Nevin Manimala

Adv Ther. 2025 Dec 22. doi: 10.1007/s12325-025-03441-y. Online ahead of print.

ABSTRACT

INTRODUCTION: PTEN hamartoma tumor syndrome (PHTS) is a rare genetic disorder caused by germline pathogenic variants in the PTEN tumor suppressor gene. Everolimus, an oral mTORC1 inhibitor, is approved for the treatment of tuberous sclerosis complex-related tumors; however, evidence for its efficacy in PHTS remains limited. A recent randomized controlled trial (RCT) reported safety and efficacy findings, but the composite primary efficacy endpoint did not reach statistical significance.

METHODS: We conducted a sensitivity analysis of this RCT to further evaluate the efficacy of everolimus in PHTS. Five statistical approaches were applied: analysis of covariance and four linear mixed-effects models. Outcomes included the composite neurocognitive score as a primary endpoint and multiple secondary neurocognitive and behavioral measures.

RESULTS: Across all analysis approaches, everolimus did not significantly improve the composite neurocognitive score compared with placebo. However, several secondary outcomes showed consistent benefits. Fine motor function assessed by the Purdue Pegboard Test (left hand) demonstrated sustained improvement over placebo across models. Social functioning, assessed by the total score (higher values indicating better functioning) of the reverse-coded Social Responsiveness Scale, second edition, improved over time, with significant differences observed at 6 months in the everolimus group. Several additional secondary endpoints showed consistent trends favoring everolimus.

CONCLUSION: Although the composite primary endpoint did not demonstrate significant improvement, sensitivity analyses identified potential benefits of everolimus in motor and social domains in individuals with PHTS. These results are consistent with the original trial findings and provide further support for investigating everolimus as a therapeutic option in this population.

PMID:41428178 | DOI:10.1007/s12325-025-03441-y

Curr Med Sci. 2025 Dec 22. doi: 10.1007/s11596-025-00146-9. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to investigate the associations of the triglyceride-glucose (TyG) index with kidney function decline, cardiovascular disease (CVD) events, and all-cause mortality across different glucose tolerance statuses.

METHODS: We analyzed 8,434 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. The primary outcomes were kidney function decline, CVD events, and all-cause mortality. Associations between the TyG index and outcomes were evaluated using binary logistic regression models.

RESULTS: During a 5-year follow-up, 150 participants (1.80%) developed kidney function decline, 357 (4.30%) experienced CVD events, and 335 (4.00%) died from all causes. An elevated TyG index was associated with increased risks of kidney function decline, nonfatal CVD events, and all-cause mortality in the overall population and among participants with diabetes (quartile 4 [Q4] vs. quartile 1 [Q1]: hazard ratio [HR] [95% confidence interval, P-value] = 4.97 [1.41-31.71, P = 0.034], 4.63 [1.25-30.19, P = 0.047], and 4.54 [1.70-15.88, P = 0.007], respectively). These associations were not statistically significant in participants with normal glucose tolerance or prediabetes. Notably, an elevated TyG index was significantly associated with increased risk of fatal CVD events in the overall population and across all glucose tolerance subgroups, with the strongest association observed in participants with prediabetes rather than diabetes.

CONCLUSIONS: The TyG index is significantly associated with the risks of kidney function decline, CVD events, and all-cause mortality, and these associations differ by glucose tolerance status.

PMID:41428156 | DOI:10.1007/s11596-025-00146-9

Eur J Clin Pharmacol. 2025 Dec 22;82(1):13. doi: 10.1007/s00228-025-03954-z.

ABSTRACT

PURPOSE: We conducted a comprehensive analysis of esketamine-related adverse events (AE) on the FDA Adverse Event Reporting System (FAERS) database, taking into account for the first time drug-drug interaction signals.

METHODS: We conducted a retrospective case/non-case study of esketamine-related AEs reported in the FAERS database up to the last quarter (Q4) of 2024. Potential signals were detected using the reporting odds ratio (ROR) and confidence intervals (CI), while drug-drug interactions were studied using different metrics such as lift, conviction and the combination risk ratio detection algorithm. An analysis of sex differences was also performed using the relative ROR and CI.

