Nevin Manimala

Toxicol Sci. 2025 Aug 21:kfaf117. doi: 10.1093/toxsci/kfaf117. Online ahead of print.

ABSTRACT

There is an urgent need for high-throughput screening (HTS) models to replace, refine, and/or reduce (“3Rs”) vertebrate toxicity testing. Replacing in vivo animal studies is challenging for neurotoxicity and developmental neurotoxicity (DNT) where the functional relevancy of adverse outcomes needs to be assessed on the whole organism. We previously screened the NTP 87-compound library (NTP87), consisting of known and suspected developmental neurotoxicants, and showed that planarian HTS can identify known (developmental-) neurotoxicants. Because analysis methods can impact screening results and our original analysis used lowest observed effect level (LOEL) only, we hypothesized that use of state-of-the-art statistical analysis would increase sensitivity of planarian HTS to identify neurotoxicity and DNT. Using the original NTP87 planarian data, we quantified eight additional behavioral endpoints for a total of 26 readouts on days 7 and 12 of exposure days, evaluated at 5 log-scale concentrations (10 nM-100 µM). Benchmark concentration (BMC) modeling replaced LOEL analysis. We also calculated a concentration-independent multi-readout summary measure using weighted Aggregate Entropy (wAggE), providing insight into systems-level toxicity. Lastly, we compared the planarian BMC data to in vitro and developing zebrafish data from independent screens of the NTP87 library that were analyzed using the same BMC pipeline. Planarian and developing zebrafish screens showed similar sensitivity. Regenerating planarian hits helped correctly identify known neurotoxicants of the NTP87 library. Hierarchical clustering showed that organismal, neuron outgrowth, and neuron firing models were the main contributors to the NTP87 DNT battery’s information content, emphasizing their relevance for DNT testing.

PMID:40839344 | DOI:10.1093/toxsci/kfaf117

Sports Med. 2025 Aug 21. doi: 10.1007/s40279-025-02292-5. Online ahead of print.

ABSTRACT

BACKGROUND: Urolithin A (UA) is a metabolite produced by gut bacteria following the consumption of ellagitannin-rich foods. Clinical trials in middle-aged and older adults demonstrated that supplementation with UA improves muscle strength, endurance, and biomarkers of mitochondrial health, suggesting that UA may be an effective ergogenic aid in other populations.

METHODS: In this double-blind, parallel group, placebo-controlled clinical trial (NCT04783207), competitive male distance runners (n = 42, 27.2 ± 1.0 years, V ˙ O 2max 66.4 ± 0.6 mL·kg^-1·min^-1, mean ± SEM) were randomized to consume either 1000 mg·day^-1 UA (n = 22) or placebo (PL; n = 20) for 4 weeks during an altitude training camp (~ 1700-2200 m). Physiological outcomes including body composition, hemoglobin mass, running economy, and maximal aerobic capacity ( V ˙ O 2max ) were measured in all subjects at baseline and at the end of the 4-week camp to assess training- and supplementation-induced adaptations. During the camp, a weekly downhill running bout was performed to challenge skeletal muscle, with capillary blood samples collected to assess inflammation (C-reactive protein; CRP) and indirect markers of muscle damage (creatine kinase; CK). A subset of athletes also either completed a 3000 m track time trial (n = 11 PL, n = 11 UA) or had skeletal muscle biopsies taken (n = 9 PL, n = 11 UA) pre/post supplementation to determine the effect of UA on running performance and for exploration of alterations in skeletal muscle proteome and mitochondrial function, respectively.

