Frontiers in Pharmacology

The aim of this study was to develop a framework for assessing the incremental value of decisions on drug amount, timing, input structure, cessation and restart. The LOGOS (Longitudinal Optimization of Global Outcomes and Strategies) approach combines matched nested regimen classes, mechanism-specific benchmarks and evidence requirements in a single longitudinal comparison. Thus, the contribution of additional regimen freedom is assessed separately from improvements due to different resources, constraints or evaluation horizons. Nested feasible classes have nondecreasing objective suprema, whereas a strict gain requires a feasible witness above a valid bound for the smaller class. The approach is illustrated through analytical examples of periodic smoothing, matched desensitization, relaxed exposure allocation, finite-course loading and safety after cessation. In a normalized finite Emax model, integrated benefit increased from 0.629606 for three equal boluses to 0.672945 after optimization of amounts, 0.677043 for an amount-and-time candidate and 0.679553 for a globally certified loading-maintenance-coast solution. The adjacent observed gains were 6.88%, 0.61% and 0.37%, respectively, and all schedules satisfied the full-tail injury bound. In addition, a periodic factorial example separated response curvature from a joint recovery and repair process, including a null case and results dependent on feasibility constraints. The LOGOS framework allows assessment of whether additional regimen flexibility improves benefit, provides no added value or restores feasibility. These dimensionless examples support conditional mathematical and model-based conclusions; clinical superiority and safe restart in patients have not been established.

Aims Rosuvastatin is commonly co-administered with ticagrelor in patients with acute coronary syndrome. Ticagrelor inhibits breast cancer resistance protein (BCRP/ABCG2), increasing rosuvastatin exposure and potentially the risk of rhabdomyolysis. This risk may be further influenced by age and the ABCG2 c.421C>A variant. We aimed to predict optimal rosuvastatin dosing with ticagrelor in elderly patients stratified by ABCG2 genotype using physiologically based pharmacokinetic (PBPK) modelling Methods PBPK models for rosuvastatin and ticagrelor were developed and validated in PK-Sim using clinical data from healthy adults, elderly patients, and individuals with wild-type or homozygous ABCG2 c.421C>A genotypes. Key parameters, including BCRP catalytic activity and age-dependent declines in CYP2C9 and CYP3A4 activity, were optimized. The drug-drug interaction model incorporated competitive BCRP inhibition by ticagrelor. Rosuvastatin steady-state exposure was simulated with half or quarter standard doses during ticagrelor co-administration, and exposure matching approach was used to identify optimal dosing. Results The PBPK models demonstrated good predictive performance across populations and genotypes. In young adults with the wild-type genotype, halving the rosuvastatin dose resulted in an AUC fold change of 1.44, supporting a half-dose strategy. In young homozygous variant carriers, half-dose co-administration produced comparable exposure (AUC fold change 0.78). In elderly wild-type individuals, a four-fold dose reduction achieved comparable exposure (AUC fold change 1.06), whereas elderly variant carriers required only a half-dose reduction (1.12). Conclusions PBPK modelling supported age- and ABCG2 genotype-specific rosuvastatin dosing with ticagrelor. Elderly wild-type patients may require a further dose reduction to minimise toxicity while maintaining therapeutic exposure.

Background: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for EGFR-mutated non-small cell lung cancer (NSCLC) but have distinct toxicity profiles across generations. Aims: To investigate relationships between EGFR-TKI physicochemical, pharmacokinetic and pharmacological properties and drug-specific adverse drug reactions (ADRs) using national and global pharmacovigilance data. Methods: ADRs for erlotinib, afatinib and osimertinib were extracted from the UK MHRA Yellow Card scheme and WHO VigiAccess. Disproportionality analysis used reporting odds ratios (RORs). Signals were defined as ROR >2, lower 95% confidence interval >1 and >3 cases. Drug properties were curated from ChEMBL, emc, SmPC and EMA sources. Results: VigiAccess contained 88,662 individual case safety reports (163,619 ADRs) and Yellow Card contained 752 reports (1,814 ADRs). Four System Organ Class (SOC) signals were identified in VigiAccess and three in Yellow Card, with five additional Yellow Card Preferred Term signals. Eye disorders showed the strongest consistent association with erlotinib (VigiAccess ROR 4.33; Yellow Card ROR 4.18). Osimertinib was associated with pneumonitis (ROR 7.67) and pulmonary embolism (ROR 3.94). Afatinib showed psychiatric disorder signals in both databases (ROR 3.2-3.3) and diarrhoea (ROR 2.79). Neoplasm-related signals likely reflected confounding by indication. Conclusions: EGFR-TKIs demonstrate generation-specific pharmacovigilance profiles. Integration with drug properties supports mechanistic plausibility for several signals, while the atypical afatinib psychiatric association warrants further investigation. Findings are hypothesis-generating and require confirmation in controlled observational or mechanistic studies.