RESULTS: The analysis of 7,790 reports in which esketamine was a primary or secondary suspect identified potential safety signals for 173 AEs. Novel signals include homicidal ideation (ROR = 5.30, 95% CI: 2.38-11.82) and substance use disorder (ROR = 6.12, 95% CI: 2.54-14.73). Women showed a longer time to onset than men (p = 0.003). In addition, we detected sex differences in 23 AEs, seven of which were more likely to be reported in women, while 16 in men. Among these, four were significant exclusively in women (oxygen saturation decreased, abnormal behaviour, unresponsive to stimuli and aggression) and two in men (vision blurred and bradycardia). Potential signals of additive and multiplicative drug-drug interactions were detected for antidepressants (venlafaxine for”dizziness” and bupropion for “agitation”) and antipsychotics (risperidone for “vertigo”).

CONCLUSIONS: Our results increase knowledge on potential risks related to esketamine AEs and potential drug-drug interaction signals in a real-world setting.

PMID:41428148 | DOI:10.1007/s00228-025-03954-z

J Neurol. 2025 Dec 22;273(1):37. doi: 10.1007/s00415-025-13574-3.

ABSTRACT

BACKGROUND: Structural MRI studies have shown hypothalamic atrophy and altered white matter (WM) connectivity in amyotrophic lateral sclerosis (ALS), as a possible substrate of hypermetabolism in this condition. However, hypothalamic functional connectivity and its association with clinical features in ALS remain unclear. This study explored hypothalamic resting-state functional connectivity (RS-FC) in ALS patients compared to controls and its relationship with disease severity defined by the ALS Functional Rating Scale (ALSFRS-r), body mass index (BMI), disease duration, progression rate, survival, hypothalamic volume, and WM integrity.

METHODS: Seventy-one ALS patients and 39 healthy controls underwent structural and RS functional MRI. The bilateral hypothalamus was segmented, and a seed-based RS-FC analysis was performed. Group differences in hypothalamic RS-FC and their correlations with ALSFRS-r scores, BMI, disease duration, progression rate, survival, hypothalamic volume, and WM integrity were assessed. Tract-based spatial statistics was performed to estimate the correlation between WM damage in ALS and hypothalamic RS-FC.

RESULTS: ALS patients showed increased hypothalamic RS-FC with caudate nuclei compared to controls. Additionally, greater disease severity correlated with increased hypothalamic RS-FC with the caudate nuclei and orbitofrontal cortex. Hypothalamic RS-FC mean values also associated with FA in the genu of corpus callosum and forceps minor and disease progression rate. No significant correlations were observed with other clinical features.

CONCLUSIONS: These findings support hypothalamic alterations in ALS. Early detection of hypothalamic changes could be useful in prognostic stratification and evaluating intervention effects.

PMID:41428120 | DOI:10.1007/s00415-025-13574-3

Neuromolecular Med. 2025 Dec 22;28(1):1. doi: 10.1007/s12017-025-08900-x.

ABSTRACT

Lactylation has been identified as a novel epigenetic modification involved in neuroinflammation, mitochondrial dysfunction, and tau pathology. Although its relevance has been suggested in Alzheimer’s disease (AD), its causal contribution to distinct dementia subtypes remains unclear. We conducted a two-sample Mendelian randomization (MR) study to investigate whether the genetically predicted expression of 15 lactylation-related genes is causally associated with the risk of five dementia subtypes: Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). Gene expression instruments were selected from whole-blood eQTL data (n = 31,684), and outcome data were derived from large-scale GWASs. The inverse-variance weighted (IVW) method served as the primary analytical approach, with Bonferroni correction (α = 0.05/15) applied for multiple testing. After correction, six gene-dementia associations remained statistically significant. Increased expression of EP300 and PFKP was associated with higher AD risk, while SIRT1 and LDHC showed protective effects against PDD. NUP50 was associated with increased FTD risk, and STMN1 with reduced risk of DLB. No significant associations were detected for VaD. All findings were robust in sensitivity analyses and supported by brain expression evidence from GTEx. Genetic evidence was provided for a causal relationship between lactylation-related gene expression and dementia subtype risk, offering potential mechanistic insights and therapeutic targets.

