Nevin Manimala

JAMA Netw Open. 2025 May 1;8(5):e258903. doi: 10.1001/jamanetworkopen.2025.8903.

ABSTRACT

IMPORTANCE: Scarce population-based data exist on whether APOE4 modifies associations of blood-based neurodegenerative biomarkers with cognitive decline, particularly in a diverse, biracial population of community-dwelling older adults without dementia.

OBJECTIVE: To assess whether APOE4 carrier status is associated with an accelerated rate of cognitive decline in older adults without dementia and with elevated neurodegenerative burden.

DESIGN, SETTING, AND PARTICIPANTS: This 20-year prospective cohort study started in 1993 and was conducted through 2012 on the South Side of Chicago among community-dwelling older adults without dementia from the longitudinal biracial Chicago Health and Aging Project. The interaction of APOE4 carrier status with prospective associations of serum neurodegenerative biomarkers with global cognitive decline was examined using a mixed-effects regression model, adjusting for demographics and chronic health conditions. Statistical analyses were conducted from June 2024 to January 2025.

EXPOSURE: APOE4 carrier status and serum biomarker levels for total tau (t-tau), neurofilament light (NfL) chain, and glial fibrillary acidic protein (GFAP) measured with a Quanterix Neuroplex kit at baseline.

MAIN OUTCOMES AND MEASURES: Cognitive decline calculated from composite global cognition scores across study waves.

RESULTS: Among 1038 community-dwelling older adults (mean [SD] age, 77.1 [5.9] years; 615 Black [59.2%] and 423 White [40.8%]; 651 female [62.7%]), there was a mean (SD) of 12.8 (3.4) years of education and 343 individuals (33.0%) were APOE4 carriers. Higher levels of blood-based neurodegenerative biomarkers (ie, t-tau, NfL, and GFAP) were associated with a faster rate of cognitive decline among APOE4 carriers than noncarriers. Specifically, compared with noncarriers, APOE4 carriers had annual rates of cognitive decline per 1-log10 unit higher levels in t-tau and GFAP that were accelerated by a β (SD) of -0.03 (0.02) (P = .046) and -0.07 (0.03) (P = .02), respectively. Similarly, compared with noncarriers and participants in the lower NfL tertile, APOE4 carriers with middle and upper tertiles of NfL levels experienced accelerated cognitive decline, with a β (SD) of -0.04 (0.02) (P = .006) and -0.03 (0.02) (P = .07), respectively, although the difference was not significant for upper tertiles.

CONCLUSIONS AND RELEVANCE: This study found that higher levels of neurodegeneration (t-tau), axonal injury (NfL), and reactive astrocytes and neuroinflammation (GFAP) biomarkers were associated with accelerated cognitive decline in genetically susceptible APOE4 carriers. These findings highlight the association of APOE4 with exacerbation of neurodegenerative processes, with not only significant implications for understanding and tracking the progression of neurodegenerative diseases, but also a call for inclusivity of APOE4 status in scientific investigations and clinical trials.

PMID:40332937 | DOI:10.1001/jamanetworkopen.2025.8903

JAMA Netw Open. 2025 May 1;8(5):e258927. doi: 10.1001/jamanetworkopen.2025.8927.

ABSTRACT

IMPORTANCE: Agitation events are increasing in emergency departments (EDs), exacerbating safety risks for patients and clinicians. A wide range of clinical etiologies and behavioral patterns in the emergency setting make agitation prediction difficult in this setting.

OBJECTIVE: To develop, train, and validate an agitation-specific prediction model based on a large, diverse set of past ED visit data.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included electronic health record data collected from 9 ED sites within a large, urban health system in the Northeast US. All ED visits featuring patients aged 18 years or older from January 1, 2015, to December 31, 2022, were included in the analysis and modeling. Data analysis occurred between May 2023 and September 2024.

EXPOSURES: Variables that served as potential exposures of interest, encompassing demographic information, patient history, initial vital signs, visit information, mode of arrival, and health services utilization.

MAIN OUTCOMES AND MEASURES: The primary outcome of agitation was defined as the presence of an intramuscular chemical sedation and/or violent physical restraint order during an ED visit. A clinical model was developed to identify risk factors that predict agitation development during an ED visit prior to symptom onset. Model performance was measured using area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (PR-AUC).

RESULTS: The final cohort comprised 3 048 780 visits. The cohort had a mean (SD) age of 50.2 (20.4) years, with 54.7% visits among female patients. The final artificial intelligence model used 50 predictors for the primary outcome of predicting agitation events. The model achieved an AUROC of 0.94 (95% CI, 0.93-0.94) and a PR-AUC of 0.41 (95% CI, 0.40-0.42) in cross-validation, indicating good discriminative ability. Calibration of the model was evaluated and demonstrated robustness across the range of predicted probabilities. The top predictors in the final model included factors such as number of past ED visits, initial vital signs, medical history, chief concern, and number of previous sedation and restraint events.

