Category: Nevin Manimala

Neurol Res. 2025 Aug 14:1-9. doi: 10.1080/01616412.2025.2541908. Online ahead of print.

ABSTRACT

OBJECTIVE: Based on the principles of Predictive, Preventive, and Personalized Medicine (PPPM), this study aimed to identify ferroptosis-related genes associated with multiple sclerosis (MS) and to explore the underlying mechanisms through genetic approaches.

MATERIALS AND METHODS: Summary statistics of circulating proteins were obtained from the UK Biobank Pharma Proteomics Project (UKB-PPP), ferroptosis-related genes were curated from the FerrDb database, and MS genome-wide association study (GWAS) data were sourced from the International Multiple Sclerosis Genetics Consortium (IMSGC). Two-sample Mendelian randomization (MR) analyses were performed to assess the causal relationships between proteins, ferroptosis-related genes, and MS risk. Mediation MR analysis was conducted to explore the potential mediating role of ferroptosis-related genes. The primary analytical method was inverse variance weighting (IVW), supplemented by MR-Egger and weighted median approaches.

RESULTS: After Bonferroni correction, one ferroptosis-related gene (Ferritin Mitochondrial, FTMT) and 21 circulating proteins were significantly associated with MS. Eleven protein-gene pairs were identified. Mediation analysis further revealed that FTMT mediated the effects of several proteins on MS risk, including CD8A (17.6%), CFB (9.0%), ENPP6 (9.5%), GZMA (22.9%), KIR2DL2 (17.4%), KIR2DL3 (16.9%), and TNXB (13.2%).

CONCLUSIONS: This study highlights the critical role of FTMT in linking circulating proteins to MS pathogenesis through ferroptosis regulation, providing novel insights into predictive, preventive, and personalized medicine strategies for MS management.

PMID:40813130 | DOI:10.1080/01616412.2025.2541908

Zhonghua Zhong Liu Za Zhi. 2025 Aug 23;47(8):750-755. doi: 10.3760/cma.j.cn112152-20240922-00409.

ABSTRACT

Objective: To detect the association of tumor circumferential involvement range (CIR) with neoadjuvant chemoradiotherapy (NCRT) efficacy and long-term survival outcomes in locally advanced rectal cancer (LARC) patients. Methods: Clinical data of 451 patients admitted to our hospital from January, 2018 to January, 2022 were retrospectively collected. According to the CIRs as determined by rectal magnetic resonance imaging, patients were divided into the High group (≥2/3 cycle, 270 patients) and the Low group (＜2/3 cycle, 181 patients). The primary outcome was three-year disease-free survival. The baseline characteristics, pathological features, and survival outcomes were compared. Results: Compared to patients in the Low group, patients in the High group exhibited significantly larger tumor vertical diameters [(4.7±1.7) vs. (3.6±1.4)cm, P＜0.001], higher rates of mrT4 stage (37.8% vs. 13.2%, P＜0.001), and higher rates of positive mesorectal fascia (54.1% vs. 29.8%, P＜0.001) and extramural vascular invasion (55.6% vs. 38.1%, P＜0.001). Patients in the High group were mainly pT3-4 stages (46.7% vs. 30.9%, P=0.002), with significantly lower rates of pathological complete response (22.2% vs. 33.1%, P=0.010) , poorer tumor regression grades (48.9% vs. 60.8%, P=0.013), and higher rates of positive peripheral nerve invasion (11.5% vs. 5.5%, P=0.031), as compared to patients in the Low group. The median follow-up time was 40 months. About 11 (2.4%) and 48 patients (10.6%) experienced tumor local recurrence and distant metastasis, respectively. The recurrence rates were 2.2% and 2.6%, and the distant metastasis rates were 7.7% and 12.6%, respectively, in the Low group and the High group, with no statistical significance (P=0.957, P=0.096). The three-year disease-free survival in the High group was significantly lower than that in the Low group (84.4% vs. 92.4%, P=0.014). Conclusions: The CIR is closely related to tumor burden, which can judge tumor response to NCRT, and is negatively related to survival prognosis. For patients who have more than a 2/3 cycle of CIR, intensified or consolidated treatments may be required to improve survival outcomes.

PMID:40813119 | DOI:10.3760/cma.j.cn112152-20240922-00409

Zhonghua Zhong Liu Za Zhi. 2025 Aug 23;47(8):734-744. doi: 10.3760/cma.j.cn112152-20231006-00164.

