Tag: pubmed

JAMA Netw Open. 2025 Feb 3;8(2):e2459311. doi: 10.1001/jamanetworkopen.2024.59311.

ABSTRACT

IMPORTANCE: Clozapine is an effective medication for treatment-resistant schizophrenia but can cause agranulocytosis. Since its approval, patients taking clozapine have been required to undergo regular blood testing to screen for neutropenia. In 2015, the risk management programs were merged into a single risk evaluation and mitigation strategy (REMS), which mandates that prescribers undergo a certification process in which they attest to understanding the risk of agranulocytosis and commit to performing required blood testing. It is unknown how the clozapine REMS program has affected clinical practice.

OBJECTIVE: To understand physicians’ perceptions of and experiences with the clozapine REMS program.

DESIGN, SETTING, AND PARTICIPANTS: This survey study included US physicians who prescribed clozapine in 2021 or 2022. A 57-question, closed-field questionnaire was administered via paper or online. The first survey wave took place from May to October 2022 and the second from October 2022 to January 2023.

EXPOSURES: Gender, race and ethnicity, practice specialty, practice setting, practice region, professional time in clinical practice, years since graduation from medical school, and number of patients prescribed clozapine in the past 3 years.

MAIN OUTCOMES AND MEASURES: Experiences with and perceptions of the REMS certification process, patient initiation, and the REMS safe use requirements were measured using Likert scales. Descriptive statistics and multivariable modeling were used to analyze the study results.

RESULTS: Of 750 physicians contacted, 196 responded (30% response rate). Most respondents were male (129 [67%]), most identified as Asian (48 [25%]) or White (124 [63%]), and most were psychiatrists (165 [86%]); almost half (88 [45%]) practiced in an outpatient group setting. Most respondents reported that the information provided during certification was clear (179 [92%]) and contained useful drug information (145 [75%]) and that the paperwork associated with required blood testing facilitated physician-patient conversation (102 [53%]). Most respondents wanted certification materials to include all clinically important risks (172 [89%]) and benefits (139 [72%]) and reported frequent delays in medication access owing to required blood testing (115 [60%]). Two-thirds of respondents agreed that the positives of the certification process (123 [64%]) and blood testing requirements (129 [68%]) outweighed the negatives. In multivariable analysis, negative REMS perceptions were less common among physicians in practice longer (≥35 vs <15 years since medical school: odds ratio [OR], 0.28; 95% CI, 0.10-0.80) and among American Indian or Alaska Native, Black, and Native Hawaiian or Other Pacific Islander physicians compared with White physicians (OR, 0.08; 95% CI, 0.01-0.73).

CONCLUSIONS AND RELEVANCE: In this survey study of physician prescribers of clozapine, a majority were satisfied with the clozapine REMS program but highlighted the need for enhanced educational materials and administrative efficiency.

PMID:39946132 | DOI:10.1001/jamanetworkopen.2024.59311

JAMA Netw Open. 2025 Feb 3;8(2):e2459692. doi: 10.1001/jamanetworkopen.2024.59692.

ABSTRACT

IMPORTANCE: Current practices in axillary treatment for patients with breast cancer who receive a mastectomy for node-positive disease are unknown. For patients who receive postmastectomy radiotherapy (PMRT), the addition of axillary lymph node dissection (ALND) may result in significant overtreatment.

OBJECTIVES: To evaluate trends in axillary treatment for patients with limited nodal metastases who receive a mastectomy and identify factors that can be targeted to reduce axillary overtreatment.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted of patients identified from the National Cancer Database who received a diagnosis of breast cancer from January 1, 2012, to December 31, 2021. Patients included were women aged 18 years or older with clinical (c) T1-T2N0 breast cancer who underwent mastectomy with axillary staging with sentinel lymph node biopsy (SLNB) and/or ALND and had 1 to 2 positive lymph nodes. Patients who received neoadjuvant therapies were excluded. Statistical analysis was performed from December 2023 to July 2024.

EXPOSURE: Axillary management based on ALND and PMRT receipt: (1) ALND alone, (2) PMRT alone, (3) both ALND and PMRT, and (4) neither ALND nor PMRT.

MAIN OUTCOMES AND MEASURES: Axillary management strategies were evaluated, and clinicopathologic characteristics based on treatment type were compared with multivariable analysis.