PMID:41428114 | DOI:10.1007/s12017-025-08900-x

Environ Monit Assess. 2025 Dec 22;198(1):63. doi: 10.1007/s10661-025-14910-w.

ABSTRACT

Climate change can affect the dispersion of air pollutants, and it is important to investigate how the emission sources would contribute to air pollution in the context of future climate scenarios. The main objective of this study is to examine the impact of climate-induced changes on dispersion and concentration of local air pollutants related with aircraft operations in airport. The dispersion modelling was implemented considering current and future climate conditions (Copernicus data for 2050). The emission inventory for NO₂ from aircraft was compiled for winter and summer periods using current publicly available flight-tracking data and emission factors provided by the European Environment Agency. The methodology is applied to Lisbon International Airport allowing quantification of climate-induced changes on local air pollution near the airport. Although the highest NO₂ levels related to aircraft activities occur in winter, the most pronounced difference between the two climate scenarios is obtained for summer, with an increase up to 73% in the daily average concentration under future climate conditions. The area exceeding the EU daily average limit value expands by 59% in summer, while a slight 4% decrease is obtained for winter. Additionally, the data were analysed considering modelling receptor point co-located with the current measurements and showing that at some hours the airport may contribute up to 25% of NO₂ observed in densely populated area. This study highlights the importance of climate change in shaping future airport-related air pollution, emphasizing the need for effective air quality management strategies in the context of climate change.

PMID:41428112 | DOI:10.1007/s10661-025-14910-w

J Robot Surg. 2025 Dec 22;20(1):104. doi: 10.1007/s11701-025-03075-w.

ABSTRACT

Even though robotic surgery is well described in simple vesico-ureteral reflux (VUR), few studies explore its role in complex uretero-vesical junction (UVJ) anomalies or redo surgery. This study assesses the role of different robotic surgical procedures and clinical features that can impact the result of complex robotic ureteral reimplantation in children. Retrospective, multicenter cohort of pediatric patients who underwent robotic reimplantation between 2017 and 2023 in case of redo surgery or complex UVJ anatomy. Reimplantation techniques included: dismembered and non-dismembered Lich-Gregoire(D-RALUR, ND-RALUR), Dismembered Extravesical Cross-Trigonal reimplantation(RADECUR). Major criteria of resolution: no symptoms and/or reintervention with a minimum follow-up of 6 months. The study included 6 centers, 134 patients, median age 4 years (IQR 2.1-6.6; range: 0.5-17.4), median weight 15.2 Kg(IQR 13.1-22.0; range: 6.7-80.0). Redo surgery(48, 35.8%), duplex systems(38, 28.4%), obstructive megaureter(29, 21.6%) and others(27, 20.1%). D-RALUR 65 (48.5%), ND-RALUR 56(41.8%), RADECUR 13(9.7%). Early post-operative complication rate was 17.9%(including Clavien I-IIIb, with major complications, grade IIIb in 4.5% of patients – 2 incisional hernia, 4 UVJ stenosis). At a median follow-up of 21.2 months (IQR 11.7-33.3; range 6.0-80.1) the resolution was 82.2%. The comparative analysis found no significant difference in resolution respect to pathology (p = 0.179), technique (p = 0.331), age (p = 0.937) and weight (p = 0-495). There was no statistical difference in resolution rate when stratifying on weight ≤ 10Kg (p = 0.633) and ≤ 15 kg (p = 0.586). Within patients who experienced treatment failure we recorded 9 UVJ obstruction: 5(9%)D-RALUR, 4(8%)ND-RALUR; 11 VUR: 2(15%)RADECUR, 7(12%) D-RALUR, 2 (4%)ND-RALUR and 1 recurrent febrile UTI without VUR or obstruction: 1(D-RALUR). Robotic reimplantation is a valid option in case of complex pediatric UVJ pathologies, with good results also in children with a < 10 kg body weight.

PMID:41428111 | DOI:10.1007/s11701-025-03075-w

Eur J Psychotraumatol. 2025 Dec;16(1):2590402. doi: 10.1080/20008066.2025.2590402. Epub 2025 Dec 22.