ABSTRACT

Objective: To investigate the survival outcomes and prognostic factors of patients with double primary breast cancer (BC) and endometrial cancer (EC). Methods: A retrospective cohort study was conducted using data for the period 1992-2018 from the Surveillance, Epidemiology, and End Results (SEER) database. There were 3 465 patients with BC as the first primary cancer (BC-EC group) and 2 804 patients with EC as the first primary cancer (EC-BC group). Kaplan-Meier analysis and cumulative incidence function were used to estimate overall mortality, breast cancer-specific mortality, and endometrial cancer-specific mortality, respectively. Cox regression and Fine-Gray regression were used to analyze the prognostic factors of overall mortality, breast cancer-specific mortality, and endometrial cancer-specific mortality, respectively. Results: During a median follow-up of 160 months, 1 616 deaths occurred in the BC-EC group, with EC being the leading cause of death (37.69%); 994 deaths occurred in the EC-BC group, with BC being the leading cause of death (28.77%). Cox regression identified patients with older ages at first primary cancer diagnosis (54-61 years: HR=1.46, 95% CI: 1.26-1.69; 62-68 years: HR=2.64, 95% CI: 2.29-3.03; ≥69 years: HR=4.89, 95% CI: 4.27-5.60), shorter time interval between the diagnoses (0-5 months: HR=6.13, 95% CI: 5.21-7.21; 6-23 months: HR=5.69, 95% CI: 4.95-6.55; 24-59 months: HR=3.44, 95% CI: 3.04-3.89; 60-119 months: HR=2.32, 95% CI: 2.07-2.59), mixed ductal-lobular BC (HR=1.29, 95% CI: 1.11-1.48), endometrial mixed cell adenocarcinoma (HR=1.23, 95% CI: 1.01-1.50), advanced tumor grade (grade Ⅱ BC: HR=1.13, 95% CI: 1.01-1.27; grade Ⅲ BC: HR=1.24, 95% CI: 1.10-1.41; grade Ⅱ EC: HR=1.19, 95% CI: 1.06-1.33; grade Ⅲ EC: HR=1.68, 95% CI: 1.48-1.90), advanced tumor stage of the two cancers (distant BC: HR=3.14, 95% CI: 2.50-3.94; regional EC: HR=1.53, 95% CI: 1.36-1.71; distant EC: HR=3.00, 95% CI: 2.59-3.47) had increased risk of overall mortality. Fine-Gray regression showed that compared with BC-EC patients, EC-BC patients had a higher risk of breast cancer-specific mortality [sub-distribution hazard ratio (sHR=1.24, 95% CI: 1.04-1.47], but a lower risk of endometrial cancer-specific mortality (sHR=0.37, 95% CI: 0.30-0.46). Older ages at first cancer diagnosis, shorter intervals between the diagnoses, negative ER and PR status, and advanced BC grades/stages were associated with increased breast cancer-specific mortality (P＜0.05). Similarly, older ages, shorter intervals, endometrial serous carcinoma/mixed cell adenocarcinoma, and advanced EC grades/stages correlated with elevated endometrial cancer-specific mortality (P＜0.05). Conclusion: The management of double primary BC and EC patients requires multidisciplinary strategies, with particular attention to patients presenting older ages at first cancer diagnosis, shorter intervals between the diagnoses, and unfavorable tumor characteristics.

PMID:40813117 | DOI:10.3760/cma.j.cn112152-20231006-00164

Zhonghua Zhong Liu Za Zhi. 2025 Aug 23;47(8):726-733. doi: 10.3760/cma.j.cn112152-20231007-00168.

ABSTRACT

Objective: To investigate the differences in the clinicopathological and magnetic resonance imaging (MRI) imaging features between ductal carcinoma in situ (DCIS) and ductal carcinoma in situ with microinfiltration (DCIS-MI) of the breast, and to clarify the risk factors for the development of DCIS-MI. Methods: Forty-four patients diagnosed with DCIS and 21 patients diagnosed with DCIS-MI by postoperative pathology at Guangdong Maternal and Child Health Hospital from November 2017 to November 2022 were included, and the clinicopathological and preoperative breast MRI data of these patients were retrospectively collected. The patients’ MRI images were categorized and diagnosed with reference to the Breast Imaging Reporting and Data System (BI-RADS) criteria. The χ² test or Fisher exact probability method was used to compare the differences in the clinicopathological and MRI imaging characteristics between the two groups of patients, and generalized linear model analysis was used to clarify the influencing factors of DCIS-MI. Results: The differences in the histologic grading, estrogen receptor (ER) expression, progesterone receptor (PR) expression, human epidermal growth factor receptor 2 (HER-2) expression, Ki-67, and molecular typing between patients in the DCIS and DCIS-MI groups were statistically significant (all P＜0.05). The results of generalized linear model analysis showed that Ki-67 expression and specific molecular typing (Luminal B and triple-negative types) were significantly associated with the risk of developing DCIS-MI (P＜0.05). Breast fibroglandular tissue density, lesion type, background parenchymal enhancement, type of time-intensity curves (TICs), distribution of non-mass enhancement, non-mass enhancement internal enhancement characteristics, mass morphology, mass boundary, mass enhancement mode, and other MRI imaging features were not statistically significant (all P＞0.05).The MRI diagnostic accuracy of the DCIS group and the DCIS-MI group was 77.3% (34/44) and 95.2% (20/21), respectively, and the difference in the MRI BI-RADS classification of the patients in the two groups was not statistically significant (P=0.227). Conclusions: There was no significant difference in the breast MRI imaging characteristics between patients in the DCIS and DCIS-MI groups. Patients in the DCIS-MI group were more likely to present with high histologic grades, negative ER, negative PR, positive HER-2, high Ki-67 expression, HER-2 overexpression, and triple-negative phenotypes. The association between Ki-67 expression and specific molecular typing (Luminal B and triple-negative phenotypes) and the risk of developing DCIS-MI risk were correlated.

