Tag: pubmed

JMIR Res Protoc. 2025 Nov 12;14:e73766. doi: 10.2196/73766.

ABSTRACT

BACKGROUND: The incidence of chronic diseases associated with physical inactivity is on the rise, being one of the leading risk-increasing factors for early death rates throughout the world. Often, physical activity interventions fail to deliver sustained adherence over time due to limiting tailoring to individual baseline characteristics, leaving out contextual changes over time. One solution for this issue may be the use of adaptive interventions relying on contextual multiarmed bandits, a type of reinforcement learning algorithm, that can use baseline and contextual individual data to personalize aspects of the intervention, such as developing personalized workout plans.

OBJECTIVE: The main objectives of this study are (1) to determine the effectiveness of contextual bandits for automated goal setting in the context of a web-based physical activity intervention, (2) to understand the role of user characteristics impacting ideal workout schedules based on adherence to predetermined goals, and (3) to explore the influence of user autonomy on recommendation effectiveness.

METHODS: We developed a protocol for a web-based adaptive intervention trial to investigate the effectiveness of goal recommendation (task difficulty) based on reinforcement learning. The web application (named Apptivate) creates workout routines with 3 different difficulty levels, changing the total workout duration as well as rest times between exercises. Physical activity professionals validated the routine design, ensuring that workouts match recommended guidelines for healthy adults. An initial pilot was conducted, aiming for 800 university students to test the web application for 1 week, to provide initial data to calibrate the algorithm as well as overall feedback for the web application. For the main study, a total of 500 university students will be recruited to participate for 40 days during early 2026. Participants will be divided into 3 groups: user choice (no recommendation), user choice with automated recommendations (contextual bandits), and automated plans without choice.

RESULTS: The pilot was conducted in September 2025. Data analysis for the pilot is undergoing, and the main study is planned for early 2026. Our main statistical analysis includes a direct comparison (paired tests) between success rates across intervention arms, as well as by difficulty level and individual characteristics.

CONCLUSIONS: Physical activity maintenance is key to achieving long term health goals. Tailored digital interventions are promising strategies for physical activity adherence, but personalization often fails to consider dynamic contextual changes. The proposed protocol for a physical activity intervention using adaptive experimentation can provide robust causal inference on the role of choice versus autonomy when goal difficulty is tailored under an adaptive data-driven approach.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/73766.

PMID:41222972 | DOI:10.2196/73766

JAMA Netw Open. 2025 Nov 3;8(11):e2543107. doi: 10.1001/jamanetworkopen.2025.43107.

ABSTRACT

IMPORTANCE: Brain metastases reduce overall survival rates of patients with non-small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC.

OBJECTIVE: To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases.

DESIGN, SETTING, AND PARTICIPANTS: This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024.

INTERVENTION: Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks.

MAIN OUTCOME AND MEASURE: Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety.

RESULTS: This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose.

CONCLUSIONS AND RELEVANCE: In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2-mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population.

PMID:41222935 | DOI:10.1001/jamanetworkopen.2025.43107

JAMA Netw Open. 2025 Nov 3;8(11):e2543398. doi: 10.1001/jamanetworkopen.2025.43398.

ABSTRACT

IMPORTANCE: The COVID-19 pandemic disrupted long-standing trends in hospital quality and patient safety, prompting questions about whether risk-adjusted outcomes have resumed their prepandemic trajectories.

OBJECTIVE: To determine whether trends in risk-adjusted mortality and case mix index (CMI) among hospitalized patients in hospitals have returned to prepandemic trajectories.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was a multicenter analysis that used the Vizient Clinical Data Base, which contains encounter-level administrative and financial data from more than 1300 hospitals in the US. The study included continuously reporting hospitals and examined inpatient discharges between October 2019 and March 2024. Data were analyzed between January and May 2025.

MAIN OUTCOMES AND MEASURES: Quarterly estimates of CMI and standardized mortality ratio (SMR) (observed-to-expected ratio). Ordinary least squares (OLS) regression was used to evaluate overall linear trends, and joinpoint regression was used to identify inflection points. Statistical significance was defined as P < .05, with slope estimates reported alongside 95% CIs.

RESULTS: Among 715 hospitals and 7 802 606 million inpatient encounters, the mean CMI increased from 1.70 in the fourth quarter (Q4) of 2019 to 1.79 in the first quarter (Q1) of 2024 (difference, 0.09; 95% CI, 0.01 to 0.17; P = .02). In OLS regression, CMI showed no significant overall linear trend (R2 = 0.006; P = .77). The mean SMR decreased from 1.00 in Q4-2019 to 0.80 in Q1-2024 (difference, -0.20; 95% CI, -0.32 to -0.08; P = .001), with a significant linear decline across the study period (R2 = 0.735; P < .001). Joinpoint regression identified a CMI inflection point in Q4-2020 (slope, 1.85; 95% CI, 0.73 to 4.14; P < .001 before; slope, -0.30; 95% CI, -0.62 to -0.09; P = .006 after) and an SMR inflection point in Q3-2021, after which SMR declined significantly by -3.17% per quarter (P < .05).