RESULTS: In total, 62 332 patients were included (median age, 58 years [IQR, 48-68 years]; 82.2% with Charlson-Deyo comorbidity score 0). The proportion of patients who received ALND alone decreased from 47.1% to 17.6% from 2012 to 2021, while the percentage of patients who received PMRT alone increased from 9.8% to 36.8%. Overall, 21.3% of patients received treatment with both ALND and PMRT, with little change over time (from 21.7% in 2012 to 17.7% in 2021). Most patients (88.4%) who received both PMRT and ALND underwent ALND at the same operation as SLNB. Younger age (odds ratio [OR] per year increase, 0.98 [95% CI, 0.98-0.98]; P < .001), high-grade tumors (grade 2: OR, 1.18 [95% CI, 1.09-1.29]; P < .001; grade 3: OR, 1.34 [95% CI, 1.22-1.48]; P < .001), presence of lymphovascular invasion (OR, 1.26 [1.19-1.33]; P < .001), and larger tumor size (cT2 tumors compared with cT1: OR, 1.10 [95% CI, 1.03-1.17]; P = .004; upstaging to pathologic T3 tumors: OR, 2.29 [95% CI, 1.15-4.99]; P = .03) were associated with increased likelihood of concurrent treatment with ALND and PMRT.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of patients with breast cancer who received a mastectomy, a substantial proportion of those with 1 to 2 positive lymph nodes were treated with both ALND and PMRT. Delaying the decision for ALND until after multidisciplinary input may reduce overtreatment.

PMID:39946126 | DOI:10.1001/jamanetworkopen.2024.59692

JAMA. 2025 Feb 13. doi: 10.1001/jama.2024.27676. Online ahead of print.

NO ABSTRACT

PMID:39946125 | DOI:10.1001/jama.2024.27676

JAMA. 2025 Feb 13. doi: 10.1001/jama.2024.28517. Online ahead of print.

ABSTRACT

IMPORTANCE: The impact of recent abortion bans on infant mortality is not fully understood. There is also limited evidence on how these bans may interact with long-standing racial and ethnic disparities in infant health.

OBJECTIVE: To examine the association of abortion bans with changes in infant mortality and to compare this association in racial and ethnic groups based on analyses within and across states.

DESIGN, SETTING, AND PARTICIPANTS: This population-based, serial, cross-sectional study used a bayesian panel model to examine infant mortality rates in 14 states that implemented complete or 6-week abortion bans and compared them with predictions of infant mortality rates based on pre-ban mortality rates and states without bans. Data included all live births and infant deaths from all 50 US states and the District of Columbia for 2012 through 2023. Models accounted for temporal trends and state-specific factors, with analyses stratified by race and ethnicity, timing of death, and cause of death.

EXPOSURE: Complete or 6-week abortion bans.

MAIN OUTCOME AND MEASURES: Infant mortality rate, analyzed overall and by subgroups.

RESULTS: The analysis found higher than expected infant mortality in states after adoption of abortion bans (observed vs expected, 6.26 vs 5.93 per 1000 live births; absolute increase, 0.33 [95% credible interval (CrI), 0.14-0.51]; relative increase, 5.60% [95% CrI, 2.43%-8.73%]). This resulted in an estimated 478 excess infant deaths in the 14 states with bans during the months affected by bans. The estimated increases were higher among non-Hispanic Black infants compared with other racial and ethnic groups, with 11.81 observed vs 10.66 expected infant deaths per 1000 live births, an absolute increase of 1.15 (95% CrI, 0.53-1.81) and relative increase of 10.98% (95% CrI, 4.87%-17.89%). The observed infant mortality rate due to congenital anomalies was 1.37 vs 1.24 expected (absolute increase, 0.13 [95% CrI, 0.04-0.21]; relative increase, 10.87% [95% CrI, 3.39%-18.08%]), while the rate not due to congenital anomalies was 4.89 observed vs 4.69 expected (absolute increase, 0.20 [95% CrI, 0.02-0.38]; relative increase, 4.23% [95% CrI, 0.49%-8.23%]). Texas had a dominant influence on the overall results and there were larger increases in southern vs nonsouthern states.

CONCLUSIONS: US states that adopted abortion bans had higher than expected infant mortality after the bans took effect. The estimated relative increases in infant mortality were larger for deaths with congenital causes and among groups that had higher than average infant mortality rates at baseline, including Black infants and those in southern states.

PMID:39946113 | DOI:10.1001/jama.2024.28517

J Clin Psychopharmacol. 2025 Feb 14. doi: 10.1097/JCP.0000000000001964. Online ahead of print.

ABSTRACT

BACKGROUND: This randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifer NCT04285515) evaluated efficacy and safety of lumateperone to treat major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features.