CONCLUSIONS AND RELEVANCE: Using a cross-sectional cohort of ED visits across 9 hospitals, the prediction model included factors for detecting risk of agitation that demonstrated high accuracy and applicability across diverse patient populations. These results suggest that clinical application of the model may enhance patient-centered care through preemptive deescalation and prevention of agitation.

PMID:40332935 | DOI:10.1001/jamanetworkopen.2025.8927

JAMA Netw Open. 2025 May 1;8(5):e258942. doi: 10.1001/jamanetworkopen.2025.8942.

ABSTRACT

IMPORTANCE: Motor vehicle crashes are the leading cause of death for US teens. Newer vehicles and driver assistance technologies show promise in reducing crashes and injury severities; however, research on the age and technologies of vehicles driven by teens involved in fatal crashes is limited.

OBJECTIVE: To examine the differences in vehicle age and driver assistance technologies between vehicles driven by teen and middle-aged drivers involved in fatal crashes and to investigate the associations among vehicle age, driver assistance technologies, and driver death in these crashes.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used fatal crash data (2016-2021) obtained from the Fatality Analysis Reporting System. Data analysis was restricted to passenger vehicles. Participants included teen drivers (15-18 years old) and middle-aged drivers (31-55 years old). All analyses were performed between December 1, 2023, and July 25, 2024.

EXPOSURES: Exposures include the vehicle age (≤5, 6-15, or >15 years) and the number of driver assistance technologies installed (0 to 4).

MAIN OUTCOMES AND MEASURES: The main outcome was whether the driver died in fatal crashes. Multivariable logistic regressions examined the associations between vehicle age (or driver assistance technologies installed) and driver death in fatal crashes, adjusting for driver sex, restraint use, and crash year.

RESULTS: Among 81 145 drivers (49 838 male [61.4%]) involved in fatal crashes, there were 9809 teen drivers (mean [SD] age, 17.2 [0.9] years) and 71 336 middle-aged drivers (mean [SD] age, 41.7 [7.3] years). A higher proportion of teen drivers were operating vehicles older than 15 years compared with middle-aged drivers (2706 drivers [27.6%] vs 16 239 drivers [22.8%]). Driving vehicles aged 6 to 15 years (adjusted risk ratio [aRR], 1.19; 95% CI, 1.17-1.22) or older than 15 years (aRR, 1.31; 95% CI, 1.28-1.34) was associated with significantly higher odds of driver death in fatal crashes compared with driving vehicles 5 years old or newer, independently of driver age. Additionally, each installed driver assistance technology was associated with a 6% reduction (aRR, 0.94; 95% CI, 0.90-0.98) in the risk of driver death in fatal crashes.

CONCLUSIONS AND RELEVANCE: These findings suggest that older vehicles and those with fewer driver assistance technologies are associated with increased risk of driver death in fatal crashes; thus, teens should drive the safest vehicles available, not older family cars. The findings underscore the urgent need to ensure teens drive safer vehicles to protect their lives.

PMID:40332934 | DOI:10.1001/jamanetworkopen.2025.8942

JAMA Netw Open. 2025 May 1;8(5):e259043. doi: 10.1001/jamanetworkopen.2025.9043.

ABSTRACT

IMPORTANCE: In 2016, the Centers for Disease Control and Prevention (CDC) published guidelines cautioning against prescribing opioids for chronic noncancer pain. Little is known about unintended outcomes of this guideline on analgesic prescribing for older adults with cancer, who commonly require opioids as first-line pain treatment.

OBJECTIVE: To determine whether the 2016 CDC guideline was associated with altered analgesic prescribing among older adults with cancer.

DESIGN, SETTING, AND PARTICIPANTS: Interrupted time series analysis of a longitudinal cohort using Medicare Current Beneficiary Survey (MCBS) dataset (2010-2020), a nationally representative longitudinal survey of Medicare beneficiaries linked to Medicare claims. MCBS participants older than 65 years who reported a non-skin cancer diagnosis were followed up for up to 4 years. Subgroup analysis conducted for those with poor prognosis cancer or a cancer-related pain encounter (advanced cancer/cancer pain). Data were analyzed from January 2023 to February 2025.

EXPOSURE: CDC Guideline for Prescribing Opioids for Chronic Pain publication in March 2016.

MAIN OUTCOMES AND MEASURES: Quarterly prescribing rates of opioids (typical opioids, tramadol, and buprenorphine) and gabapentinoids (gabapentin and pregabalin). For each time series analysis outcome, a level change estimated immediate change and trend (ie, slope) change estimated ongoing change following the guideline.

