Medicine and Pharmacology

Abstract: Background and Objectives: Hypothyroidism can alter lipid metabolism, vascular resistance, body composition, and myocardial function. Yet the cardiovascular risk engines used in routine practice were developed in general populations and do not include thyroid status. This review examines what contemporary risk models capture, what they omit, and how thyroid dysfunction should influence interpretation without being treated as an unvalidated numerical correction. Materials and Methods: A focused narrative search of PubMed was performed for publications from January 2014 through 6 September 2026, supplemented by earlier landmark cohort studies, risk-model derivation papers, randomized trials, and professional guidelines. Evidence was organized around overt and subclinical hypothyroidism, traditional risk factors, observed cardiovascular events, and the design and validation of major risk equations. Results: SCORE2, SCORE2-OP, Framingham, QRISK3, and PREVENT differ in predicted outcomes, age ranges, geography, and required inputs; their percentages and categories are therefore not interchangeable. Thyroid status is absent from these engines. A prospective community cohort found that adding TSH produced little incremental discrimination beyond conventional scores, whereas cross-sectional studies sometimes found higher calculated risk in women with subclinical hypothyroidism. Individual-participant data suggest that excess coronary and heart-failure risk is concentrated at higher TSH levels, while a large 2025 pooled analysis found only small differences in conventional risk factors between subclinical thyroid dysfunction and euthyroidism. Levothyroxine improves lipids most clearly in overt hypothyroidism, but cardiovascular outcome benefit in older adults with mild subclinical disease remains unproven. Conclusions: Clinicians should use one validated, region- and age-appropriate cardiovascular model, confirm that the patient meets its intended-use criteria, and evaluate thyroid disease in parallel. Cross-model percentage comparisons should be avoided. Persistent TSH elevation, overt hormone deficiency, treatment status, frailty, and severe dyslipidemia belong in clinical judgment and follow-up, not in an improvised score multiplier.

Abstract: Non-dilated left ventricular cardiomyopathy (NDLVC) presents a unique clinical paradox: patients with nearly identical phenotypes can face radically different clinical outcomes. NDLVC has been recently recognized as a distinct dynamic phenotype within the spectrum of non-ischemic cardiomyopathies, linked by a high risk of life-threatening arrhythmias. Recent advances in genetics have overcome clinical phenotyping in prognostic accuracy. Specifically, gene-specific scores have been introduced to guide primary prevention ICD in high-risk gene carriers. On the other hand, while gene-elusive cases present a more favourable arrhythmic profile, their long-term clinical outcome is more challenging to predict. Despite advancements in therapeutic strategies, the heterogeneity of the disease represents an ongoing dilemma for risk stratification and long-term surveillance. This review offers a comprehensive analysis of NDLVC management in clinical practice, highlighting the profound prognostic divergence between genetic (both in actionable and VUS carriers) and gene elusive cohorts. By synthesizing current evidence, we aim to clarify how genotype-phenotype correlations influence clinical outcomes and to provide a framework for more personalized approaches in the follow-up and treatment of these distinct patient populations. Furthermore, we address the current lack of standardized guidelines specifically tailored to gene-elusive phenotypes.

Abstract: Intervertebral disc disorders (IVDD), spinal stenosis and spondylosis are the commonest degenerative spinal phenotypes and a leading source of pain and disability worldwide, yet no disease-modifying drugs exist; immune regulation is implicated, but causal evidence at immune-cell resolution is scarce. We performed cis-Mendelian randomization (MR) using single-cell cis-eQTL instruments from OneK1K (982 donors; 14 immune cell types; 8,733 independent eGenes) against genome-wide association data for the three phenotypes from FinnGen R13 and the Million Veteran Program (MVP), analysed independently, with Bayesian colocalisation and cross-cohort evidence tiering, followed by network, druggability, novelty and phenome-wide association (PheWAS) annotation. Significant MR exposures numbered 395, 291 and 134 (FinnGen) and 96, 99 and 51 (MVP) for stenosis, IVDD and spondylosis, with 96.8 - 100% cross-cohort direction concordance. Tiering nominated 145 gene - cell-type pairs covering 72 genes. GFPT1 was the only gene with top-tier evidence in all three phenotypes (consistent risk-increasing direction; its lead variant's 13 PheWAS associations were all musculoskeletal); METTL21B showed cell-type-dependent bidirectional effects; 51 genes (71%) had no prior spinal-disease association. Immune-cell-resolved, cross-cohort-tiered evidence nominates GFPT1 and METTL21B as candidate therapeutic targets for degenerative spinal diseases, delineating candidates for functional follow-up rather than constituting validation.