RESULTS: Running performance (3000 m time trial) was not significantly improved in either treatment group (UA; p = 0.116, PL; p = 0.771), although UA supplementation significantly lowered ratings of perceived exertion (RPE, p = 0.02) and reduced indirect markers of post-exercise muscle damage (CK, total area under the curve p < 0.0001) following the 3000 m time trial compared with PL. Although there was no statistically significant time × treatment interaction for aerobic capacity (p = 0.138), UA supplementation showed a large within-group increase in V ˙ O 2max (5.4 ± 0.9%, 66.4 ± 0.8 to 70.0 ± 1.0 mL·kg^-1·min^-1, p = 0.009, d = – 0.83), with a smaller increase in the PL group (3.6 ± 1.3%, 66.4 ± 0.9 to 68.7 ± 1.0 mL·kg^-1·min^-1, p = 0.098, d = – 0.54). Proteomic screening of skeletal muscle biopsies revealed UA upregulated pathways associated with mitochondria, while downregulating inflammatory pathways. While not statistically significant, UA led to a medium effect for increased markers of mitophagy (d = – 0.74), without changes in mitochondrial function.

CONCLUSIONS: Our results show that 4 weeks of daily UA supplementation facilitates recovery by downregulating inflammatory pathways and indirect markers of muscle damage. However, despite a reduction in rating of exertion and increased aerobic capacity, UA supplementation did not further enhance performance in highly trained male endurance athletes.

PMID:40839339 | DOI:10.1007/s40279-025-02292-5

Prog Orthod. 2025 Aug 21;26(1):29. doi: 10.1186/s40510-025-00577-z.

NO ABSTRACT

PMID:40839319 | DOI:10.1186/s40510-025-00577-z

Virchows Arch. 2025 Aug 21. doi: 10.1007/s00428-025-04219-x. Online ahead of print.

ABSTRACT

Retinoblastoma is a malignant childhood neoplasm where MYCN amplification defines a subset of tumors with worse prognosis. FISH (fluorescence in situ hybridization) represents a fast and reliable method to measure gene copy numbers in various tumors but has not yet been systematically evaluated in retinoblastoma. In this study, we define criteria for FISH detection of MYCN amplification in a systematic unbiased approach by using a well characterized series of 44 clinical retinoblastoma samples. We (i) determined potential measurements and parameters by a comprehensive literature review, (ii) analyzed a retrospective cohort of samples with known MYCN amplification, (iii) determined statistically measurements and cut-offs, which allow reliable detection of amplified tumors, and (iv) applied these criteria to a prospective cohort. We demonstrate that average gene copy number (AVGCN) of MYCN/cell, MYCN/CEN2 ratio, and MYCN-CEN2 difference reveal the lowest statistical variance in amplified samples, if at least 50 cells were counted. The combination of these three parameters and cut-offs, namely AVGCN ≥ 10, MYCN/CEN2 ratio ≥ 3, and MYCN-CEN2 difference ≥ 8, allowed a reliable distinction between amplified and non-amplified cases. The prevalence of MYCN-amplified cases was 4/33 (12.1%) among prospective clinical samples indicating a higher percentage of positive tumors than previously reported. Our data provide the first evidence for well-grounded MYCN FISH criteria in retinoblastoma.

PMID:40839307 | DOI:10.1007/s00428-025-04219-x

Aging Clin Exp Res. 2025 Aug 21;37(1):253. doi: 10.1007/s40520-025-03166-6.

ABSTRACT

BACKGROUND: As a novel ultra-short-acting benzodiazepine derivative, remimazolam’s impact on postoperative neurocognitive recovery remains poorly characterized. Our research specifically evaluated its influence on postoperative delirium (POD) incidence compared with propofol in the geriatric surgical population.

METHODS: A comprehensive literature search was performed across four electronic databases, including the Cochrane Library, PubMed, Embase, and Web of Science, to identify eligible randomized controlled trials (RCTs). The methodological quality of the included studies was assessed using the Cochrane Collaboration’s risk of bias tool. Statistical analyses were performed using Review Manager 5.3 software; effect estimates were expressed as risk ratios (RR), standardized mean differences (SMD), and 95% confidence intervals (CI). The overall quality of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.

RESULTS: The meta-analysis incorporated five RCTs encompassing 1,368 patients. Pooled analysis revealed no statistically significant difference in POD incidence between the remimazolam and propofol groups (RR = 0.88, 95% CI: 0.58-1.33; P = 0.53). However, remimazolam administration was associated with a significant reduction in hypotensive events (RR = 0.55, 95% CI: 0.34-0.90; P < 0.05). No between-group differences were detected in postoperative nausea and vomiting incidence.