PMID:40813116 | DOI:10.3760/cma.j.cn112152-20231007-00168

J Oral Pathol Med. 2025 Aug 14. doi: 10.1111/jop.70034. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the interaction between fluconazole-resistant (Flu-R) and -susceptible dose-dependent (Flu-SDD) isolates of Candida albicans and Candida glabrata with oral streptococci, exploring autoaggregation, coaggregation, and the impact of streptococcal biofilm-secreted components on Candida biofilms.

METHODS: Autoaggregation and coaggregation of Candida Flu-R and Flu-SDD isolates with streptococci (S. mutans, S. gordonii, and S. sanguinis) were assessed using an optical density assay. The inhibitory effects of streptococcal biofilm-secreted components on Candida biofilms were examined, quantifying biofilm inhibition by crystal violet staining and assessing viability through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Statistical analysis of the data was done by one-way ANOVA, considering a p-value of < 0.05 as significant.

RESULTS: Flu-R C. albicans exhibited higher autoaggregation (71%) than Flu-SDD (62%), both surpassing Streptococcus spp. (32%-49%). Flu-R and Flu-SDD C. glabrata had less autoaggregation ability than C. albicans (p < 0.05). Coaggregation increased steadily, with Flu-SDD C. albicans exhibiting the highest coaggregation with S. mutans (69% ± 8% at 2 h). Flu-R strains showed significant coaggregation differences with streptococcal species (p-values 0.05-< 0.001). Biofilm inhibition was significant in Candida Flu-R and Flu-SDD isolates treated with streptococcal biofilm supernatants. Supernatants of all three streptococcal species decreased Flu-R C. albicans viability (1.15-2.15-fold).

CONCLUSIONS: Fluconazole susceptibility/resistance significantly influences aggregation and biofilm formation with oral streptococci. Streptococcal biofilm supernatants hinder Candida strains’ growth and viability, suggesting implications for colonization, biofilm formation, and oral infections.

PMID:40813110 | DOI:10.1111/jop.70034

RMD Open. 2025 Aug 14;11(3):e005785. doi: 10.1136/rmdopen-2025-005785.

ABSTRACT

OBJECTIVE: To investigate the prevalence of difficult-to-treat psoriatic arthritis (D2T-PsA) and classify patients with persistent inflammatory PsA (PIPsA) and non-inflammatory PsA (NIPsA) based on a combination of clinical and musculoskeletal ultrasound (MSUS) evidence of inflammation.

METHODS: A multicentre cross-sectional study was conducted on PsA patients treated with biological disease-modifying anti-rheumatic drugs/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). D2T-PsA status was characterised by an inadequate response to ≥2 classes of b/tsDMARDs and the persistence of active disease, defined as a DAPSA >14.

RESULTS: Out of 517 PsA patients on b/tsDMARDs, 53 (10.3%) met the criteria for D2T-PsA with 30 (57%) classified as PIPsA and 23 (43%) classified as NIPsA. The PIPsA phenotype had higher swollen joint count (2.5 (IQR 1.0-7.0) vs 0.0 (IQR 0.0-1.0), p<0.001), dactylitis (20% vs 0%, p=0.030) and nail psoriasis (40% vs 13%, p=0.027). Conversely, NIPsA patients had significantly greater ΔPtGA-PhGA (4.0 (IQR 2.5-5.0) vs 0.0 (IQR 0.0-1.5), p<0.001), higher tender points (16.0 (IQR 0.0-18.0) vs 0.0 (IQR 0.0-8.0), p=0.009), a higher SPARCC enthesitis index (5.0 (IQR 2.0-8.0) vs 2.0 (IQR 0.0-5.0), p=0.023). The MSUS showed higher ultrasound activity (3.81±2.0 vs 0.91±0.5, p<0.001) and greater structural damage (4.12±1.0 vs 2.38±2.1, p<0.001), with both activity and damage scores being higher in PIPsA patients.

