Nevin Manimala

JAMA Netw Open. 2025 Jul 1;8(7):e2519236. doi: 10.1001/jamanetworkopen.2025.19236.

ABSTRACT

IMPORTANCE: Etiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.

OBJECTIVE: To examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.

DESIGN, SETTING, AND PARTICIPANTS: This study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.

EXPOSURE: MHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).

MAIN OUTCOMES AND MEASURES: Breast cancer intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched-like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-<25; overweight, 25-<30; or obesity, ≥30).

RESULTS: This study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A-like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B-ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B-like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A-like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B-ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched-like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P < .04 for heterogeneity) tumors.

CONCLUSIONS AND RELEVANCE: In this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.

PMID:40622713 | DOI:10.1001/jamanetworkopen.2025.19236

JAMA Netw Open. 2025 Jul 1;8(7):e2519266. doi: 10.1001/jamanetworkopen.2025.19266.

ABSTRACT

IMPORTANCE: Suicide-prevention interventions often recommend removing firearms from the homes of individuals at elevated risk of suicide or, short of removal, locking and unloading all household firearms. The recommendation to remove firearms is based on strong and consistent evidence. For adults, however, the recommendation to lock firearms is based on few studies with inconsistent findings.

OBJECTIVE: To assess the association between firearm storage practices and suicide method by sex and age.

DESIGN, SETTING, AND PARTICIPANTS: This case-control study investigated decedents aged 15 years or older who lived in a home with firearms in the last year of their life and who died by suicide. Data were from the 1993 National Mortality Followback Survey. Analyses were conducted from June 1, 2024, to March 30, 2025.

EXPOSURES: The presence of 1 or more unlocked firearm in the decedent’s residence and/or 1 or more loaded firearm.

MAIN OUTCOMES AND MEASURES: The main outcome was firearm storage practices by suicide method. Logistic models, including both exposures, compared the relative odds of exposure among decedents who died by firearm suicide vs nonfirearm suicide, adjusted for sex, age, and region of residence at the time of death.

RESULTS: Among the 725 individuals who died by suicide (mean [SD] age, 47.1 [19.7] years; 554 males [85.0%]), 606 (83.6%) decedents died by firearm suicide and 119 (16.4%) died by nonfirearm suicide. Adult suicide decedents who used firearms were neither more nor less likely than those who used other suicide methods to have lived in a home where all firearms were locked (odds ratio [OR], 1.15 [95% CI, 0.67-1.95]) or unloaded (OR, 0.78 [95% CI, 0.44-1.36]). Corresponding ORs for locked firearms were 1.29 (95% CI, 0.69-2.44) for men and 0.58 (95% CI, 0.24-1.41) for women; for unloaded firearms, ORs were 0.80 (95% CI, 0.41-1.56) for men and 0.61 (95% CI, 0.25-1.51) for women. Among adolescent and young adult (hereinafter adolescent) decedents aged 15 to 20 years, approximately half (26 of 43 [60.5%]) who died by firearm suicide, but none of the 7 who died by nonfirearm suicide, had lived in a home with unlocked firearms. Among adolescents in households in which all firearms were locked, suicide method was not associated with whether any firearm was unloaded (OR, 1.36 [95% CI, 0.10-18.9]).

CONCLUSIONS AND RELEVANCE: In this case-control study, neither locking nor unloading household firearms was associated with whether adults used a firearm in their suicide. By contrast, adolescents who died by firearm suicide were far more likely to have lived in a household with unlocked firearms than were adolescent decedents who died by nonfirearm suicide methods. Suicide-prevention approaches that aim to reduce suicide mortality, especially for adult subpopulations likely to own firearms, should focus on firearm access rather than storage practices.

PMID:40622712 | DOI:10.1001/jamanetworkopen.2025.19266

JAMA Netw Open. 2025 Jul 1;8(7):e2519274. doi: 10.1001/jamanetworkopen.2025.19274.

ABSTRACT

IMPORTANCE: The introduction of immune checkpoint inhibitors (ICIs) has been associated with substantial improvement in median survival among individuals with cancer; however, people without health insurance coverage may be unable to afford ICIs due to their high costs.