CONCLUSION: The current meta-analysis provided evidence that perioperative remimazolam administration did not significantly increase the risk of POD in elderly surgical patients, while demonstrating clinically significant benefits in hemodynamic stability.

PMID:40839287 | DOI:10.1007/s40520-025-03166-6

Arch Orthop Trauma Surg. 2025 Aug 21;145(1):419. doi: 10.1007/s00402-025-06044-y.

ABSTRACT

BACKGROUND: Mechanical alignment (MA) has long been the gold standard in total knee arthroplasty (TKA), but patient dissatisfaction has driven interest in more personalized alignment strategies. Functional alignment (FA) aims to restore a patient’s native joint line and balance flexion-extension gaps while minimizing soft tissue releases. This study compares the effects of robotic-assisted MA and FA on coronal plane alignment and clinical outcomes, using the Coronal Plane Alignment of the Knee (CPAK) classification as a reference.

METHODS: This retrospective cohort study included 300 patients who underwent robotic-assisted TKA (RA-TKA) using the ROSA system. Patients were divided into MA (n = 150) and FA (n = 150) groups. Preoperative and postoperative CPAK classifications, coronal alignment parameters, and clinical outcomes-including the Forgotten Joint Score (FJS) and Knee Society Score (KSS)-were analyzed at five years postoperatively. Statistical analyses assessed the impact of CPAK class changes on functional outcomes.

RESULTS: CPAK classification changed in 74.1% of MA cases and 46.1% of FA cases (p < 0.05), suggesting that FA better preserved native coronal alignment. LDFA varied significantly between groups (p = 0.005), while MPTA remained similar (p = 0.90). CPAK changes did not independently affect PROMs. In the MA group, LDFA increased significantly from 87.4° ± 2.2 to 89.7° ± 1.8 (p < 0.001), whereas in the FA group it remained stable (87.6° ± 2.1 to 87.9° ± 2.0;p = 0.12). The original CPAK classification was maintained in 81.1% of FA cases compared to 43.4% in the MA group (p < 0.001). No significant differences in FJS or KSS were observed between groups at five years, with mean scores of 82.1 (MA) vs. 83.5 (FA) for FJS and 89.6 (MA) vs. 90.2 (FA) for KSS (p > 0.05). Both alignment strategies achieved comparable long-term clinical outcomes.

CONCLUSION: FA in RA-TKA preserves coronal alignment better than MA while achieving similar clinical outcomes at mid-term follow-up. FA showed a greater ability to maintain the patient’s native CPAK phenotype, potentially supporting a more physiological joint line orientation and soft tissue balance. CPAK classification changes did not negatively affect patient satisfaction or function, suggesting that both alignment strategies can yield favorable results. Further research should explore the role of sagittal alignment and patellofemoral biomechanics in optimizing TKA outcomes.

PMID:40839284 | DOI:10.1007/s00402-025-06044-y

JAMA Netw Open. 2025 Aug 1;8(8):e2528006. doi: 10.1001/jamanetworkopen.2025.28006.

ABSTRACT

IMPORTANCE: Managed Long-Term Services and Supports (MLTSS) has been implemented by more than half of all state Medicaid programs, but knowledge of its scope and consequences for caregiving is limited.

OBJECTIVE: To describe observed trends in MLTSS program presence and care hours among older adults dually enrolled in Medicare and Medicaid between 2012 and 2022.

DESIGN, SETTING, AND PARTICIPANTS: This repeated cross-sectional study used data from the 2012-2022 National Health and Aging Trends Study (NHATS) linked with county-level measures of MLTSS program presence. Included in the study were adults aged 70 years or older dually enrolled in Medicare and Medicaid (hereafter older dual enrollees) who were living in the community and receiving assistance with self-care or mobility activities. Data analyses were conducted from December 2023 to June 2025.

EXPOSURE: Residence in an area with MLTSS program presence.

MAIN OUTCOMES AND MEASURES: The primary outcome was the total care hours per week received by older dual enrollees estimated as the mean (SD) care hours received per week overall and by caregiver type for each survey round. Percentages were weighted to account for the complex survey design.