Background. Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events in almost any organ. While myocarditis has received the most attention, data on pericardial disease with ICI use are limited. We examined pericardial adverse event reporting with nine ICIs using the FDA Adverse Event Reporting System (FAERS). Methods. We combined legacy AERS and current FAERS quarterly files from January 2011 to June 2026 into 18,629,240 unique cases, deduplicated by case number, and removed cases the FDA had listed as deleted. ICI exposure was identified from generic names, brand names, development code names and the active-ingredient field. Pericardial events were defined by seven MedDRA preferred terms. We estimated reporting odds ratios (ROR), proportional reporting ratios (PRR), Bayesian information components (IC) and empirical Bayes geometric means (EBGM). We also examined myocarditis co-reporting, time trends, a comparison with other antineoplastic agents, a MedDRA query-based outcome, and 14 alternative definitions. Results. The analysis included 18,514,045 cases: 277,434 involved an ICI, 34,792 carried a pericardial term, and 1,680 had both. Pericardial events were reported disproportionately with ICIs (ROR 3.35 (95% CI 3.19 to 3.52); PRR 3.34; IC025 1.62). Eight of nine agents had a ROR above 1 (3.32 to 5.63). Among the most frequently reported terms, estimates were highest for cardiac tamponade (5.59 (95% CI 4.98 to 6.28)), followed by pericardial effusion (3.83 (95% CI 3.60 to 4.07)) and pericarditis (2.09 (95% CI 1.89 to 2.31)). After removing cases that also reported myocarditis, the ROR was 3.13 (95% CI 2.98 to 3.30). Most sensitivity analyses gave similar estimates (ROR 3.13 to 3.47); defining exposure by generic drug names alone, which identified only 44% of exposed cases, gave 3.99. Compared with cases naming other L01 antineoplastic agents, the ROR was 1.13 (95% CI 1.08 to 1.19): 1.28 (95% CI 1.20 to 1.36) for ICI-only cases and 0.96 (95% CI 0.89 to 1.04) when another antineoplastic was also named. The ICI-specific reporting odds ratio fell each quarter (odds ratio 0.977 per quarter, 95% CI 0.973 to 0.980). Conclusions. In FAERS, pericardial events were reported more often with ICIs than with other drugs across most agents and terms; however, incidence and causation cannot be determined. The excess over other antineoplastic agents was small, and reporting disproportionality declined over time. These findings support clinical awareness of pericardial disease in patients receiving ICIs and warrant study in data that can measure incidence.

Nicotinamide riboside (NR), a precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD+), has been extensively studied following oral administration, while the longer-term safety and physiological effects of injectable NR remain less characterized. Following an initial in-clinic phase evaluating repeat intramuscular (IM) and subcutaneous (SC) administration of pharmaceutical-grade NR, participants transitioned to an at-home phase designed to assess the safety, feasibility, and exploratory physiological effects of repeated self-administered SC administration. Participants continued their assigned 50 or 100 mg dose group and self-administered NR subcutaneously 3 times weekly for approximately 90 days. Safety was assessed through adverse event (AE) monitoring, vital signs, and clinical laboratory health measures. Exploratory assessments included markers of mitochondrial bioenergetics, urinary biomarkers of oxidative stress, and participant-reported outcomes related to fatigue, sleep, pain, and quality of life. At-home administration of NR was generally well-tolerated, with no clear dose-dependent safety concerns identified over the study period. Further, participants were able to successfully self-administer repeated SC injections over the study period, demonstrating positive feasibility. Whole-blood NAD+ concentrations remained largely stable over time in both dose groups. MeScreen analysis demonstrated a reduction in GlycoATP at Day 30 and increases in the MitoATP/GlycoATP ratio at Day 30 and Day 90, signifying a preferential shift toward oxidative metabolism. These findings may be indicative of positive metabolic health shifts. Urinary oxidative stress profiling demonstrated heterogeneous temporal responses. Several lipid oxidation markers significantly declined at Day 30 but returned toward baseline at Day 90. Select markers of nucleic acid, nitrative stress, and advanced glycation end-product oxidation demonstrated more sustained reductions. These results for which the majority of measured oxidative stress markers improved suggest that NR injections may exhibit anti-oxidative characteristics. Validated participant-reported sleep and fatigue measures showed improvements. Self-reported facial skin improvement increased descriptively from 11.4% at baseline to 27.8% at Day 30 and 36.8% at Day 90; improvements noticed by others increased from 9.1% to 23.7%, while reported body-skin improvement increased more modestly, from 8.8% to 16.7%. As these outcomes were not designed or powered to establish efficacy or definitive clinical claims, the findings should be considered hypothesis generating and provide preliminary data to inform the selection of outcomes and design considerations for future randomized, placebo-controlled, adequately powered trials of SC NR administration.