OBJECTIVE: To examine the association between the introduction of ICIs and changes in survival disparities by health insurance coverage among people with a new diagnosis of advanced-stage cancer.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted among individuals who received a new diagnosis at age 18 to 64 years of stage IV melanoma (n = 12 048), non-small cell lung cancer (NSCLC; n = 152 610), or renal cell carcinoma (RCC; n = 18 782) who were identified from the National Cancer Database before and after US Food and Drug Administration approval of ICIs (January 1, 2002, to December 31, 2019, for melanoma and January 1, 2010, to December 31, 2019, for other cancers). Statistical analysis was conducted from December 2023 to April 2025.

EXPOSURE: Health insurance coverage at the time of diagnosis (private, Medicaid, or uninsured).

MAIN OUTCOMES AND MEASURES: The primary study outcome was 2-year overall survival. For each type of cancer, a 6-group propensity score weighting difference-in-differences (DID) approach was applied to examine the changes in 2-year survival before and after the ICI approval date among individuals without insurance or with Medicaid compared with those with private insurance.

RESULTS: Among the 183 440 individuals included, the mean (SD) age was 55.5 (7.0) years, and 56.5% were male. Two-year overall survival rates increased post-ICI approval among uninsured individuals (from 16.2% to 28.3%) and individuals with private insurance (from 28.7% to 46.0%) for those with a diagnosis of melanoma, resulting in a widening disparity of 6.1 percentage points (pp) (95% CI, 1.7-10.6 pp) after adjusting for sociodemographic characteristics. Similarly, among people with a diagnosis of NSCLC, the survival disparity between people without insurance and people with private insurance widened to 1.3 pp (95% CI, 0.2-2.3 pp). Survival differences between people with Medicaid and those with private insurance did not change significantly with the introduction of ICIs (DID for melanoma, -1.9 pp [95% CI, -5.6 to 1.8 pp]; DID for NSCLC, 0.4 pp [95% CI, -0.4 to 1.2 pp]; and DID for RCC, -3.8 pp [95% CI, -9.4 to 1.9 pp]).

CONCLUSIONS AND RELEVANCE: This serial cross-sectional study found that the introduction of ICIs was associated with widening survival disparity between people without health insurance and those with private insurance. Policies expanding access to health insurance coverage options and making new treatments more affordable are needed.

PMID:40622711 | DOI:10.1001/jamanetworkopen.2025.19274

Spine Deform. 2025 Jul 7. doi: 10.1007/s43390-025-01139-3. Online ahead of print.

ABSTRACT

PURPOSE: Early-onset scoliosis (EOS) significantly affects lung development and life expectancy. Magnetically Controlled Growing Rods (MCGR) effectively promote thoracic growth while managing curvature progression. This study aims to assess the impact of definitive spinal fusion on residual deformity and complications in EOS patients treated with MCGRs.

METHODS: The study included 27 EOS patients who underwent final fusion surgery between January 2017 and September 2022. The primary outcome was the evaluation of coronal and sagittal radiographic parameters postoperatively and at a minimum of 2 years of follow-up (FUP). Secondary outcomes included major complications (≥ IIIB, according to Clavien-Dindo Classification), surgery duration, blood loss and length of hospital stay (LOS).

RESULTS: Major curve (45.5° and 33.5°, p = 0.003, Brunner-Munzel Test Statistic = – 3.869254) and Thoracic Kyphosis (TK) (19.8° and 13.5°, p = 0.002, Brunner-Munzel Test Statistic = – 2.258845) were statistically impacted by arthrodesis, and maintained at the final follow-up. The surgeries had an average duration of 254.2 ± 39.5 min (range: 195-336 min) and an average blood loss of 574.1 ± 255.1 mL (range: 200-1300 mL). The mean LOS was 8.5 ± 1.8 days (range: 6-13 days). Following the final fusion, 5 patients (18.5%) developed a complication, of which one was classified as major.