Abstract: Transcatheter tricuspid valve-in-valve replacement offers an alternative to high-risk redo surgery for failed tricuspid bioprostheses. We report a 36-year-old woman with severe right-heart failure, hepatic dysfunction, thrombocytopenia, and a mechanical mitral prosthesis after a previously abandoned transcatheter attempt. Redo implantation was performed under dexmedetomidine-ketamine sedation with spontaneous ventilation and a femoral nerve block. Transoesophageal echocardiography was avoided because of bleeding risk. Fluoroscopy and transthoracic echocardiography provided procedural guidance. Valve deployment was successful, the transvalvular gradient decreased and she was discharged on postoperative day 3, highlighting individualized management of competing haemorrhagic and thrombotic risks.

Abstract: The Geometro-Diffusion Theory (GDT) proposes that neural propagation generates a relational geometry whose differentiation and intrinsic accessibility contribute to consciousness. Here, we extend GDT from conservative diffusion to open cortical systems in which the propagated quantity can be created, amplified, removed, or exchanged with a reservoir. We compare conservative diffusion with linear Lerman–Ghosh propagation and bounded nonlinear logistic propagation in cat, macaque, and human cortical networks. Because conventional Euclidean distances confound response geometry with the large amplitude changes produced by nonconservative dynamics, we introduce cosine–chordal indices that separate directional differentiation from amplification, activation, and recruitment. Nonconservative propagation does not universally maximize geometric differentiation: conservative diffusion produces larger and more persistent differentiation in the cat and macaque networks, whereas logistic propagation provides substantially greater differentiation before a finite processing deadline in the human network. Nevertheless, the nonconservative maximum consistently emerges earlier. Community analyses show that nonconservative dynamics generate locally coherent but more strongly reconfiguring cortical hierarchies. They also diversify visual-to-prefrontal communication routes, increasing the repertoire of intermediate cortical regions while tending to recruit vertices of lower anatomical degree. Finally, we show that the Lerman–Ghosh solution is a uniformly rescaled communicability kernel and that the approximate logistic response is a bounded nonlinear transformation of communicability. These results suggest that coupling to a reservoir may benefit conscious information processing not by maximizing a single differentiation index, but by accelerating geometric access and expanding the repertoire of transient cortical organizations and communication routes available to the mechanisms postulated by GDT.

Abstract: Every nervous system must preserve sensitivity to change while reducing responses to constancy. We define this adaptive objective as sensory homeostasis: familiar information recedes while unexpected or biologically important events remain salient. Its disruption is particularly relevant to autism spectrum disorder (ASD), in which sensory abnormalities occur across multiple modalities. Large-scale sequencing studies have identified hundreds of ASD-risk genes spanning neuronal excitability, synaptic function, intracellular signaling, transcription, and chromatin regulation. Here, we ask whether the established functions of independently identified ASD-associated genes reconstruct a directional pathway through which genetic vulnerability to ASD could compromise sensory homeostasis. Beginning with a prespecified Autism Sequencing Consortium–derived set of 185 ASD-associated genes, and separately classifying complementary genetic and mechanistic evidence, we organize a bounded subset of genes into three functional levels: generation and spatial organization of intracellular Ca²⁺ signals; interpretation of those signals by electrical, biochemical, synaptic, and transcriptional decoders; and stabilization of selected responses through transcriptional and chromatin-regulatory mechanisms that establish cellular memory.