CONCLUSION: The classification into PIPsA and NIPsA based on easily detectable clinical features can support a tailored therapeutic management of patients with D2T-PsA.

PMID:40813109 | DOI:10.1136/rmdopen-2025-005785

RMD Open. 2025 Aug 14;11(3):e005557. doi: 10.1136/rmdopen-2025-005557.

ABSTRACT

BACKGROUND: Iscalimab (CFZ533) is a novel, anti-CD40 monoclonal antibody. This study evaluated the efficacy, pharmacokinetics and safety of iscalimab versus placebo as add-on to standard-of-care (SoC) therapy in patients with biopsy-proven active proliferative lupus nephritis (LN).

METHODS: This was a phase II, randomised, double-blind, placebo-controlled, multicentre study including patients with a diagnosis of systemic lupus erythematosus with active LN. Patients were randomly assigned (2:1) to receive either intravenous iscalimab (10 mg/kg) or placebo for 24 weeks on top of SoC for LN. The primary efficacy endpoint was the ratio from baseline in urinary protein-to-creatinine ratio (UPCR) at week 24. Safety assessments included adverse events (AEs) and serious AEs (SAEs) during treatment and follow-up up to 49 weeks.

FINDINGS: Of the 57 patients (iscalimab, n=39; placebo, n=18) randomised, 31 (54.4%) completed the study. The primary efficacy endpoint was met: at week 24, the relative improvement from baseline in proteinuria (UPCR) was 63.1% and 36.3% in the iscalimab and placebo arms, respectively. UPCR to baseline at week 24 showed a statistically significant reduction of 42.1% in the iscalimab versus placebo arm. Most AEs were of mild to moderate severity in both treatment arms. Overall, seven SAEs were reported in six patients (15.4%) in the iscalimab arm versus four in three patients (16.7%) in the placebo arm.

INTERPRETATION: Iscalimab showed a significant improvement in proteinuria (UPCR) in patients with active LN. Iscalimab was generally well tolerated with the exception of a few severe infections and one case of macrophage-activation syndrome in immunosuppressed and comorbid patients.

TRIAL REGISTRATION NUMBER: NCT03610516.

PMID:40813108 | DOI:10.1136/rmdopen-2025-005557

Stat Med. 2025 Aug;44(18-19):e70222. doi: 10.1002/sim.70222.

ABSTRACT

Advancements in wearable device technology have enabled accelerometers to continuously record minute-by-minute physical activity over consecutive days, yielding curves serially correlated in dense and regular longitudinal design. Motivated by a large-scale cohort of physical activity data throughout a week, the collected repeatedly measured functional data exhibits longitudinal (interday) and functional (intraday) interactions on fine grids. To accommodate this complex data structure and investigate the relationship between health assessment results and weekly physical activity patterns, we propose an innovative and efficient two-dimensional functional mixed-effect model (2dFMM), characterizing the longitudinal and functional cross-variability while incorporating two-dimensional fixed effects and four-dimensional correlation structure in marginal representation. We develop a fast three-stage estimation procedure to provide accurate fixed-effect inference for model interpretability and improve computational efficiency when encountering large datasets. We find strong evidence of intraday and interday varying significant associations between physical activity and mental health assessments among our cohort population, which sheds light on possible intervention strategies targeting daily physical activity patterns to improve school adolescent mental health. Our method is also used in environmental data to illustrate the wide applicability.

PMID:40813095 | DOI:10.1002/sim.70222

Huan Jing Ke Xue. 2025 Aug 8;46(8):5059-5069. doi: 10.13227/j.hjkx.202407169.