ABSTRACT

Background: The International Trauma Questionnaire – Child and Adolescent Version (ITQ-CA) is an assessment tool designed to evaluate ICD-11 defined post-traumatic stress disorder (PTSD) and Complex PTSD (CPTSD) symptoms in children and adolescents and is widely utilized on an international scale.Objective: In this study, the psychometric properties of the ITQ-CA in the Turkish cultural context were evaluated.Method: The research sample consisted of 204 children and adolescents aged 7-17 who experienced the earthquakes centred in Kahramanmaraş, Turkey, in February 6, 2023. To determine the construct validity of the scale, four different models were established based on ICD-11, and their structures were analysed through confirmatory factor analysis (CFA).Results: The CFA results indicated that among the models tested, only the first-order six-factor model demonstrated an acceptable fit. Although it was determined to exhibit better model fit compared to other models, high correlations between subscales and inappropriate factor loadings in items (Heywood cases) were observed. This indicates a potential issue of model misspecification, suggesting that the obtained results should be interpreted with caution.Conclusions: This study provides evidence of the validity and reliability of the ITQ-CA, a widely used international assessment tool, in the Turkish cultural context. However, consistent with the literature, Heywood cases were observed in the models tested. These results indicate that models used to examine trauma symptoms with the ITQ should be carefully evaluated.

PMID:41424344 | DOI:10.1080/20008066.2025.2590402

Int J STD AIDS. 2025 Dec 22:9564624251410773. doi: 10.1177/09564624251410773. Online ahead of print.

ABSTRACT

BackgroundThis study aimed to identify people living with HIV (PLWH) with tuberculosis (TB) co-infection, explore their demographic and clinical characteristics, and determine predictors of early mortality within 6 months of TB diagnosis.MethodsA cross-sectional study was conducted in a tertiary referral center in Türkiye of PLWH diagnosed with TB between 2004 and 2023. Demographic, clinical, and laboratory data were reviewed, and statistical analyses were performed to identify early mortality predictors.ResultsAmong 1541 PLWH, 62 (4%) had TB, and 23 (37%) died within 6 months. TB presentations were pulmonary (44%), extrapulmonary (27%), and both (29%). Predictors significantly associated with early mortality included lymphopenia (p = 0.009), a CD4 + T lymphocyte count ≤50 cells/mm³ (p = 0.015), anemia (p = 0.009), and thrombocytopenia (p = 0.034), particularly platelet counts below 150,000/mm³ (p = 0.001). Clinical predictors also included symptoms such as fever (p = 0.017), anorexia (p = 0.012), weight loss (p = 0.012), and altered mental status (p = 0.043). Additionally, receiver operating characteristic (ROC) analysis demonstrated that CD4 + T lymphocyte count ≤50 cells/mm³ (AUC = 0.76, p = 0.039) and platelet count <150,000/mm³ (AUC = 0.71, p = 0.034) were significant predictive cutoffs for early mortality. TB culture positivity was high (84%), while PCR positivity was low (15%). Opportunistic infections were seen in 11% of cases.ConclusionsHigh early mortality among people living with HIV/TB co-infection is associated with advanced immunosuppression and hematological abnormalities. These results highlight the importance of early HIV detection and close clinical monitoring to reduce mortality.

PMID:41424343 | DOI:10.1177/09564624251410773

J Appl Gerontol. 2025 Dec 22:7334648251408868. doi: 10.1177/07334648251408868. Online ahead of print.

ABSTRACT

IntroductionAgeism is an understudied issue in prisons, especially among people with intersecting vulnerabilities. This study examined the prevalence and determinants of age-based discrimination among incarcerated older adults in Mexico using nationally representative data.MethodsWe analyzed the 2021 National Survey of Incarcerated People, focusing on adults aged 50 and older (n = 8,116). Descriptive statistics assessed prevalence and reasons for discrimination, and multinomial logistic regression identified associated factors.ResultsOverall, 21.4% of older adults reported discrimination, with age as the main reason (11.6%). Older women were almost twice as likely as men to report ageism. Older age, hypertension, other illnesses, disability, perceived insecurity, and experiences of violence were strongly associated with discrimination.ConclusionAge-based discrimination represents a significant and intersectional vulnerability for older adults. Findings underscore the need for age-responsive prison policies that promote safety, equity, and dignified aging.

PMID:41424333 | DOI:10.1177/07334648251408868