Abstract: Background/Objectives: Maternal-birth cohort studies are critical epidemiologic tools to assess patterns, breadth, and duration of immunity derived from influenza vaccines, natural infections, and maternal immunologic contributions. Historically, this study design has been important to the development of well-designed pediatric vaccines. We systematically reviewed international influenza maternal-birth cohort studies to discern commonalities and gaps in their approaches to evaluating influenza immune development. Methods: We performed a scoping review of published maternal-birth cohorts studying influenza virus infections and immunity. Principal themes included, a.) incidence rates and percentages of acute respiratory and influenza infections, b.) sample collection methods, c.) laboratory methods and diagnostic tests, d.) symptomatology and asymptomatic infections, e.) medically attended infections, f.) maternal and child vaccination status, g.) maternal samples and obstetric history, and h.) reported sources of cohort funding. Results: Nine cohorts met the inclusion criteria and were selected for review. Only two cohorts were conducted in countries classified as lower-middle income, and none were conducted in low-income countries. Syndromic definitions, statistical measures, specimen types, and laboratory techniques differed greatly across these cohorts. Most of these cohorts relied on governmental funding. Conclusions: The resource- and time-intensive information obtained from each of these cohorts independently contributes valuable knowledge to the study of influenza exposures and immunity. However, cross-cohort comparisons and analyses are challenged by methodologic variability. Scientific knowledge could be improved by including cohorts of infants at high risk of negative influenza outcomes, by purposeful standardization of core data element collection, timing, and procedures, by standardized analytic measurements, and coordinated reporting of results of scientific interest.

Abstract: Background: Preserving neurological function in multiple sclerosis (MS) requires understanding why inflammatory injury, systemic vulnerability, and functional capacity evolve differently across patients. Biological-aging measures offer complementary perspectives on this heterogeneity.Objective: To examine how cerebral, molecular, and systemic aging measures relate to one another in MS, distinguish directly demonstrated within-person findings from apparent cross-domain contrasts, and assess their implications for brain-health preservation and Gulf Cooperation Council (GCC) practice.Methods: This critical structured review combined five modular PubMed searches with an evidence cutoff of 5 September 2026 and targeted source verification. Source-directed, AI-assisted selection and charting distinguished adult clinical evidence from mechanistic, pediatric, non-MS, regional, and preprint findings. Independent duplicate screening and formal risk-of-bias assessment were not completed.Results: MRI studies consistently identify older-appearing brain structure at group level, with clinical associations varying by model, cohort, and comparator. Tissue-dependent epigenetic findings and systemic, telomere, and frailty measures suggest partly distinct dimensions of vulnerability. Direct paired evidence includes modest MRI–clinical-blood concordance, opposing exploratory treatment responses, and an MRI–immune comparison without improvement over brain age alone in its disability model. Independent assay cohorts cannot establish within-person discordance. Integrating these distinctions with reserve yields a testable framework for interpreting domain, injury–function, and temporal relationships. GCC cardiometabolic context and research infrastructure support regional evaluation and coordinated prevention, without establishing a distinct regional MS aging phenotype.Conclusions: The contribution of a multidimensional aging framework is to connect measured injury and vulnerability with preserved function and potentially actionable needs. Disease control, cardiometabolic care, rehabilitation, and support for cognition and participation are relevant now. Whether paired aging profiles improve prognosis or treatment decisions requires reproducibility, longitudinal validation, and demonstrated benefit beyond established assessment.

Abstract: Methylene blue is the active substance of an authorised medicinal product and is increasingly taken as a self-administered oral preparation. It is offered to final consumers in dosed form, mostly declared as a laboratory chemical, reagent or dye rather than as a food supplement. No health-based guidance value (HBGV) for oral intake has been established in any jurisdiction. Points of departure were derived from 2-year gavage bioassays: a no-observed-adverse-effect level (NOAEL) of 1.8 mg/kg body weight per day for oxidative erythrocyte injury, and benchmark dose lower confidence limits (BMDL) of 2.6 and 10.3 mg/kg body weight per day for pancreatic islet and small intestinal neoplasms. A survey of 63 products offered to final consumers in eight European Union (EU) member states found that only five stated an intake amount. Intakes estimated from these statements, co-marketed consumer literature, user reports and documented oral therapeutic regimens spanned 6 to 200 mg per day. Margins of exposure fell from 20.9 to 0.6 against the NOAEL and from 30.2 to 0.9 against the BMDL, so that neither the required margin of 100 nor that of 10,000 was attained in any scenario, including the lowest, which is a supplier's own recommendation. No presentation examined could deliver an amount within a provisional HBGV of 0.018 mg/kg body weight per day, or 1.26 mg per day for an adult (based on NOAEL with uncertainty factor of 100 and adult bodyweight of 70 kg).