Objective: Amphetamine (AMP) and its derivates are commonly prescribed for the management of attention-deficit/hyperactivity disorder (ADHD). This study aimed to 1) quantify AMP's transfer into human milk in lactating women receiving therapeutic doses and 2) contextualize infant exposure. Methods: Milk samples and dyad health histories of thirteen lactating women treated with varying doses of either mixed AMP, dextroamphetamine, or lisdexamfetamine were released for this study from the InfantRisk Human Milk Biorepository. Milk drug concentrations were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) and used to calculate standard relative infant dose (RIDmat) and RID standardized to the defined daily dose (RIDDDD) of 15 mg AMP base. Results: Average milk concentrations (Cavg) of AMP base ranged from 23.3 to 297.0 ng/mL and increased linearly (R^2 = 0.92) with maternal daily dose. The RIDmat ranged 3.6-10.8% and RIDDDD ranged 1.4-21.8%. The fitted regression line crossed the 10% RIDDDD threshold at 1.17x DDD, with the upper 95% prediction limit crossing at 0.84x DDD. No adverse event reported by the mother-infant dyads were attributed to AMP exposure, notably including absence of reduced milk supply. Conclusions:The levels of AMP observed in human milk followed a dose predictable manner. The average patient was predicted to remain below the 10% RID DDD safety threshold at total daily doses at or below approximately 28 mg of mixed AMP salts or 59 mg of lisdexamfetamine. Ninety-five percent of patients were predicted to remain below the threshold at or below approximately 20 mg and 40 mg, respectively.

Background and Objective: Adding belzutifan to adjuvant pembrolizumab improved disease-free survival (DFS) in LITESPARK-022, but its durability beyond the 1-year treatment is unknown. Methods: Following a registered plan, we reconstructed individual patient data from published Kaplan-Meier curves of ten phase 3 adjuvant renal cell carcinoma trials. Within each trial, we estimated restricted mean survival time differences ({Delta}RMST), hazard ratios (HRs) before and after planned treatment ended, and DFS differences. Key Findings and Limitations: In LITESPARK-022 (central review), the 24-month {Delta}RMST was 1.34 months (95% confidence interval 0.73-1.95), and the belzutifan arm remained ahead after month 12 ({Delta}RMST increment 0.74 months/yr, 0.32-1.19). The HR was 0.55 (0.43-0.71) before month 12 and 1.16 (0.87-1.54) afterwards (post/pre ratio 2.10); investigator assessment showed similar attenuation. Similar ratios occurred in KEYNOTE-564 at its first interim analysis (2.02), whose benefit persisted, and in SORCE and PROTECT (2.09, 2.59), whose benefit faded. From months 12 to 30 (post hoc), the DFS difference changed by -3.7 percentage points (-8.1 to 0.8) with central review and 0.6 (-4.0 to 5.0) with investigator assessment. Data were reconstructed, and follow-up was short. Conclusions and Clinical Implications: Relative hazard reductions with belzutifan were greater before month 12; durability of the absolute DFS advantage is uncertain and assessment-dependent, so single-HR projections should be avoided.