CONCLUSIONS: This study demonstrated substantial improvements in coronal and sagittal alignment following graduation surgery, with results maintained at the two-year FUP. Further research with larger sample sizes is needed to provide a more comprehensive assessment of radiographic and surgical outcomes and to establish guidelines for implant density in MCGR graduation surgery.

PMID:40622674 | DOI:10.1007/s43390-025-01139-3

Rheumatol Ther. 2025 Jul 7. doi: 10.1007/s40744-025-00781-7. Online ahead of print.

ABSTRACT

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation and pain. Baricitinib, a targeted JAK inhibitor indicated for moderate to severe RA, has shown efficacy and safety, but real-world data on effectiveness and discontinuation rates are limited. This study aimed to report time to discontinuation, effectiveness, and patient-reported outcomes in patients initiating baricitinib or other biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) in the Spanish clinical practice.

METHODS: The subgroup from 11 Spanish hospitals in the multinational prospective RA-BE-REAL study was analysed. Patients treated for the first time with baricitinib or other b/tsDMARD were included. The primary objective was time to all-cause discontinuation of treatment at 24 months. Secondary objectives included assessing baseline characteristics, treatment patterns, and effectiveness on disease activity, health-related quality of life (HRQoL) and pain. Statistical analyses were descriptive in nature.

RESULTS: Eighty patients initiating baricitinib (cohort A, n = 31) or any b/tsDMARD (cohort B, n = 49) were included. Most patients were women, with mean age 62.6 and 57.0 years, respectively; 58.1% in cohort A and 40.8% in cohort B had prior b/tsDMARD treatment. After 24 months, 61.3% and 44.9% continued their initial treatment, respectively. Main reason for discontinuation was secondary loss of response (19.4% and 26.5%, respectively). After 3 months, both cohorts showed improvements in disease activity, swollen and tender joint counts, physician and patient global assessments, disability, pain, and HRQoL. This trend to improvement was maintained for up to 24 months, suggesting a rapid and sustained response. At 24 months, 46.4% and 29.3% achieved low disease activity; 10.7% and 26.8% achieved remission, respectively.

CONCLUSION: The study suggests that baricitinib, despite being used in an older and more treatment-experienced cohort, shows comparable effectiveness and a trend towards lower discontinuation rates for up to 24 months, reinforcing its potential as a treatment option.

PMID:40622673 | DOI:10.1007/s40744-025-00781-7

Psychon Bull Rev. 2025 Jul 7. doi: 10.3758/s13423-025-02703-8. Online ahead of print.

ABSTRACT

Statistical learning of spatial regularities during visual search leads to prioritization of target-rich locations. The resulting attentional bias may subsequently affect orienting and search behavior in similar tasks but its transfer to free viewing has not been demonstrated. We exploited a novel closed-loop paradigm where human observers searched for invisible target locations on a screen only guided by real-time auditory feedback conveying gaze-target distance. Unbeknownst to participants, location probability was biased towards one hemifield. Free viewing during rest, free image viewing, and spatial judgments were assessed before and after the search task. Search performance systematically improved and peaked in the biased hemifield, showing the unfolding of statistical learning. Importantly, the spatial bias transferred to both free-viewing conditions in terms of mean horizontal fixation position, while it did not transfer to spatial judgments. Exploratory results suggest that search performance was influenced by participants’ viewing pattern, whereas transfer was modulated by pre-existing (natural) spatial biases. Our results demonstrate that task-based statistical learning transfers to ecological scenarios, paving the way for future research and clinical applications aimed at ameliorating pathological spatial biases.

PMID:40622671 | DOI:10.3758/s13423-025-02703-8

Dermatol Ther (Heidelb). 2025 Jul 7. doi: 10.1007/s13555-025-01468-1. Online ahead of print.

ABSTRACT

INTRODUCTION: Therapeutic burden (TB) has been proposed as a potential predictor of treatment outcomes in both dermatological and non-dermatological diseases. This study aims to introduce the concept in the context of alopecia areata (AA) and assess its potential value in supporting therapeutic decision-making in clinical practice.

