given the refractory nature of his disease course, he was subsequently treated with a repeat dose of IVIG and prednisone, then transferred to an outside facility for plasma exchange. Despite these interventions, the patient ultimately succumbed to his illness. This case highlights the rare but potentially fatal concurrent occurrence of immune-related myasthenia gravis and myocarditis as irAEs in a patient receiving durvalumab for cholangiocarcinoma. While checkpoint inhibitors have revolutionized outcomes across many solid tumor malignancies, this case underscores the diagnostic and management challenges posed by severe, refractory irAEs, and the importance of early recognition and aggressive treatment in this patient population.
Fetal fat accretion follows a spatiotemporal pattern. Fetuses who are small-for-gestational-age (SGA) demonstrate reduced fat accumulation, but whether specific body regions are disproportionately affected remains unclear. To characterize regional fat differences between SGA and appropriate-for-gestational-age (AGA), assess the modifying effects of SGA-onset timing and cerebroplacental ratio (CPR), and evaluate associations with neonatal morbidity. SGA pregnancies were prospectively recruited, and AGA controls retrospectively identified. SGA was defined as estimated fetal weight <10th centile and classified as early-onset (< 32 weeks) or late-onset (≥ 32 weeks), with CPR categorized as normal (≥ 5th centile) or abnormal (< 5th centile). Fetal Magnetic resonance imaging was performed at 3-T using T1-weighted two-point Dixon. Subcutaneous fat was segmented and subdivided into cheeks, trunk, upper and lower limbs. Fat signal fraction and fat mass were computed, with regional fat mass adjusted to global fat mass. Linear mixed models compared groups, and univariate logistic regression assessed associations with adverse outcomes. Sixty-four participants (35 SGA, 29 AGA) were included. Fat signal fraction was significantly lower in SGA across all regions (P<0.001). Upper limb adjusted fat mass was reduced in SGA (P=0.043), while other regions showed no differences (P≥0.08). Fat signal fraction and adjusted fat mass did not differ by SGA onset or CPR status. Lower fat signal fraction in all regions was associated with higher morbidity rates, whereas adjusted fat mass was not. SGA fetuses exhibit globally reduced lipid content with a disproportionate upper limb fat mass deficit, suggesting selective vulnerability of peripheral fat depots.
Stroke remains a major cause of disability and mortality globally, particularly among older adults in low- and middle-income countries. Integrating the 4Ms framework (What Matters, Medication, Mentation, and Mobility) into nursing-led preventive interventions offers a holistic, person-centered model for promoting healthy aging and mitigating stroke risk. This study evaluated the effectiveness of a nurse-led, age-friendly educational program, grounded in the 4Ms framework, in reducing stroke risk and enhancing health-promoting behaviors among older adults. A randomized controlled trial was conducted with 170 community-dwelling adults (≥ 60 years) attending outpatient clinics in Egypt. Participants were randomized to either a 4Ms-based educational intervention (two structured sessions and materials) or a control group receiving routine care. Outcomes were measured using the Revised Framingham Stroke Risk Profile, the Health-Promoting Lifestyle Profile II, and a stroke prevention practices questionnaire. Post-intervention, the intervention group demonstrated a significant reduction in 10-year stroke risk scores (p<.001) and significant improvements across all health-promoting behavior domains, especially physical activity, nutrition, and stress management (all p<.001). The percentage of participants with good stroke-prevention practices increased from 7.1% to 55.3%. Stroke risk was also inversely correlated with domains like health responsibility and stress management. The nurse-led educational program based on the 4Ms framework was associated with short-term improvements in reducing stroke risk indicators and improving health-promoting behaviors among older adults. Integration of age-friendly principles into preventive nursing care may offer a feasible and holistic approach for supporting healthy ageing in low-resource settings. Longer-term studies remain necessary.Trial RegistrationPan African Clinical Trials Registry (PACTR), registration number PACTR202606898663018. Registration was completed retrospectively.