Background Psychiatric diagnoses and psychotropic medication use among children, adolescents, and young adults have increased in high-income countries, with concerns about geographic variation. We described national trends and geographic variation in Denmark from 2010 to 2025 and developed an interactive online tool to explore these patterns. Methods We conducted a nationwide, descriptive, repeated cross-sectional register-based study of all Danish residents aged 0-24 years in 2010-2025 (n=2,930,744), using the Danish National Patient Registry and the Danish National Prescription Registry. We estimated annual incidence, prevalence, and, for selected diagnoses, lifetime prevalence, by age and sex, and age- and sex-standardised rates across regions, health councils, and municipalities. We assessed geographic variation using deviations from national means, coefficients of variation, Gini coefficients, and funnel plots. Findings Psychiatric diagnoses and psychotropic medication use increased from 2010 to 2025. The annual prevalence of attention-deficit hyperactivity disorder (ADHD) increased from 0.41 to 2.3 per 100 individuals, autism spectrum disorders from 0.20 to 1.2, and melatonin use from 0.14 to 3.0. ADHD and autism spectrum disorders were more prevalent among boys and anxiety disorders among girls. Sertraline use was also more prevalent among girls. Geographic variation was observed across diagnoses and psychotropic medications at regional, health council, and municipal levels. For example, lifetime prevalence of autism ranged from 1.3 to 5.9 per 100 across municipalities, and in 2025 regional coefficients of variation ranged from 0.11 (sertraline) to 0.41 (atomoxetine). Results can be explored in the interactive online tool (https://bupstat.sdu.dk/?lang=en). Interpretation Psychiatric diagnoses and psychotropic medication use increased among Danish children, adolescents, and young adults, with marked geographic variation. Descriptive data cannot establish the causes of this variation, but the findings identify areas for further review and support continued monitoring. Funding Best for Us project (www.bedstforos.dk), funded by the Novo Nordisk Foundation (NNF24SA0093635) and the Obel Family Foundation (69348).

Background: Chronic kidney disease (CKD) may progress to stage 5 CKD (end-stage renal disease, ESRD), but stage-associated molecular alterations remain incompletely characterized. This study aimed to identify candidate biomarkers associated with CKD and ESRD. Methods: Two discovery datasets comparing CKD or ESRD with healthy controls were analyzed using differential expression analysis and weighted gene co-expression network analysis. Candidate genes were identified by intersecting differentially expressed genes with key co-expression modules, followed by protein-protein interaction network analysis using Degree, Closeness, and Maximal Clique Centrality algorithms. Candidate genes were evaluated in independent GEO validation datasets and further examined by quantitative real-time PCR and western blotting using clinical blood samples. Results: Ten hub genes were identified, among which EPB42, KLF1, and H3F3A were prioritized for further evaluation. EPB42 showed decreased expression in CKD but increased expression in ESRD, indicating an opposite-direction pattern between the two disease states. KLF1 showed no significant difference between healthy controls and CKD but was increased in ESRD, whereas H3F3A was increased in CKD and further increased in ESRD. Functional enrichment analysis highlighted processes related to oxygen transport, mitochondrial function, muscle-associated processes, and inflammation, suggesting possible involvement of hypoxia-associated oxidative injury and ferroptosis-related processes. Conclusions: Integrated transcriptomic and experimental analyses identified EPB42, KLF1, and H3F3A as candidate stage-associated biomarkers in CKD and ESRD. In particular, the opposite-direction expression pattern of EPB42 may provide additional molecular information for distinguishing CKD from ESRD.

Objective: Current guidelines recommend different adjuvant treatment strategies for women with endometrioid early stage endometrial cancer exhibiting a p53 abnormal pattern. We aimed to evaluate recurrence patterns and explore the clinical implications for adjuvant therapy in this population. Materials and methods: This multicenter retrospective study included 86 patients with endometrioid, p53 abnormal, FIGO stage I, II endometrial cancer treated between 2013 and 2023 at six hospitals in the Republic of Korea. Clinicopathologic data were collected through medical record review. Progression free survival (PFS) was estimated using the Kaplan Meier method, and prognostic factors were analyzed using Cox proportional hazards regression models. Results: The 12, 24, and 36 month PFS rates were 91%, 78%, and 76%, respectively. Among the 16 patients who experienced recurrence, 12 (75%) had distant metastases. Adjuvant chemotherapy showed a trend toward improved PFS compared with adjuvant radiation therapy with or without chemotherapy (p=0.10). In multivariable analysis, the p53 overexpression pattern was independently associated with worse PFS compared with the p53 null pattern (HR 8.59, 95% CI 1.61 to 45.79, p=0.01). Conclusion: Given the poor PFS, the predominance of distant recurrence and the observed trend toward improved PFS with chemotherapy, adjuvant chemotherapy may be considered in women with endometrioid early stage endometrial cancer exhibiting a p53 abnormal pattern. Further studies are warranted to clarify the prognostic impact of p53 abnormality subtypes.