METHODS: A prospective cohort study was conducted including patients with AA who started treatment with baricitinib between January 2022 and January 2025 at a third-level hospital center. The main variable was TB, defined as the cumulative sum of previous systemic treatment cycles. An analysis was performed on whether socio-demographic or clinical factors were associated with TB.

RESULTS: Forty-four patients with AA treated with baricitinib were included. Most were women (65.90%) with a mean age of 37.70 (16.10) years. The predominant type of AA was multi-plaque (65.90%) and approximately one third (34.10%) had total/universal forms of the disease. Lower TB was statistically significantly associated with a greater reduction in Severity of Alopecia Tool (SALT) scores during the first 12 months of barictinib treatment compared with those patients with high TB (p < 0.05). This association was observed independently of all other known progression factors (duration of AA, baseline SALT, total/universal AA, female sex) (p < 0.05).

CONCLUSIONS: We present the concept of AA-adapted TB as a useful tool for categorizing patients with AA and contributing to therapeutic decision-making. Patients with AA with low TB showed a greater response to baricitinib treatment than patients who had received a greater number of systemic treatments previously.

PMID:40622665 | DOI:10.1007/s13555-025-01468-1

J Epidemiol Glob Health. 2025 Jul 7;15(1):93. doi: 10.1007/s44197-025-00433-7.

ABSTRACT

PURPOSE: Measles is a highly contagious but vaccine-preventable infectious disease. According to health authorities such as the ECDC (20240, urgent action is required to address the increasing spread of measles and insufficient vaccination coverage across the EU. The main objective of the present research is a comparative analysis of measles outbreak risk in two neighbouring countries with intensive economic relations and similar socio-economic challenges-Bulgaria and Romania. This research aims to deliver results on measles outbreak risk assessment in Bulgaria’s neighbouring countries to gain broader insight on the potential threats faced regionally and globally.

METHODS: Data from a 50-year period was collected on immunization coverage and demographic dynamics in Bulgaria and Romania. The main objective of the paper is the calculation of an annual Risk Index defined as the ratio of all susceptible individuals to the total population. A mathematical model is applied to estimate the immunization coverage and demographic parameters on an annual basis. This allows us to calculate with satisfactory precision the accumulation of susceptible persons tracing at least 20 years back in the history, needed for the calculation of an annual Risk Index.

RESULTS: The Risk Index curves for measles outbreak in Bulgaria and Romania are calculated for the period 2000 to 2023. The Risk Index curve for Bulgaria reveals a concerning increase after 2015, with particularly alarming values projected for 2017 and later. The results of the Risk Index for Romania after 2016 are also concerning. In 2023, the Risk Index for Bulgaria hits 7.55%, whereas in Romania it hits 8.1%.

CONCLUSION: Comparing the findings from the Risk Index to the real data from measles outbreaks for two neighbouring countries-with similar socio-demographic challenges-shows that the Risk Index is a good indicator for risk of measles outbreak. It can help the health authorities to forecast potential measles outbreaks – alongside vaccination coverage, demographic factors should also be considered when monitoring public health.

PMID:40622651 | DOI:10.1007/s44197-025-00433-7

Mol Biol Rep. 2025 Jul 7;52(1):676. doi: 10.1007/s11033-025-10793-9.

ABSTRACT

BACKGROUND: Indigenous cattle in India are known for their resilience to diseases, parasites, and heat stress. Belahi is a newly registered indigenous breed reared by pastoralist communities in the North Himalayan foothills (Shivalik range). It has been naturally selected for adaptability to nomadic grazing, disease resistance, and milk production. This study aimed to identify genomic selection signatures in Belahi cattle.

METHODS AND RESULTS: Genome-wide SNP data were analyzed using three intra-population statistics-Tajima’s D, Integrated Haplotype Score (iHS), and Nucleotide Diversity-which were combined into De-correlated Composite of Multiple Signals (DCMS). Additionally, Runs of Homozygosity (ROH) were used to detect regions under putative selection. DCMS identified 290 significant SNPs, while ROH revealed 8 overlapping regions. A total of 822 and 339 protein-coding genes were identified from DCMS and ROH, respectively, with 15 genes overlapping. Key genes included IL2 and IL21 (immune response) on BTA 17, and DNAJB13 (stress-related protein-folding) on BTA 15. QTL analysis revealed associations with tick resistance, susceptibility to respiratory and mycobacterial diseases, and pigmentation traits. Significant pathways included interleukin-2 receptor binding, leukocyte-mediated immunity, and peptidyl-tyrosine phosphorylation.