Abstract: Background: Primary hyperparathyroidism (PHPT) is most commonly caused by a solitary parathyroid adenoma, whereas compressive symptoms from large adenomas are uncommon. This report describes an unusual presentation with dysphagia. Methods: A 66-year-old woman with one month of progressive dysphagia and approximately 10 kg of weight loss underwent gastroenterological and otorhinolaryngological assessment, contrast-enhanced computed tomography, ultrasonography, biochemical testing, and parathyroid hormone (PTH) washout. Results: Endoscopy and flexible fiberoptic examination did not identify a cause of dysphagia. CT demonstrated a 3.0 × 1.9 × 4.7 cm heterogeneous cervical mass extending toward the superior mediastinum and displacing adjacent structures. Total calcium was 3.02 mmol/L, ionized calcium 2.60 mmol/L, and serum PTH 365.1 pg/mL. PTH washout exceeded 3438 pg/mL. Surgical excision and histopathology confirmed a parathyroid adenoma. Postoperative PTH decreased to 58.4 pg/mL and dysphagia resolved completely. Conclusions: A large parathyroid adenoma should be considered in patients with unexplained dysphagia, particularly when hypercalcemia and elevated PTH are present.

Abstract: Background/Objectives: Juvenile-onset systemic lupus erythematosus (jSLE) is a multisystem disease requiring disease control, glucocorticoid minimization, and treat-to-target assessment. We characterized phenotype, treatment exposure, childhood lupus low disease activity state (cLLDAS), and outcomes. Methods: This retrospective cohort included 54 patients followed during 2020–2025. One patient who died 10 days after diagnosis contributed to baseline and cumulative analyses but not longitudinal or last-visit analyses (n=53); all survivors had ≥6 months of follow-up. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and Paediatric Rheumatology European Society (PReS)-endorsed cLLDAS were assessed; paired changes were analyzed with the Wilcoxon signed-rank test. Results: Forty-three patients (79.6%) were female; median age at diagnosis was 15.0 years and median follow-up among survivors was 34.6 months. Cumulative hematologic and mucocutaneous involvement occurred in 64.8% and 61.1%, respectively. Biopsy-proven lupus nephritis occurred in 29.6%, with class IV in 13/16 cases (81.3%). Hydroxychloroquine was used in 53/54 (98.1%), and oral prednisolone in 46/54 (85.2%) for a median 17.5 months. Median SLEDAI-2K decreased from 8.0 to 4.0 (p< 0.001); anti-double-stranded DNA antibody (anti-dsDNA), complement C3, and spot urine protein-to-creatinine ratio improved significantly. At last follow-up, 29/53 (54.7%) fulfilled cLLDAS. Flare, infection-related hospitalization, intensive care unit (ICU) admission, and mortality occurred in 22.2%, 20.4%, 5.6%, and 1.9%, respectively. Conclusions: Disease activity and serological and renal markers improved, and just over half achieved cLLDAS, although residual disease activity and infection-related morbidity remained relevant.

Abstract: Arterial spin labelling (ASL) MRI provides a noninvasive measure of cerebral perfusion, raising the possibility of distinguishing Parkinson's disease (PD) from atypical parkinsonian syndromes (corticobasal syndrome, multiple system atrophy, progressive supranuclear palsy) and of separating the associated cognitive disorders, PD dementia and dementia with Lewy bodies (DLB), from Alzheimer's disease (AD). Whether perfusion can make either distinction in an individual patient has not been established. We conducted a scoping review reported in accordance with PRISMA-ScR, searching PubMed to 17 July 2026 (968 records, 33 studies included), and mapped the cohort-level diagnostic evidence available for each contrast. The review was restricted to pseudo-continuous ASL (pCASL), the consensus-recommended implementation for clinical use. For every study we charted acquisition parameters (post-labelling delay scheme, field strength), processing pipelines, the perfusion measures reported (absolute and normalised cerebral blood flow, arterial transit time), and any diagnostic accuracy metric, recording absence of reporting as such, and assessed risk of bias and applicability against criteria tailored to the review question. Four thresholds for single-patient use were fixed in writing before any study was counted, then applied descriptively rather than as eligibility criteria. Direct comparison against atypical parkinsonian syndromes was near-absent: one study addressed corticobasal syndrome (median AUC 0.787 across regions), none addressed multiple system atrophy or progressive supranuclear palsy, and PSP patients appeared only within a pooled parkinsonism-plus group. Evidence on the cognitive contrasts was more substantial, with DLB separating from AD at both the dementia and prodromal stages, reaching an arterial transit time AUC of 0.861. No study reported external validation in an independent cohort, and no contrast met the prespecified thresholds. Answering the question requires cohorts recruited consecutively from patients in whom the diagnosis is genuinely uncertain, multi-delay acquisition, thresholds specified in advance, and validation outside the derivation cohort, with PD against PSP and PD against corticobasal syndrome the highest priority.