CONCLUSIONS AND RELEVANCE: In this cohort study of 715 US hospitals from 2019 to 2024, risk-adjusted in-hospital mortality declined significantly following the COVID-19 pandemic, resuming its prepandemic trajectory of improvement, while patient acuity as measured by CMI remained elevated. These findings suggest a new postpandemic baseline for patient acuity, whereas hospital mortality outcomes have returned to prior improvement trends.

PMID:41222931 | DOI:10.1001/jamanetworkopen.2025.43398

Clin Pharmacokinet. 2025 Nov 12. doi: 10.1007/s40262-025-01566-5. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Atogepant is an oral calcitonin gene-related peptide receptor antagonist developed for the preventive treatment of migraine. This work aimed to develop a population pharmacokinetic (popPK) model to support dosage regimen selection during the clinical development of atogepant in patients with episodic migraine (EM) or chronic migraine (CM) and to guide the dosing recommendations for regulatory approval.

METHODS: Pharmacokinetic data collected from 12 phase 1 studies, 1 phase 2b/3 study, and 1 phase 3 study in healthy participants and patients with EM were used to develop a popPK model that was externally validated with data from a CM phase 3 study and a phase 3 study in patients with EM for whom two to four classes of conventional oral preventive treatments have failed. The model was built and evaluated using nonlinear mixed-effect modeling and diagnostic assessments.

RESULTS: The final model featured three disposition compartments, with linear elimination from the central compartment and a sequential zero-/first-order lagged absorption process. Formulation, dose, food status, liver function, concomitant medication, and body weight were each found to have a statistically significant influence on atogepant’s pharmacokinetics. Absorption was affected by dose and formulation, the apparent central volume of distribution (V₁/F) increased with body weight, relative bioavailability (F_rel) modestly increased with dose, and a high-fat meal lengthened absorption lag time. Severe hepatic impairment and coadministration of itraconazole, quinidine, or a single rifampin dose decreased apparent clearance (CL/F) by ~37% and ~66%, ~29%, and ~13%, respectively, while coadministration of multiple rifampin doses increased CL/F by 1.82-fold. F_rel increased by 1.95 and 2.4 fold with coadministration of itraconazole and a single rifampin dose, respectively, and decreased by ~25% with multiple rifampin doses. Mild/moderate renal impairment, coadministration of breast cancer resistance protein (BCRP) inhibitors, BCRP substrates and statins, age, and sex had no clinically relevant effect on atogepant pharmacokinetics. No statistically significant differences were observed in atogepant’s pharmacokinetics between healthy participants and patients with migraine.

CONCLUSIONS: The pharmacokinetics of atogepant are similar in healthy participants and patients with CM or EM. Dose adjustments owing to intrinsic factors of age, sex, race, and body weight, or owing to concomitant medications consisting of P-glycoprotein (P-gp) inhibitors, BCRP inhibitors, oral contraceptive components (ethinyl estradiol and levonorgestrel), famotidine, esomeprazole, sumatriptan, acetaminophen, and naproxen are not necessary. Atogepant’s popPK model provides a valuable tool for evaluating specific questions for patients, healthcare providers, and regulatory agencies. Integration into other modeling approaches has also aided in model-informed drug development decisions.

CLINICAL TRIAL REGISTRATION: NCT03855137 (EudraCT number: 2018-004337-32).

PMID:41222899 | DOI:10.1007/s40262-025-01566-5

Clin Pharmacokinet. 2025 Nov 12. doi: 10.1007/s40262-025-01589-y. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Tenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofovir-diphosphate concentrations during pregnancy among participants taking tenofovir disoproxil fumarate (TDF). Currently, there are no mechanism-based models describing the pharmacokinetics of tenofovir diphosphate (the active anabolite) in peripheral blood mononuclear cells (PBMCs) of pregnant individuals receiving TDF or tenofovir alafenamide (TAF), and the mechanisms behind observed differences between dried blood spots and PBMCs remain unclear.

METHODS: To address this gap, we developed a semi-mechanistic model to simultaneously describe the pharmacokinetics of all clinically relevant TDF and TAF-derived moieties and conducted clinical trial simulations to compare TDF and TAF pharmacokinetics during pregnancy and postpartum.