Background: Although opioids are frequently prescribed for refractory chronic neuropathic pain, few data are available on baseline factors that may identify individuals more likely to respond and inform individually tailored practice. Methods: This was a post hoc, exploratory analysis of individual-level data from a placebo-controlled trial of methadone for chronic neuropathic pain (NCT05235191). Baseline clinical, psychological, psychophysical and radiological variables were tested for association with 30% or more pain reduction in the methadone group. The correlation between expectation of improvement and pain reduction was examined in both groups. Results: Of the 81 participants completing the 8-week follow-up, 28 (70%) on methadone and 14 (34.1%) on placebo achieved 30% or more pain reduction. In the methadone group, responders had higher baseline expectation of improvement (median 100 [80-100] vs. 55 [50-81]; p=0.004), which correlated moderately with percentage pain reduction (rs=0.508; p<0.001). Neither finding was observed in the placebo group (p=0.211 and p=0.161, respectively), although the correlation did not differ significantly between groups (p for interaction=0.728). Other clinical, sociodemographic, psychological and psychophysical variables were not associated with response. In the subsample with peripheral neuropathic pain and structural MRI (n=37), lower left precentral cortex volume was associated with response to methadone (p=0.041), and lower right paracentral volume with response to placebo (p=0.003). Conclusions: Baseline expectation may influence treatment outcomes, supporting its inclusion as a covariate to improve the precision of treatment effect estimates in trials, and its use in clinical practice to help tailor treatment to individual patients. These exploratory findings require confirmation in larger studies.

Background: Psychological health is an important aspect of health and well-being among adults with irritable bowel syndrome, yet the interrelationships among individual vulnerabilities, social experiences, perceived stress, and psychological health outcomes remain poorly understood. Objective: To characterize psychological health and examine direct and indirect associations of childhood adversity and adult attention-deficit/hyperactivity disorder-related symptoms within an adapted Stress Process Model. Design: Cross-sectional secondary analysis. Setting: The United States All of Us Research Program. Participants: 2,417 adults with electronic health record-documented irritable bowel syndrome and complete data on the primary analysis variables and covariates. Methods: Separate structural equation models examined childhood adversity and adult attention-deficit/hyperactivity disorder-related symptoms in relation to perceived stress, anxiety and depressive symptoms, and positive psychological well-being, with loneliness and perceived social support as psychosocial pathways. Models adjusted for sociodemographic and social-context factors. Results: The median age was 54.39 years; 80.7% were female and 84.4% were White. Moderate-to-high perceived stress was reported by 56.2%, at least moderate anxiety symptoms by 21.0%, and at least moderate depressive symptoms by 24.3%. Higher ACE-8 scores were associated with greater perceived stress, anxiety symptoms, and depressive symptoms and lower psychological well-being ({beta} = 0.063, 0.089, 0.116, and -0.100, respectively); corresponding associations for higher ASRS-6 scores were {beta} = 0.299, 0.355, 0.390, and -0.260. Loneliness-specific indirect associations were positive for perceived stress, anxiety, and depressive symptoms (ACE-8: {beta} = 0.023-0.034; ASRS-6: {beta} = 0.043-0.075) and negative for psychological well-being (ACE-8: {beta} = -0.039; ASRS-6: {beta} = -0.089; all p < .001). Social support-specific indirect associations were not significant in the ACE-8 model and were small and significant only for anxiety and depression in the ASRS-6 model ({beta} = 0.003-0.004). Conclusions: Psychological health among adults with irritable bowel syndrome was associated with interconnected individual and social factors within an adapted Stress Process Model. Childhood adversity and adult attention-deficit/hyperactivity disorder-related symptoms showed direct and indirect associations with psychological health, with loneliness emerging as the most consistent social factor. These findings support prospective investigation of individual vulnerabilities and social experiences in psychological health. The cross-sectional design does not establish temporal ordering or causal mediation.