PROCEDURES: Patients (18-75 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)-defined MDD with mixed features (n = 185) or bipolar disorder with mixed features (n = 200) and experiencing an MDE were randomized 1:1 to 6-week placebo (n = 195) or lumateperone 42 mg (n = 193). Primary and key secondary endpoints were change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale Total and Clinical Global Impression Scale-Severity (CGI-S) scores in 3 populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression. Safety included adverse events (AEs), extrapyramidal symptoms, and laboratory parameters.

RESULTS: Lumateperone met the primary endpoint, significantly improving Montgomery-Åsberg Depression Rating Scale total score at day 43 in populations with combined MDD/bipolar depression (least squares mean difference vs placebo [LSMD], -5.7; 95% confidence interval [CI], -7.60,-3.84; effect size [ES], -0.64; P < 0.0001), MDD (LSMD, -5.9; 95% CI, -8.61,-3.29; ES, -0.67; P < 0.0001), and bipolar depression (LSMD, -5.7; 95% CI, -8.29,-3.05; ES, -0.64; P < 0.0001). Lumateperone significantly improved CGI-S and Young Mania Rating Scale total scores at day 43 in these populations. Lumateperone was well-tolerated. Treatment-emergent AEs (≥5%, twice placebo) in the combined population were somnolence (placebo, 1.6%; lumateperone, 12.5%), dizziness (placebo, 2.1%; lumateperone, 12.0%), and nausea (placebo, 1.6%; lumateperone, 9.9%). There were no mania/hypomania treatment-emergent AEs with lumateperone and minimal extrapyramidal symptoms or metabolic risk.

CONCLUSIONS: Lumateperone 42 mg significantly improved depression symptoms and disease severity and was generally safe and well-tolerated in patients with MDD or bipolar depression with mixed features.

PMID:39946099 | DOI:10.1097/JCP.0000000000001964

Bioinformatics. 2025 Feb 13:btaf072. doi: 10.1093/bioinformatics/btaf072. Online ahead of print.

ABSTRACT

MOTIVATION: Copy number alterations are driving forces of tumour development and the emergence of intra-tumour heterogeneity. A comprehensive picture of these genomic aberrations is therefore essential for the development of personalised and precise cancer diagnostics and therapies. Single-cell sequencing offers the highest resolution for copy number profiling down to the level of individual cells. Recent high-throughput protocols allow for the processing of hundreds of cells through shallow whole-genome DNA sequencing. The resulting low read-depth data poses substantial statistical and computational challenges to the identification of copy number alterations.

RESULTS: We developed SCICoNE, a statistical model and MCMC algorithm tailored to single-cell copy number profiling from shallow whole-genome DNA sequencing data. SCICoNE reconstructs the history of copy number events in the tumour and uses these evolutionary relationships to identify the copy number profiles of the individual cells. We show the accuracy of this approach in evaluations on simulated data and demonstrate its practicability in applications to two breast cancer samples from different sequencing protocols.

AVAILABILITY: SCICoNE is available at https://github.com/cbg-ethz/SCICoNE.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:39946094 | DOI:10.1093/bioinformatics/btaf072

Eur Arch Paediatr Dent. 2025 Feb 13. doi: 10.1007/s40368-025-01006-9. Online ahead of print.

ABSTRACT

PURPOSE: Molar-incisor hypomineralisation (MIH) impacts children’s oral health and quality of life, but research on the stomatognathic system of unilateral cases, remains limited. This study evaluated the effects of unilateral MIH on the stomatognathic system in children, focusing on postural and masticatory activities and occlusal force contacts.

METHODS: In this cross-sectional observational study, 28 children (mean age: 8.21 years) were divided into two groups: without MIH (CG) and with unilateral MIH (MIHG). Electromyography (EMG) evaluated the activity of masseter and temporalis muscles during various jaw postures and habitual chewing. Occlusal force contacts were measured using T-SCAN®. Comparisons were made between groups and sides. Statistical analysis employed the Shapiro-Wilk test, Wilcoxon signed-rank test, and paired t-test, with a significance level of 5%.

RESULTS: EMG data demonstrated increased muscle hyperactivity in MIHG compared to CG at rest for the left temporalis muscle on the contralateral side (p < .001), during left laterality for the right temporalis muscle on the ipsilateral side (p = 0.04), and habitual chewing of soft food for the left temporalis muscle on the contralateral side (p = 0.02). Greater voluntary contraction was observed on the unaffected side in MIHG for the temporalis muscle at rest (p = 0.01) and the masseter muscle during right laterality (p = 0.02). No significant differences were found in occlusal force measurements between groups or sides.

CONCLUSIONS: This study indicates that unilateral MIH is associated with increased muscle hyperactivity in the contralateral temporalis and masseter muscles, without significant differences in occlusal force.