RESULTS: The pharmacokinetics of plasma TAF and TFV were best described by one-compartment and two-compartment models, respectively, with first-order absorption. A transit compartment was included to reflect the slower elimination rate of plasma TFV after receiving TAF. Cellular matrix PBMC and dried blood spots were included using a biophase model. For TDF, plasma TFV apparent clearance increased by 24.9% and 13.1% during the second and third trimesters of pregnancy, respectively, compared with non-pregnant populations. In the postpartum period, plasma TFV apparent clearance in pregnant women was 9.3% lower than in non-pregnant women. The bioavailability for TAF decreased by 17.3% and 5.1% during the second and third trimesters, respectively, and increased by 18% during the postpartum period relative to non-pregnant women. In pregnant women, simulations showed that TAF maintains approximately five times higher tenofovir diphosphate concentrations in PBMCs compared with TDF during the second and third trimesters, despite a decrease in PBMC tenofovir diphosphate concentrations for both drugs. This finding is consistent with the higher PBMC loading effect of TAF observed in non-pregnant populations.

CONCLUSIONS: Our semi-mechanistic model provides a framework for understanding pregnancy-associated pharmacokinetic changes and supports future research to refine dosing strategies for HIV treatment and prevention in pregnancy.

PMID:41222898 | DOI:10.1007/s40262-025-01589-y

J Relig Health. 2025 Nov 12. doi: 10.1007/s10943-025-02489-y. Online ahead of print.

ABSTRACT

The aim of the research is to evaluate the possible effectiveness of interactive participation between Muslim and Christian participants. The study employed an experimental design including 120 participants, randomly assigned into two groups: an intervention (experimental) group (n = 60) and a control group (n = 60). The findings indicate a significant increase in tolerance levels among the experimental group, with an average rise of 25 points on a 100-point scale, whereas the control group exhibited minimal change. The between-group difference following the intervention was statistically significant (t = 12.87, p < 0.001). Participants who engaged in interfaith dialogue reported increased empathy, recognition of shared ethical values, and a decline in exclusivist attitudes. These results highlight the potential of structured interfaith engagement as an effective tool for fostering religious tolerance in multicultural societies.

PMID:41222878 | DOI:10.1007/s10943-025-02489-y

Ophthalmol Ther. 2025 Nov 12. doi: 10.1007/s40123-025-01270-4. Online ahead of print.

ABSTRACT

INTRODUCTION: To report the 1-year efficacy of Myofix Defocus spectacles, designed to control the progression of myopia in childhood.

METHODS: A total of 47 children with myopia aged 7-15 years were enrolled. Cycloplegic objective refraction (spherical equivalent refraction, SE) and axial length (AL) were measured at baseline, 6 months, and 12 months. Linear regression models were used to identify risk factors of 12-month changes in SE and AL. For comparison, two virtual control groups of children were included. Tolerance was assessed through a questionnaire at each follow-up visit.

RESULTS: Of the initial cohort, 11 participants were lost to follow-up after 6 months due to reasons unrelated to lens design (77.1% retention rate). Over 12 months, the mean SE change in all eyes was – 0.21 ± 0.30 D, and AL change was 0.19 ± 0.13 mm. Progression was significantly different in participants who reported good compared to poor compliance (p < 0.001). At the 12-month follow-up, participants with good compliance had a mean SE progression of – 0.12 ± 0.25 D and a mean AL change of 0.17 ± 0.11 mm. In virtual controls, the mean annual SE progression was – 0.47 ± 0.36 D, and AL change was 0.26 ± 0.17 mm (both p < 0.001). In compliant participants, Myofix Defocus lens demonstrated a 75% reduction in SE and 37% reduction in AL compared to virtual controls.

CONCLUSIONS: After 1 year, Myofix Defocus spectacles slowed myopia progression in children, demonstrating comparable efficacy to other defocus-incorporated spectacle designs. Greater compliance resulted in better treatment effect. Further long-term studies are warranted to confirm these findings.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT07092072. Registered retrospectively on July 29, 2025.

PMID:41222872 | DOI:10.1007/s40123-025-01270-4

Eur J Epidemiol. 2025 Nov 12. doi: 10.1007/s10654-025-01303-z. Online ahead of print.

NO ABSTRACT

PMID:41222860 | DOI:10.1007/s10654-025-01303-z

Clin Drug Investig. 2025 Nov 12. doi: 10.1007/s40261-025-01485-0. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Parkinson’s disease (PD) affects a large population worldwide with millions of people losing motor function control. Although there is no recognized cure for PD, current medications aim to manage the symptoms and slow down the progression of the disease. Amantadine is one such treatment option that can be used in both early and late stages of PD. The current study aimed to assess the relative bioequivalence of two test prototypes (Ta and Tb) of amantadine extended-release (ER) oral formulation manufactured by Sun Pharmaceuticals Industries Limited with the reference immediate-release (IR) formulation (R) of amantadine hydrochloride manufactured by Morton Grove Pharmaceuticals Inc.