Abstract Background Health-related quality of life (HRQoL) is an important outcome in patients with chronic kidney disease (CKD) receiving kidney replacement therapy (KRT), but the relationship between comprehensive metabolic control and the Symptoms/Problems domain of kidney diseasespecific HRQoL remains uncertain. Objective To evaluate the association between composite metabolic control and the Symptoms/Problems domain of the Kidney Disease Quality of Life-36 (KDQOL-36) in patients with stage 5 CKD receiving KRT, and to explore the relationship between individual metabolic parameters and the continuous Symptoms/Problems score. Materials and Methods We conducted an observational, cross-sectional, analytical study of 177 adults receiving hemodialysis or peritoneal dialysis at a nephrology unit in Chihuahua, Mexico. Metabolic control included blood pressure, glycated hemoglobin (HbA1c), total cholesterol, and triglycerides. Adequate control was defined as achievement of at least three of four studydefined operational thresholds. The KDQOL-36 Symptoms/Problems score was analyze as a continuous variable and categorized as low, moderate, or high according to the study protocol. Group comparisons, Spearman correlations, Pearson chi-square tests, and ordinal logistic regression were performed. Results Adequate metabolic control was present in 106 patients (59.9%). No, statistically significant association was observed between achievement of at least three of four study-defined operational thresholds and Symptoms/Problems score category (x2=3.983; p=0.137; Cramers V=0.150). None of the individual metabolic parameters differed significantly across Symptoms/Problems score categories or showed significant correlations with the continuous score. In ordinal logistic regression, adequate metabolic control yielded an odds ratio of 1.81 (95% CI: 0.98-3.35; p=0.057) after adjustment for age, sex, time receiving KRT, and KRT modality. Conclusions No, statistically significant association was identified between the operational definition of metabolic control used in this study and the KDQOL-36 Symptoms/Problems domain in patients with stage 5 CKD receiving KRT. The findings support evaluating HRQoL multidimensionally and warrant confirmation in larger longitudinal studies. Categories: Family/General Practice, Internal Medicine, Nephrology Keywords: chronic kidney disease (ckd), hemodialysis, kdqol-36, kidney replacement therapy, metabolic control, peritoneal dialysis (pd)

Importance. Plasma phosphorylated tau 217 (p-tau217) is entering clinical use with fixed diagnostic threshold that do not account for kidney function. Chronic kidney disease (defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2), raises plasma p-tau217 concentrations and can produce false positive results. It remains unclear whether milder reductions in kidney function, above the CKD threshold, have the same effect. Objective. To determine whether plasma p-tau217 is elevated with mildly reduced kidney function, above the chronic kidney disease threshold, in adults without neurological disease. Design. Cross-sectional analysis of a cohort enrolled between 2023 and 2025 and biomarker analysis blinded to clinical data. Setting. Two private psychiatric inpatient facilities in Australia. Participants. Adults admitted with psychiatric disorders and free of neurological disease. Exposures. eGFR calculated from serum creatinine using the CKD-EPI 2021 equation. Main Outcomes and Measures. Plasma p-tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), measured on the Simoa platform. Multivariable linear regression compared eGFR groups (< 60, 60 to 90, and [&ge;] 90 mL/min/1.73 m2), adjusted for age, BMI, and sex. Results. Among 180 participants (median age, 50.5 years [IQR, 38.0-61.5]; 94 [52%] female), eGFR was [&ge;] 90 mL/min/1.73 m2 in 106 (59%), 60 to 90 in 61 (34%), and < 60 in 13 (7.2%). Compared with an eGFR [&ge;] 90, plasma p-tau217 was 36% higher in both the 60 to < 90 group ({beta} = 0.42 [95% CI: 0.11, 0.74]; P = .008) and 116% higher in the < 60 group ({beta} = 1.05 [95% CI: 0.43, 1.72]; P = .002). Plasma NfL and GFAP were elevated in the < 60 group but differences in the 60 to < 90 group did not reach significance. Modelled continuously, plasma p-tau217 was 9.5% lower per 10 mL/min/1.73 m2 higher eGFR (95% CI: 3.3%, 15.4%). Conclusions and Relevance. Plasma p-tau217 was elevated in adults with mildly reduced kidney function, above the CKD threshold, in a cohort free of neurological disease. Kidney function across its full range should be incorporated into plasma p-tau217 reference ranges and clinical interpretation to reduce false positive and false negative results.