PMID:39946081 | DOI:10.1007/s40368-025-01006-9

J Endocrinol Invest. 2025 Feb 13. doi: 10.1007/s40618-025-02550-3. Online ahead of print.

ABSTRACT

PURPOSE: To detect the expression of miR-27a-5p in differentiated thyroid cancer (DTC) and to explore its correlation with SREBP1 expression, DTC malignant progression, and TSH suppression therapy.

METHODS: The expression levels of SREBP1 and miR-27a-5p in DTC tissues (n = 75) were detected by qRT-PCR. The expression of miR-27a-5p and SREBP1 was statistically analyzed for correlation with patients’ postoperative TSH inhibition therapy. Dual luciferase reporter gene assay was performed to verify the target-regulatory relationship between miR-27a-5p and SREBP1. qRT-PCR and Western blots were performed to detect the effect of miR-27a-5p on the expression level of SREBP1. MTS, plate clone formation assay was performed to detect the effect of miR-27a-5p on the proliferative capacity of cells. Flow cytometry was performed to detect the effect of miR-27a-5p on cell cycle and apoptosis. Scratch assay and Transwell assay was performed to detect the effect of miR-27a-5p on cell migration invasion ability.

RESULTS: MiR-27a-5p expression was significantly downregulated in DTC cancer tissues and significantly negatively correlated with SREBP1 expression. It correlated with the outcome of postoperative TSH suppression therapy in DTC patients. The results of dual luciferase reporter gene assay showed that the 3′-UTR region of SREBP1 mRNA was the target site of action of miR-27a-5p. Overexpression of miR-27a-5p was associated with a significant reduction in cell proliferation, cell cycle arrest, increased apoptosis, and diminished cell invasive migration.

CONCLUSION: The miR-27a-5p expression level was negatively correlated with the progression of DTC, which may be inhibited by targeting SREBP1 and correlated with the outcome of TSH inhibitory therapy.

PMID:39946050 | DOI:10.1007/s40618-025-02550-3

Eur J Epidemiol. 2025 Feb 13. doi: 10.1007/s10654-024-01185-7. Online ahead of print.

ABSTRACT

Recent advancements in machine learning (ML) for analyzing heterogeneous treatment effects (HTE) are gaining prominence within the medical and epidemiological communities, offering potential breakthroughs in the realm of precision medicine by enabling the prediction of individual responses to treatments. This paper introduces the methodological frameworks used to study HTEs, particularly based on a single randomized controlled trial (RCT). We focus on methods to estimate conditional average treatment effect (CATE) for multiple covariates, aiming to predict individualized treatment effects. We explore a range of methodologies from basic frameworks like the T-learner, S-learner, and Causal Forest, to more advanced ones such as the DR-learner and R-learner, as well as cross-validation for CATE estimation to enhance statistical efficiency by estimating CATE for all RCT participants. We also provide a practical application of these approaches using the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, which compared the effects of high versus low-fat diet interventions on 2-year weight changes. We compared different sets of covariates for CATE estimation, showing that the DR- and R-learners are useful for the estimation of CATE in high-dimensional settings. This paper aims to explain the theoretical underpinnings and methodological nuances of ML-based HTE analysis without relying on technical jargon, making these concepts more accessible to the clinical and epidemiological research communities.

PMID:39946045 | DOI:10.1007/s10654-024-01185-7

Environ Sci Pollut Res Int. 2025 Feb 13. doi: 10.1007/s11356-025-36049-4. Online ahead of print.

ABSTRACT

Traditional drought indices, such as the Standardized Precipitation Index (SPI) and Standardized Runoff Index (SRI), often fail to capture the complexity of drought events, which involve multiple interacting variables. To address this gap, this study applies the Principle of Maximum Entropy (POME) copula to combine SPI and SRI into a Joint Deficit Index (JDI), offering a more complete assessment of hydrometeorological drought. We used machine learning models, including Random Forest (RF), Quantile Random Forest (QRF), Extreme Gradient Boosting (XGB), and Quantile Regression XGBoost (QXGB), to predict JDI, while also incorporating uncertainty analysis using the Uncertainty Estimation based on Local Errors and Clustering (UNEEC) method. This approach not only improves the accuracy of drought predictions but also quantifies the uncertainty of the models, enhancing reliability. Model performance, evaluated with R², RMSE, and MAE, showed XGB as the best performer, achieving R² = 0.93 and RMSE = 0.16. This integration of multivariate drought indices, machine learning, and uncertainty analysis provides a more robust tool for drought monitoring and water resource management in arid regions.

PMID:39946044 | DOI:10.1007/s11356-025-36049-4