METHODS: This was an open-label, balanced, randomized, three-treatment, six-sequence, three-period, single-dose once daily (OD) versus twice daily (BID), crossover relative bioavailability study in healthy adult male subjects under fasting condition with a total of 36 + 2 additional standby subjects meeting the eligibility criteria. The pharmacokinetic parameters including maximum concentration (C_max), time to achieve C_max (t_max), area under the plasma concentration-time curve from time zero to time t (AUC_0-t), area under the concentration-time curve from 0 to 24 h (AUC_0-24), area under the plasma concentration-time curve from time 0 to infinity (AUC_0-∞), and half-life (t_1/2) were assessed. Statistical analysis was performed using analysis of variance (ANOVA) and ratio of least square means (LSM) (log transformed) was used to calculate the relative bioequivalence of the test drugs with the reference drug. Safety monitoring was done by considering adverse and serious adverse events during the duration of the study.

RESULTS: Both Ta and Tb formulations demonstrated similar systemic exposure to the reference product, meeting the criteria for bioequivalence within acceptable limits (80.00-125.00%). The ratios of LSM for log-transformed pharmacokinetic parameters (90% confidence interval [CI]) for Ta versus R were 100.02% (96.75-103.40%) for C_max, and 107.27% (102.75-112.00%) for AUC_0-t; and for Tb versus R were 93.92% (90.38-97.60%) for C_max, and 101.12% (96.73-105.71%) for AUC_0-t. There were no adverse or serious adverse events observed during the study.

CONCLUSION: These findings confirm the bioequivalence of the two test prototypes of amantadine ER formulation manufactured by Sun Pharmaceutical Industries Limited with the IR BID formulation of amantadine manufactured by Morton Grove Pharmaceuticals Inc. The pharmacokinetic equivalence supports the use of OD amantadine ER as an alternative to the BID IR formulation, with the potential to improve patient adherence due to reduced dosing frequency.

PMID:41222848 | DOI:10.1007/s40261-025-01485-0

Ann Nucl Med. 2025 Nov 12. doi: 10.1007/s12149-025-02124-6. Online ahead of print.

ABSTRACT

OBJECTIVE: The primary role of ¹⁸F-FDG PET/CT at the initial diagnosis of breast cancer is to detect distant metastases. This study aimed to investigate locoregional characteristics associated with distant metastasis, based on clinicopathological factors, standard-of-care (SOC) imaging, and ¹⁸F-FDG PET/CT-including a novel PET parameter, subcutaneous/cutaneous uptake (SCU).

METHODS: This retrospective study included patients with newly diagnosed, unilateral invasive breast cancer who underwent pretreatment ¹⁸F-FDG PET/CT. Associations between distant metastasis and the following parameters-including age, SOC imaging-based clinical T and N stage, histology, histological grade, and subtype, as well as tumor SUVmax, subareolar SUV ratio (sSUVr), and subcutaneous/cutaneous uptake (SCU) on PET-were assessed using the Mann-Whitney U test, Fisher’s exact test, and logistic regression. Subgroup analyses were also performed after stratifying patients by locoregional clinical stage (I-IIIA vs. IIIB-C).

RESULTS: Among 197 women (mean age, 56 ± 14 years), distant metastasis was identified in 23 (11.6%). The prevalence of distant metastasis at each locoregional stage in SCU-positive versus SCU-negative patients was as follows: 0% vs. 0% for stage I; 22% vs. 1% for stage IIA; 25% vs. 14% for stage IIB; 25% vs. 13% for stage IIIA; 25% vs. 33% for stage IIIB; and 50% vs. 50% for stage IIIC, with a statistically significant difference observed at stage IIA. In the total cohort, univariate analysis showed that clinical T stage (p = .005), clinical N stage (p < .001), sSUVr (p = .002), and SCU (p < .001) were significantly associated with distant metastasis. In multivariate analysis, only clinical N stages (Odd ratio [OR], 6.5-32.6; p < .001-0.02) remained independent predictors. In the stage I-IIIA subgroup, SCU (OR, 4.86; p = .048) independently predicted distant metastasis, along with age (OR, 1.07; p = .01) and clinical N stages (OR, 8.40-30.26; p = .002-0.008). In the stage IIIB-C subgroup, none of the explanatory variables had significant associations with distant metastasis.

CONCLUSIONS: Age, clinical N stages, and SCU were associated with an elevated risk of distant metastasis in the stage I-IIIA disease. SCU may serve as a novel imaging marker of systemic disease and aid in the diagnosis of distant metastasis-particularly in patients with early-stage breast cancer, where such findings can critically influence treatment strategy.

PMID:41222829 | DOI:10.1007/s12149-025-02124-6