RESULTS: Among 2549 participants, the mean (SD) age was 80.3 (8.5) years, 70.1% were female, and 26.5% lived alone. The weighted percentage of community-living, older dual enrollees receiving assistance who resided in areas with an MLTSS program increased from 39.4% in 2012 to 71.4% in 2022. Older dual enrollees receiving assistance were helped by a mean (SD) of 2.8 (1.6) caregivers and received 65.6 care hours per week (weighted percentage of total care hours, 80.9%). Fifty percent of participants received paid help. Most care hours were provided by unpaid family caregivers (mean [SD] care hours per week, 42.0 [74.0]). Mean (SD) weekly care hours for those residing in areas with continuous MLTSS presence were higher than those living in areas that added or had no MLTSS program presence (72.9 [82.8] vs 61.6 [71.7] and 60.0 [85.0] hours, respectively; P = .03). Among those residing in areas with continuous MLTSS, mean (SD) care hours provided by paid family caregivers increased steadily over the observation period from 2.0 (11.0) hours in 2012 to 23.8 (57.9) hours in 2022.

CONCLUSIONS AND RELEVANCE: This cross-sectional study found increases in the percentage of older dual enrollees receiving assistance in the community and residing in areas with MLTSS program presence, with persistent heavy reliance on unpaid family caregivers. Systems are needed to monitor the care experiences of patients and their caregivers.

PMID:40839267 | DOI:10.1001/jamanetworkopen.2025.28006

JAMA Netw Open. 2025 Aug 1;8(8):e2528019. doi: 10.1001/jamanetworkopen.2025.28019.

ABSTRACT

IMPORTANCE: Racial and geographic disparities in breast cancer survival persist. Biological consequences of chronic stress, measured by allostatic load (AL), may contribute to these disparities, but their role in breast cancer prognosis is not well understood.

OBJECTIVE: To evaluate the association between AL and overall survival among patients with breast cancer and assess the contribution of AL to racial and rural disparities in survival.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from an institutional electronic health record and cancer registry at the University of Virginia Comprehensive Cancer Center. Participants were women diagnosed with stage I to III breast cancer between 2014 and 2024. Data were analyzed from February 2025 through April 2025.

EXPOSURES: Allostatic load was derived from 14 clinical biomarkers and medication history and categorized as low (score ≤3) or high (score >3).

MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival. Cox proportional hazards models were used to assess the association with overall survival. Blinder-Oaxaca decomposition was performed to assess the extent to which AL explained disparities in survival by race and rurality.

RESULTS: Among 3069 patients with stage I to III breast cancer followed up for a median (IQR) of 55.4 (30.1-83.3) months (353 Black [11.5%], 2530 White [82.4%], and 178 other race [5.8%]; 1565 aged ≤66 years [51.0%] and 1504 aged >66 years [49.0%]), most individuals were postmenopausal (1523 patients [49.6%]) and married (1766 patients [57.5%]). There was a higher mean (SD) AL score in patients who were older (4.39 [1.68] for ages >66 years vs 3.84 [1.68] for ages ≤66 years), Black (4.54 [1.81] vs 4.07 [1.68] for White patients), rural residents (4.25 [1.72] vs 4.08 [1.70] for urban residents), uninsured (4.35 [1.55]) or on public insurance (eg, 4.33 [1.93] for Medicaid vs 3.70 [1.56] for private insurance), and unemployed (4.14 [1.77]) or retired (4.39 [1.65] vs 3.63 [1.60] for employed) and who reported no alcohol use (4.33 [1.74] vs 3.94 [1.66] for reported use) or a history of tobacco use (4.20 [1.69] vs 4.05 [1.72] for no reported use). High AL score (>3) was associated with an increased risk of mortality (hazard ratios [HRs] ranged from 1.26; 95% CI, 1.04 to 1.54 for model 5 [adjustment for demographics, social economic status, lifestyle factors, and clinical factors] to 1.53; 95% CI, 1.26 to 1.86 for model 1 [crude model]) compared with low AL score (≤3). Stratified analyses indicated a larger HR in the association between AL score and mortality among rural Black patients (HR per 1-unit increase in AL, 3.33; 95% CI, 1.27-8.77). In decomposition analyses, the total explained portion accounted for -0.0708 of the racial disparity, with AL score accounting for -0.0100 (95% CI, -0.0219 to 0.0018), or 14.2% of the explained portion, while the total explained portion of the geographic disparity was -0.0127, with AL score accounting for -0.0043 (95% CI, -0.0107 to 0.0021), or 34.3% of the explained rural disparity, although estimates were not statistically significant.