CONCLUSIONS: The results suggest that Belahi cattle have undergone natural selection for immunity and environmental stress tolerance due to their nomadic lifestyle. These genomic insights support the breed’s potential use in improving disease resistance and climate adaptability in cattle breeding programs.

PMID:40622616 | DOI:10.1007/s11033-025-10793-9

Cell Mol Neurobiol. 2025 Jul 7;45(1):66. doi: 10.1007/s10571-025-01583-9.

ABSTRACT

Vascular dementia (VaD) is a prevalent form of dementia caused by cerebrovascular disease, leading to cognitive impairment. While various risk factors have been identified, the role of plasma proteins in VaD etiology remains poorly understood. This study employs Mendelian randomization (MR) to investigate the causal relationship between plasma proteins and VaD risk, complemented by experimental validation. We conducted a two-sample MR analysis using summary statistics from genome-wide association studies (GWAS) on plasma proteins and VaD. Plasma protein data were derived from the deCODE Health study, encompassing 35,559 Icelandic participants and genetic associations for 4907 circulating proteins. VaD GWAS data were obtained from the FinnGen biobank, comprising 2717 VaD patients and 393,024 controls. Instrumental variables (IVs) were selected based on genome-wide significance thresholds (P < 5 × 10^-8 for plasma proteins, P < 5 × 10^-6 for VaD). The primary analysis used inverse variance weighting (IVW), supplemented by weighted median, MR-Egger, simple mode, and weighted mode methods. The Sensitivity analyses included heterogeneity tests, horizontal pleiotropy assessments, and leave-one-out analyses. Additionally, a 2-vessel occlusion (2-VO) animal model was used to validate key genes, with gene expression measured by quantitative real-time PCR (qPCR). Our initial MR analysis identified 123 plasma proteins significantly associated with VaD (P < 0.05), of which 12 maintained significance after FDR correction (FDR < 0.05). Importantly, the comprehensive pleiotropy analysis ultimately confirmed robust causal relationships for nine of these proteins with VaD. Among these, MED4 (OR = 1.819, 95% CI: 1.493-2.217, FDR < 0.001), COPS7B (OR = 1.136, 95% CI: 1.076-1.199, FDR < 0.001), CSF3 (OR = 1.262, 95% CI: 1.139-1.398, FDR < 0.001), IL26 (OR = 1.125, 95% CI: 1.066-1.186, FDR < 0.001), NRXN1 (OR = 1.125, 95% CI: 1.066-1.187, FDR < 0.001), LRRTM4 (OR = 1.418, 95% CI: 1.225-1.614, FDR < 0.001), and MAGEA3 (OR = 1.883, 95% CI: 1.403-2.529, FDR < 0.001) were identified as risk factors for VaD, with MED4 showing the strongest association. Conversely, CRYZL1 (OR = 0.387, 95% CI: 0.246-0.609, FDR < 0.001) and TMCC3 (OR = 0.327, 95% CI: 0.191-0.558, FDR < 0.001) were identified as protective factors. The Reverse MR analysis indicated no significant association between VaD and the 9 plasma proteins. In the 2-VO model, MED4 expression was significantly reduced, while NRXN1 expression was elevated compared to the sham group (P < 0.05). This study identifies several plasma proteins with a significant causal relationship with VaD, highlighting MED4 and NRXN1 as potential biomarkers and therapeutic targets. The findings were further validated in an experimental model, providing robust evidence for their roles in VaD pathogenesis. Further research is needed to elucidate the underlying mechanisms and confirm their clinical relevance.

PMID:40622612 | DOI:10.1007/s10571-025-01583-9