Personalized medicine aims to tailor treatments to individual patients, but its implementation is limited by scarce clinical resources and heterogeneous treatment effects. Electronic health records now offer longitudinal data that can support data-driven therapy selection. We focus on SGLT2 inhibitors, medications with broad metabolic and cardiovascular benefits, whose clinical impact varies significantly based on individual patient profiles. We propose a counterfactual Structural Causal Model (SCM) to estimate individual treatment effects (ITE) of SGLT2 inhibitors from observational data. The model assumes counterfactual stability and uses a Gumbel-Max sampling mechanism to capture stochastic treatment assignment while enabling differentiable inference. Optimal treatments are defined by maximizing the counterfactual value of future diagnostic outcomes. We evaluate the Counterfactual Gumbel-Max SCM using a doubly robust value estimator and show that, across diagnostic categories, it outperforms real-world prescriptions in predicted treatment value, highlighting subpopulations where SGLT2 inhibitors yield superior outcomes. By integrating causal inference with electronic health data, this framework provides individualized counterfactual reasoning about SGLT2 treatment effects and can support clinicians in identifying optimal therapies for type 2 diabetes and comorbid conditions.

Background: The C-reactive protein-albumin-lymphocyte (CALLY) index integrates systemic inflammation, nutritional status, and immune function. We evaluated its association with survival in primary lung malignancies. Methods: Embase, PubMed, Scopus, and Web of Science were searched from inception to 18 September 2026. Risk of bias was assessed using the Quality In Prognosis Studies tool. Hazard ratios (HRs) were synthesized using random-effects models with restricted maximum likelihood estimation and Hartung-Knapp adjustment. Sensitivity analyses, subgroup analyses, and meta-regression examined robustness and heterogeneity. Results: Eleven studies contributed 13 cohorts to the overall survival (OS) analysis and 8 cohorts from seven studies to a combined recurrence/progression-free survival (RFS/PFS) analysis. Lower CALLY was associated with poorer OS (HR 1.78, 95% CI 1.49-2.12; I2=71.6%) and poorer RFS/PFS (HR 1.60, 95% CI 1.40-1.84; I2=0%). Associations persisted in leave-one-out analyses. No statistically significant subgroup differences were detected. Funnel-plot asymmetry suggested small-study effects for OS and RFS/PFS. Seven studies had moderate and four had high overall risk of bias. The certainty of evidence was rated as low for both OS and RFS/PFS, primarily due to risk of bias, heterogeneity, and endpoint indirectness. Conclusion: Lower CALLY was associated with adverse survival outcomes in the current synthesis. Methodological limitations and variation in biomarker measurement and endpoint definitions restrict interpretation. Prospective validation using standardized measurements and clinically coherent outcomes is needed to establish incremental prognostic value and clinical utility. Keywords: CALLY index; lung cancer; prognosis; overall survival; systematic review; meta-analysis

Glycemic control is key to prevention of complications of diabetes. Although eosinophils have been implicated in metabolic regulation, most human studies have been cross-sectional and have yielded inconsistent findings. We conducted a retrospective cohort study of adults with uncontrolled diabetes receiving primary care at Mass General Brigham. We evaluated the relationship between eosinophil count and HbA1c over one year, adjusting for demographic, socioeconomic, and clinical covariates. Among 21,447 patients included in the study, eosinophil count increased by a mean of 2.6 cells/L (SD 157.2 cells/L) and HbA1c decreased by a mean of 0.82% (SD 2.09%) during follow-up. Increases in eosinophil count were associated with reductions in HbA1c (parameter estimate -0.366 per 1,000 cells/L; 95% CI -0.526 to -0.206; P < 0.001), whereas baseline eosinophil count was not significantly associated with HbA1c changes. The association remained significant in a sensitivity analysis excluding systemic glucocorticoid users. Increases in eosinophil count were associated with improved glycemic control in adults with diabetes, whereas baseline eosinophil count was not. These findings extend prior cross-sectional observations and suggest that changes in eosinophils may represent a biomarker of glycemic improvement. Further prospective studies are needed to determine whether this relationship reflects underlying immune-metabolic mechanisms or treatment-related changes.