ABSTRACT

The heavy metal pollution in the sediments of tributaries directly affects the water quality of the Yangtze River. To investigate the distribution characteristics and pollution sources of heavy metals in the sediments of the incoming rivers in typical cities of the lower Yangtze River, the Nanjing section of the Yangtze River was selected as the study area. Sediment samples were collected from 16 monitoring points, and the monitoring data for As, Hg, Cr, Pb, Cd, Cu, and Zn were statistically analyzed. The potential ecological risk index method and the geo-accumulation index method were used to comprehensively evaluate the heavy metals in the sediments of the incoming rivers. Pearson correlation analysis and positive matrix factorization （PMF） were employed to analyze the sources of heavy metals in the sediments. The results indicated that the average values of seven heavy metals in the sediments of the incoming rivers were generally higher than those in the Yangtze River sediments, with all heavy metal coefficients of variation in the incoming river sediments exceeding 40%, indicating strong spatial heterogeneity. The primary heavy metal in the incoming river sediments in the Nanjing section of the Yangtze River was Cd, and the accumulation level and potential ecological risk of heavy metals in the Shitou River sediments were significantly higher than those in other incoming rivers. From upstream to downstream in the Nanjing section of the Yangtze River, the potential ecological risk index gradually increased, showing a spatial distribution characteristic of “lower upstream, higher downstream.” When P &lt; 0.01, Pearson correlation analysis indicated significant positive correlations among multiple heavy metals, suggesting that they may share common pollution sources. The results of the positive matrix factorization method （PMF） indicated that the main pollution sources of the incoming rivers included industrial pollution （26%）, agricultural pollution （29.7%）, and transportation （29.5%）, with the remaining 14.8% attributed to natural sources.

PMID:40813024 | DOI:10.13227/j.hjkx.202407169

Lancet Psychiatry. 2025 Sep;12(9):660-672. doi: 10.1016/S2215-0366(25)00217-2.

ABSTRACT

BACKGROUND: Family dynamics are implicated in self-harm and suicidality among children and adolescents. However, whether negative family dynamics confer a prospective risk and positive family dynamics confer a protective effect is not understood. To address this research gap, we aimed to summarise the prospective, longitudinal evidence examining the relationship between family dynamics, self-harm, and suicidality (ie, suicidal thoughts and behaviours) during childhood and adolescence.

METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, PsycINFO, and ERIC, as well as CINAHL, without language restrictions, from the date of database inception to May 20, 2025. Observational studies were eligible if they prospectively followed up a cohort of children and adolescents (age <20 years) from a general population, community, or school showing either no elevated risk or typical development of self-harm and suicidality for a minimum of 12 months. Eligible studies had to have included prospectively measured family dynamics, including positive (eg, emotionally supportive) and negative (eg, harsh, aversive, or punitive) parenting behaviours and family functioning (eg, family cohesion) or dysfunction (eg, discord or conflict) in childhood or adolescence. Extracted data consisted of study-level information and characteristics, participant characteristics, descriptions of study measures, and study results. Extracted data were entered into Covidence for consensus. The primary outcomes were self-harm (ie, thoughts of non-suicidal self-harm or self-injury, and non-suicidal self-harm or self-injury) and suicidality (ie, suicidal ideation and suicide attempt) over any reporting period. We examined individual and combined outcomes using a random-effects model. We assessed study quality using a modified Newcastle-Ottawa scale. This study is registered with PROSPERO (CRD42023434804).

FINDINGS: We screened 3860 articles and retained 38 studies, of which all 38 contributed to the narrative synthesis and 24 to the quantitative analyses. Altogether, the studies comprised 101 879 children and adolescents. Most study samples were from the USA (12 [32%]) or China (11 [29%]), with exposure and outcome ascertainment 12 months apart (25 [66%] studies) from age 10 years to 19 years (36 [95%]). Data stratified by sex, gender, race, or ethnicity were not consistently available. Female participants constituted a larger proportion of the samples than did male participants (ranges 42-100% vs 28-58%). Exposure to negative parenting was associated with an increased likelihood of combined self-harm and suicidal ideation (OR 1·29 [95% CI 1·15-1·46]) and non-suicidal self-harm or self-injury (1·46 [1·25-1·71]), but not suicidal ideation (1·07 [0·92-1·24]). Negative parenting practices and continuously measured self-harm and suicidality were not significantly associated. Positive parenting practices were not associated with suicidal ideation or with combined self-harm and suicidal ideation. Family dysfunction was longitudinally associated with an increased combined likelihood of self-harm and suicidality (OR 1·29 [95% CI 1·13-1·48]) and non-specific self-harm (1·70 [1·10-2·63]), but not suicide attempt (1·24 [0·93-1·66]). The overall rating of study quality was moderate (mean 6·5 of 10·0 stars [SD 1·29]).

INTERPRETATION: Negative parenting practices and family dysfunction seem to precede self-harm and suicidality among children and adolescents. Reducing negative family dynamics could alleviate these severe mental health concerns in the short term and assisting families to minimise early-life exposure to these dynamics could prevent the onset of self-harm and suicidality.

FUNDING: Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award Program and Canada Research Chairs Program.

PMID:40812960 | DOI:10.1016/S2215-0366(25)00217-2