Abstract: Background: This study evaluated the effects, safety, and tolerability of adjunctive brexpiprazole in adult patients with Major Depressive Disorder (MDD) who experienced an inadequate response to antidepressant monotherapy. Methods: This 12-week, multicenter, naturalistic, prospective observational study enrolled 60 adults with MDD and inadequate response to two or more antidepressant treatments who were prescribed adjunctive brexpiprazole. Outcomes in depressive symptoms, anxiety symptoms, illness severity, psychosocial functioning, and quality of life were assessed using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Clinical Global Impressions–Severity (CGI-S), Clinical Global Impressions–Improvement (CGI-I), Sheehan Disability Scale (SDS), and World Health Organization Quality of Life–Brief Version (WHOQOL-BREF). Results: Fifty participants completed the week 12 assessment. Mean PHQ-9 scores decreased from 16.68 ± 5.64 at baseline to 11.50 ± 7.30 at week 12 (p < 0.001), and mean GAD-7 scores decreased from 13.32 ± 4.98 to 9.80 ± 5.63 (p < 0.001). At week 12, PHQ-9 response and remission rates were 38.0% and 22.0%, respectively; corresponding GAD-7 rates were 34.0% and 14.0%. Mean CGI-S scores decreased from 5.00 ± 1.16 to 3.52 ± 1.79 (p < 0.001); the mean week 12 CGI-I score was 2.44 ± 1.22. Mean overall SDS scores decreased from 16.00 ± 7.27 to 11.44 ± 8.36 (p < 0.001), with improvements across all domains. Conclusions: In clinical practice, adjunctive brexpiprazole was associated with early improvement in depressive and anxiety symptoms, illness severity, psychosocial functioning, and quality-of-life domains.

Abstract: Sacituzumab govitecan-hziy (SG) is a Trop-2-directed antibody-drug conjugate (ADC) built from a humanized anti-Trop-2 immunoglobulin G1 (hRS7), a moderately hydrolyzable CL2A carbonate linker, and the topoisomerase I poison SN-38, the active metabolite of irinotecan. SG received accelerated approval from the U.S. Food and Drug Administration in April 2021 for locally advanced or metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint blockade, on the strength of the single-arm TROPHY-U-01 trial. In October 2024, following the failure of the confirmatory TROPiCS-04 trial to demonstrate an overall-survival benefit, the urothelial indication was voluntarily withdrawn, while indications in breast cancer remain in force. This review sets aside the clinical narrative that has been extensively covered elsewhere and instead reconstructs the ligand-optimization logic of SG from a bioorganic and medicinal chemistry standpoint: the structural biology of the Trop-2 ectodomain and the epitope engaged by hRS7; the structure-activity relationships that govern the camptothecin pharmacophore and dictate why SN-38, rather than camptothecin or irinotecan itself, was selected as payload; the rational design history of the CL2A linker, including its site of attachment on the SN-38 lactone, its deliberately intermediate hydrolytic stability, and the resulting drug-to-antibody ratio of approximately 7.6; and the physicochemical basis of the bystander cytotoxic effect. It then surveys the rapidly growing cheminformatic and computational toolkit -- molecular docking, molecular dynamics, quantitative structure-activity relationship and machine-learning models for drug-to-antibody ratio and payload selection, epitope/paratope prediction, and generative linker design -- that is beginning to formalize what was historically an empirical, iterative medicinal chemistry process. Finally, the review integrates pharmacogenomic (UGT1A1) and structural resistance data (TOP1 E418K, TACSTD2 T256R) to argue that the next generation of Trop-2 ADCs, in urothelial cancer and beyond, will depend less on iterative linker tinkering and more on structure- and data-guided co-optimization of antibody epitope, linker chemistry, and payload pharmacophore.