CONCLUSIONS AND RELEVANCE: In this study, high AL was independently associated with worse overall survival. The contribution of AL to the observed racial and rural disparities did not reach statistical significance.

PMID:40839266 | DOI:10.1001/jamanetworkopen.2025.28019

JAMA Netw Open. 2025 Aug 1;8(8):e2528124. doi: 10.1001/jamanetworkopen.2025.28124.

ABSTRACT

IMPORTANCE: Large-scale randomized studies evaluating the impact of catheter ablation on cardiovascular prognoses across different atrial fibrillation (AF) recurrence risk profiles are lacking.

OBJECTIVE: To investigate the benefits of catheter ablation in patients with varying numbers of nonmodifiable recurrence risk factors (NMRRFs).

DESIGN, SETTING, AND PARTICIPANTS: This study was a post hoc subanalysis of the multinational, multicenter, open-label Catheter Ablation vs Anti-Arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) randomized clinical trial, for which enrollment occurred from November 2009 to April 2016, with follow-up until December 31, 2017. Individuals with AF and at least 1 stroke risk factor were recruited in the CABANA trial. Only those with complete NMRRF data were included in this secondary analysis. Data were analyzed from November 1, 2023, to May 12, 2025.

EXPOSURE: Patients were categorized into 2 subgroups based on their number of NMRRFs (<3 or ≥3 risk factors).

MAIN OUTCOMES AND MEASURES: The primary end point of the CABANA trial was death, disabling stroke, serious bleeding, or cardiac arrest. Four NMRRFs were examined: AF duration more than 1 year, persistent or long-standing persistent AF, age older than 65 years, and female sex. Multivariable Cox proportional hazards regression models with adjustment were performed to investigate the benefit of ablation in each subgroup.

RESULTS: In total, 2185 patients (median age, 67.0 years [IQR, 62.0-72.0 years]; 1373 males [62.8%]) with complete NMRRF data were included. Of these patients, 1100 (50.3%) were randomized to receive catheter ablation and 1085 (49.7%) were randomized to receive drug therapy. Most patients (1469 [67.2%]) had fewer than 3 NMRRFs, while 716 (32.8%) had 3 or more. In patients with fewer than 3 NMRRFs, catheter ablation reduced the primary end point (adjusted hazard ratio [AHR], 0.59 [95% CI, 0.41-0.86]). However, the difference was not significant in those with 3 or more NMRRFs (AHR, 1.55 [95% CI, 0.93-2.58]). The interaction between the primary end point and the NMRRF category was significant (P for interaction = .003). Across all NMRRF groups, ablation did not reduce all-cause mortality (<3 NMRRFs: AHR, 0.65 [95% CI, 0.41-1.02] and ≥3 NMRRFs: AHR, 1.23 [95% CI, 0.66-2.33]) but decreased AF recurrence (<3 NMRRFs: AHR, 0.46 [95% CI, 0.40-0.52] and ≥3 NMRRFs: AHR, 0.58 [95% CI, 0.49-0.69]) and improved quality of life throughout follow-up for symptom frequency (<3 NMRRFs: -1.63 [95% CI, -2.18 to -1.07] and ≥3 NMRRFs: -1.15 [95% CI, -1.98 to -0.31]).

CONCLUSIONS AND RELEVANCE: In this secondary analysis of the CABANA randomized clinical trial, the findings suggest that catheter ablation yielded significant cardiovascular benefits in patients with AF with fewer than 3 NMRRFs compared with drug therapy. This study lays the foundation for more personalized AF management, potentially optimizing resource allocation and influencing the direction of research and clinical practice in this field.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00911508.