Polyendocrine Metabolic Ovarian Syndrome (PMOS, formerly PCOS) is associated with chronic low-grade inflammation. This study aimed to characterize the peripheral cytokine landscape in women with PMOS and identify cytokines associated with disease pathogenesis and phenotypic variation. Plasma concentrations of 48 cytokines were quantified using a multiplex bead-based assay in 102 women with PMOS and 114 healthy controls. We performed receiver operating characteristic (ROC) analysis, odds ratio estimation, correlation analysis, and network analyses to characterise cytokine alterations and identify phenotype-associated inflammatory signatures. Fourteen cytokines were significantly elevated in PMOS compared with healthy controls: IL-18, IL-1Ra, IL-12p70, IL-13, IL-16, MCP-1, MCP-3, CTACK, Eotaxin, RANTES, IP-10, M-CSF, HGF, and {beta}-NGF. ROC analysis identified IL-16, CTACK, and IP-10 as potential discriminators of phenotype A, whereas IL-18, M-CSF, and HGF demonstrated promising discriminatory performance for phenotype B. Odds ratio analysis identified 11 cytokines with odds ratios greater than 1, with IL-16 showing the strongest association with PMOS. Correlation analysis revealed 10 strongly correlated cytokine pairs (r [&ge;] 0.7) in the PMOS group, suggesting coordinated regulation of inflammatory mediators. Gene ontology and network analysis highlighted alterations in chemotaxis and immune cell migration pathways, implicating these processes in PMOS-associated immune dysregulation. These findings reveal a distinct peripheral inflammatory cytokine signature and phenotype-associated differences in PMOS. IL-16 emerged as a prominent candidate for further investigation, given its strong association with PMOS. Peripheral cytokine profiling may provide a minimally invasive approach to characterising immune alterations and identifying candidate biomarkers for disease characterisation and phenotype stratification.

Background. Regulatory pressure to avoid confusingly similar drug names appears to have pushed manufacturers to coin more distinctive proprietary names, but no one has quantitatively analyzed this trend. Objective. To determine whether proprietary drug names became more orthographically distinctive (unusual in spelling) over time. Methods. We examined 1,321 US Food and Drug Administration (FDA) new molecular entity (NME) names (1985-2024), 2,769 FDA Orange Book trade names (1982-2026), 177,337 US pharmaceutical trademarks (1980-2026), and 1,273 generic names (1982-2025). Compared to prior names (including those already marketed) and ordinary English, we scored each name's character trigram (three-letter sequence) surprisal (statistical unexpectedness) and its edit-distance similarity to the closest existing names. Linear regression tested time trends, controlling for name length. Results. Mean NME trigram surprisal rose in every decade between the 1980s and 2020s, from 7.21 to 8.50 nats (natural-logarithm units, higher meaning less predictable), an 18% increase (b = 0.038, p < .001, R2 = 0.34). Half of 2020s names (7% in the 1980s) contained a letter sequence found in no common English word (e.g., Jesduvroq, Omvoh). Nearest-neighbor similarity fell after the early 1990s. Trademark data showed the same trend (b = 0.016, p < .001). Generic names showed a weaker trend (b = 0.011, R2 = 0.063). Conclusions. Over four decades, drug names became more orthographically distinctive, consistent with namespace crowding, deliberate efforts to avoid confusing names, and branding strategy. Because unfamiliar letter sequences can introduce other error pathways, increased distinctiveness does not necessarily imply improved safety.

Introduction: Thyroid diseases are major health problems and among the most common endocrine disorders worldwide, including in Ethiopia. They are characterized by alterations in hormone secretion, enlargement of the thyroid gland, or both. Fine needle aspiration cytology is an important initial screening tool, and histopathologic examination is essential for the definitive diagnosis of thyroid disease. This study aimed to compare the diagnostic accuracy of fine needle aspiration cytology with histopathology in identifying thyroid diseases. Methods: A cross-sectional study was conducted at three health facilities in Hawassa City, Ethiopia, involving 304 patients who underwent both thyroid fine needle aspiration cytology and histopathologic examination of the same site between 30th October 2024 and 29th October 2025. FNAC results were classified using the Bethesda system, with histopathology as the gold standard. Data were entered into Kobo Toolbox, exported to SPSS version 27, and analyzed using cross-tabulation and chi-square ({chi}{superscript 2}) tests to determine diagnostic accuracy. Result: 304 patient records were included in the study. The fine needle aspiration cytology was determinate/diagnostic in 81.6% of cases. The study revealed the sensitivity and specificity of fine needle aspiration cytology to be 88.2% (CI 77.6-95.1%) and 94.4% (CI 90.6-97.1%), respectively. The false negative and false positive rates in this study were 2.4% and 4.4%, respectively. The positive predictive value was 80.3% (CI 68.7-89.3%), and the negative predictive value was 96.8% (CI 93.8-98.7%). The accuracy of fine needle aspiration cytology in differentiating benign from malignant thyroid lesions was 93.1%. Conclusion: FNAC demonstrated strong agreement with histopathology and remains a reliable, cost-effective first-line diagnostic tool for thyroid disease, particularly in resource-limited settings. Strengthening sample handling, ultrasound guidance, and adherence to Bethesda criteria may further improve diagnostic precision