Abstract:

Strains of Campylobacter jejuni are known to produce two distinct diarrheal manifestations in humans: watery, cholera-like diarrhea and bloody, inflammatory diarrhea. Although the inflammatory form has been extensively studied, the mechanisms underlying watery manifestations remain poorly defined, largely due to the limitations of existing animal models. Using a neonatal piglet model, which closely mimics human gastrointestinal physiology, this study characterizes the temporal development of lesions associated with watery diarrhea induced by C. jejuni strain S3 and identifies proteins potentially involved in its pathogenesis. Clinical signs of self-limiting watery diarrhea appeared within 24 h post-infection, peaking at 48 h and largely resolving by 72 h. Gross pathology revealed significant fluid accumulation in the jejunum and colon, whereas histological assessment showed mild villus atrophy and minimal inflammation. Transmission electron microscopy demonstrated marked destruction of colonic microvilli at 24-48 h, followed by evidence of regeneration by 72 h, consistent with transient disruption of fluid absorption. Proteomic analysis of intestinal fluid at 72 h post-infection identified 180 C. jejuni proteins, including three prophage (CJIE4)-encoded proteins predominantly associated with watery diarrheal strains. Together, these findings are consistent with a model in which C. jejuni watery diarrhea results from the combined effects of increased jejunal fluid secretion and transient loss of colonic absorptive capacity. This study provides new insights into the secretory pathogenesis of C. jejuni and highlights phage-derived elements as potential mediators of disease phenotypes.

Abstract: The recently proposed Bedside-to-Outside model aims to bridge inpatient efficacy and free-living effectiveness trials in human nutrition research. Its translational ambition is laudable, yet its core premise – that changes in body mass can be used to calculate energy intake with sufficient precision – rests on problematic assumptions. First, the cited correlation between mass change and energy intake is tautological, not independently validating. Second, reliance on the Wishnofsky rule ignores diet-dependent variation in tissue composition, glycogen, and water. Third, recent analytical work has exposed internal logical inconsistencies in the energy balance model (EBM), while the mass balance model (MBM) delivers superior predictive accuracy by tracking macronutrient mass directly. Finally, omission of hormonal data that reportedly track mass intake more closely than energy intake further weakens the evidentiary foundation. True triangulation requires independent anchors; the present formulation risks circularity by relying solely on EBM assumptions. Six concrete modifications are proposed: (1) inclusion of mass-based metrics as co-primary outcomes; (2) pre-specification and competitive testing of both EBM and MBM predictions; (3) routine quantification of uncertainty propagation; (4) mandatory reporting of hormonal and appetite data; (5) use of MBM predictions as independent validation anchors; and (6) transparent reporting standards for all measured variables. Implemented, these changes would convert the Bedside-to-Outside model from a framework that assumes the EBM into a rigorous test of competing paradigms.

Abstract: Background: The acyclic monoterpene β-myrcene (CAS No. 123-35-3) is a food flavoring classified by the International Agency for Research on Cancer (IARC) as “possibly carcinogenic to humans” (Group 2B) based on neoplastic findings in rodents. Its toxicological relevance is closely tied to its metabolic fate: CYP-mediated epoxidation yields reactive intermediates that are rapidly detoxified to diols, and the weight of evidence supports a non-genotoxic, threshold mode of action. This study therefore combined this metabolic understanding with benchmark dose-response (BMD) modeling to derive a health-based guidance value (HBGV). Methods: Tumor-incidence data from the two-year National Toxicology Program (NTP) gavage studies in rats and mice were modeled with BMDS Online version 25.1 from US EPA, following international guidelines. A benchmark response (BMR) of 10% extra risk and a 95% lower confidence limit were applied. Models were evaluated by goodness of fit and Akaike information criterion (AIC). Results: The BMDL₁₀ of 25.4 mg/kg b.w./day for hepatocellular adenoma (including multiple) in male mice was selected as the point of departure (POD). Applying an uncertainty factor of 100 yielded an acceptable daily intake (ADI) of 0.25 mg/kg b.w./day, equivalent to 250 µg/kg b.w./day. At estimated flavoring intakes of 3–138 µg/kg b.w./day, the ADI-to-intake ratio ranged from approximately 83 to 1.8. Conclusion: Thus, an ADI of 0.25 mg/kg b.w./day can be proposed for β-myrcene. Estimated flavoring intakes remain below this value; however, the margin at the upper exposure estimate is limited to approximately 1.8.