PMID:40839264 | DOI:10.1001/jamanetworkopen.2025.28124

JAMA Netw Open. 2025 Aug 1;8(8):e2528264. doi: 10.1001/jamanetworkopen.2025.28264.

ABSTRACT

IMPORTANCE: Prenatal intensive behavioral therapy (IBT) interventions that promote adequate gestational weight gain (GWG) have had variable and mostly modest effects on clinically relevant maternal and infant outcomes. It is unknown whether different maternal obesity metabolic phenotypes underlie the heterogeneity in response.

OBJECTIVE: To examine GWG, adverse perinatal outcomes, substrate changes, and differential changes in each in a prenatal IBT intervention conducted among pregnant individuals with 2 identified obesity phenotypes.

DESIGN, SETTING, AND PARTICIPANTS: The Lifestyle Interventions for Expectant Moms (LIFE-Moms) trial was a consortium of 7 independent but collaborative multicenter randomized clinical trials that took place between November 1, 2012, and December 31, 2017, and evaluated a prenatal IBT intervention on GWG and perinatal outcomes among women with overweight and obesity. Statistical analysis for the present preplanned secondary analysis was conducted from March 29, 2023, to June 4, 2025. Participants (n = 1150) had a confirmed viable singleton pregnancy and no previous diagnosis of cardiometabolic diseases. This analysis was limited to those with obesity. Participants were classified into 2 groups: obesity with no additional qualifying cardiometabolic disease risk factors (metabolically healthy obesity [MHO]) or obesity with 2 qualifying risk factors (metabolically unhealthy obesity [MUO]) in early pregnancy.

INTERVENTION: A behavioral lifestyle intervention incorporating diet and physical activity was delivered to increase adherence to the National Academy of Medicine GWG guidelines.

MAIN OUTCOMES AND MEASURES: GWG (total and adherence to guidelines), adverse perinatal outcomes, substrate changes, and infant body composition. Analysis was conducted on an intent-to-treat basis.

RESULTS: The mean (SD) age of the 640 participants was 30.2 (5.6) years, and the participants presented in early pregnancy with a mean (SD) body mass index of 35.2 (4.1). Participants in the MUO (n = 172) and MHO (n = 228) groups did not differ in response to treatment in weight outcomes, adverse perinatal outcomes, or substrate changes, with the exception that patients in the intervention group experienced smaller mean (SE) triglyceride increases more in the MUO group than in the MHO group (90.3% [7.4%] vs 81.8% [8.3%]; P = .02). After adjustment for maternal baseline demographics and treatment group, individuals with MUO had lower GWG (0.30 [0.23] kg/wk) compared with individuals with MHO (0.41 [0.27] kg/wk; P < .001), a 36.7% difference, and had a lower proportion exceed weight gain guidelines (57.0% [98 of 172] vs 68.0% [155 of 228]; P = .03). Participants with MUO had a higher incidence of gestational diabetes (23.8% [41 of 172] vs 9.8% [22 of 228]; P = .001) and had infants with a higher proportion of adiposity (mean [SD], 12.5% [3.9%] vs 11.7% [3.7%] fat; P = .05) compared with participants with MHO.

CONCLUSIONS AND RELEVANCE: In this preplanned secondary analysis of a randomized clinical trial of an IBT on GWG among pregnant individuals, those with MUO experienced less GWG, had a higher incidence of gestational diabetes, and had infants with a higher proportion of adiposity compared with those who MHO. Data supported that the maternal obesity metabolic phenotype has a greater clinical effect on adverse maternal and infant clinical outcomes compared with GWG alone and did not contribute to a differential response to a lifestyle intervention. Future interventions should identify methods to better optimize the maternal metabolic milieu as early in pregnancy as possible to reduce the intergenerational transmission of metabolic disease.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01545934, NCT01616147, NCT01771133, NCT01631747, NCT01768793, NCT01610752, NCT01812694.

PMID:40839263 | DOI:10.1001/jamanetworkopen.2025.28264