Abstract: These days, chemical descriptors such as molecular weight (MW) and logarithmic partition coefficient (logP) for the prediction of exposure (AUC) of drugs for drug-drug interaction (DDI) studies is drawing attention. These methods allow efficient screening tool for DDI studies and are also time and cost-effective. The objective of this study is to develop a simple quantitative method to predict AUC of P-glycoproteins (P-gP) and non-P-gp drugs following interaction studies with inhibitor(s). The AUC of a drug following inhibition was predicted by using the ratio of the MW of two interacting drugs as following. Predicted AUC = AUC of a drug before inhibition/ratio of the MW. The impact of several strong or moderate inhibitors was evaluated on 76 P-gP and non-P-gp drugs. There were 119 and 38 observations(data points) for p-gp and non-P-gp drugs, respectively. The total number of observations (data points) was 157. Out of 157 observations, 141 (89.8%), 129 (82.2%), and 85 (54.1%) observations were within 0.5-2-fold, 0.5-1.5-fold, and 0.7-1.3-fold prediction error, respectively. The average absolute fold-error (AFE) was 0.95. Overall, the predictive power of the proposed method for DDI following the administration of inhibiters was found to be a suitable and to a great extent accurate approach when compared with the observed clinical data. The proposed method does not require extensive data such as in-vitro data, many physical or chemical properties or extensive physiological parameters. The proposed method is suitable for subsequent clinical trials or in some cases may be used in clinical settings.

Abstract: Breast histopathology classification is commonly evaluated at the image level even though diagnosis and clinical decisions are made at the patient level. This mismatch can inflate apparent performance when images from the same patient are treated as independent observations and can obscure whether model confidence is reliable across magnifications. We present a reliability-aware framework for patient-level classification on the BreakHis dataset. Four ImageNet-pretrained backbones (ResNet50, EfficientNet-B0, DenseNet121, and Swin-Small) were evaluated using a patient-disjoint split (58/13/11 patients for training/validation/test). ResNet50 and Swin-Small were selected for calibration; temperature scaling was estimated on the validation set, and seven nonlearned aggregation rules combined image probabilities within patients. A compact attention network then learned patient-level weights from calibrated probability, entropy, confidence, magnification, cross-magnification variability, and inter-model disagreement. In an exploratory fixed test set of 11 patients (3 benign, 8 malignant), all four image models produced 0.909 accuracy and 0.833 balanced accuracy after simple patient-level mean aggregation. The learned reliability-aware aggregator reached 1.000 accuracy and balanced accuracy on this small test set as a proof-of-concept result, while its probability-based metrics remained modest (Brier score 0.239; negative log-likelihood 0.671). These findings support the feasibility of reliability-aware patient aggregation but do not establish generalization, because confirmatory patient-aware cross-validation has not yet been completed. The principal contribution is a leakage-conscious evaluation and aggregation workflow, with final comparative claims reserved for the planned cross-validation analysis.

Abstract: Background/Objectives: Menopausal hormone therapy (MHT) and alendronate improve bone mineral density (BMD), but their comparative effects on trabecular bone score (TBS) are unclear. We compared 12-month changes in TBS and site-specific BMD in postmenopausal women treated with MHT or alendronate. Methods: This retrospective cohort included 172 treatment-naïve postmenopausal women with newly diagnosed osteoporosis who initiated MHT (n=87) or alendronate 70 mg/week (n=85). Complete baseline and approximately 12-month DXA/TBS data were available for 164 women (MHT, n=83; alendronate, n=81). The primary outcome was the adjusted between-group difference in lumbar spine TBS at follow-up, assessed by analysis of covariance. Results: The adjusted MHT-minus-alendronate difference in TBS was 0.023 (95% CI, 0.010–0.036; P<0.001). TBS showed no significant within-group change with MHT (0.002 ± 0.044; P=0.699) but decreased with alendronate (−0.018 ± 0.040; P<0.001). BMD increased significantly in both groups, with greater gains with alendronate at the lumbar spine (adjusted difference, −0.014 g/cm²; 95% CI, −0.019 to −0.009; P<0.001), femoral neck (−0.005 g/cm²; 95% CI, −0.009 to −0.001; P=0.013), and total hip (−0.007 g/cm²; 95% CI, −0.011 to −0.003; P<0.001). Conclusions: Both treatments improved BMD, but alendronate produced larger gains, whereas no significant within-group change in TBS was observed with MHT. These findings suggest discordant treatment-related changes in BMD and TBS and warrant cautious interpretation because of the observational design and limitations of serial TBS monitoring.