RESULTS: The cohort included 11 903 older adults with cancer (mean [IQR] age, 79.4 [73-85] years, 6504 [54.6%] women), including 1283 with advanced cancer or cancer pain. Compared with preguideline trends, we observed the following changes after the guideline release: the slope of opioid prescribing decreased (typical opioids: -0.47; 95% CI, -0.63 to -0.30 percentage points [pp]/quarter; tramadol: -0.27; 95% CI, -0.36 to -0.17 pp/quarter; buprenorphine: -0.01; 95% CI, -0.02 to -0.01 pp/quarter), though tramadol prescribing rose by 11.5% overall; and gabapentinoid prescribing increased by 24.9% (slope change, -0.03; 95% CI, -0.09 to 0.02 pp/quarter).

CONCLUSIONS AND RELEVANCE: In this cohort study of older adults with cancer, the 2016 CDC guideline was associated with a decline in opioid prescribing that was less pronounced for tramadol compared with typical opioids and was followed by a 25% increase in gabapentinoid prescribing. This may reflect a shift in cancer pain management from first-line opioids to tramadol, which is less safe, and gabapentinoids, which have been shown to be less effective for cancer pain treatment.

PMID:40332933 | DOI:10.1001/jamanetworkopen.2025.9043

JAMA Surg. 2025 May 7. doi: 10.1001/jamasurg.2025.1072. Online ahead of print.

ABSTRACT

IMPORTANCE: Use of modern neoadjuvant chemotherapy (NAC) regimens has markedly increased rates of pathologic complete response (pCR) in breast cancer, raising the question of whether surgical removal of the primary tumor is required for patients with pCR. For surgery to be omitted, one must be able to accurately predict pCR before surgery.

OBJECTIVE: To investigate if adding post-NAC core needle biopsy of the tumor bed to trimodality imaging in patients who have clinical complete response (cCR) will predict pCR (resolution of both invasive disease and ductal carcinoma in situ) in 90% or more cases.

DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, prospective, nonrandomized clinical trial. Patients were enrolled from August 2017 to June 2019. This is the final analysis, which was completed in December 2023. The setting included academic and community hospital center members of NRG (ie, the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) in the US and Canada. Patients with operable (T1-T3, stage I-III) invasive ductal carcinoma who completed NAC and achieved cCR and radiological complete response (rCR) or near rCR by mammography (mass ≤1 cm and no malignant microcalcifications), ultrasound (mass ≤2 cm), and magnetic resonance imaging (no mass with rapid rise or washout kinetics).

INTERVENTIONS: Patients underwent marker-directed stereotactic multiple-core needle biopsy of the tumor bed with marker placement before breast-conservation surgery.

MAIN OUTCOMES AND MEASURES: End points were negative predictive value (NPV) and sensitivity of the biopsy.

RESULTS: A total of 105 patients were enrolled with 101 evaluable (mean [SD] age, 52.8 [10.5] years); 77 patients (76.2%) were younger than 60 years, and all breast cancer subtypes were represented with 32 (31.7%) triple-negative breast cancer, 21 (20.8%) hormone receptor-positive/epidermal growth factor receptor 2 (ERBB2; formerly HER2)-negative (ERBB2-) breast cancer, and 46 (45.5%) ERBB2-positive (ERBB2+) breast cancer. In 101 evaluable patients, 36 had residual disease at surgery (pCR = 64%). With imaging criteria, NPV of the biopsy was 78.3% (95% CI, 67.9%-86.6%), and the sensitivity of the biopsy was 50% (95% CI, 32.9%-67.1%). In an exploratory subset analysis, the NPV in patients with ERBB2+ breast cancer was 90% (95% CI, 76.3%-97.2%). On retrospective central review, 62 of 101 enrolled patients met imaging eligibility criteria. In this exploratory post hoc analysis, NPV in these patients was 86.8% (95% CI, 74.7%-94.5%).

CONCLUSIONS AND RELEVANCE: These findings do not support breast conservation treatment without surgery based on the study criteria for cCR and rCR/near rCR by trimodality imaging and negative tumor-bed biopsy. Strict adherence to imaging criteria may be required to achieve acceptable predictive values.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03188393.

PMID:40332918 | DOI:10.1001/jamasurg.2025.1072

JAMA Psychiatry. 2025 May 7. doi: 10.1001/jamapsychiatry.2025.0666. Online ahead of print.

ABSTRACT

IMPORTANCE: Representation of race and ethnicity in randomized clinical trials (RCTs) is critical for understanding treatment efficacy across populations with different racial and ethnic backgrounds.

OBJECTIVE: To examine race and ethnicity representation and reporting across RCTs of pharmacotherapies for mental disorders.

DATA SOURCES: PubMed (Medline), Embase (Ovid), APA PsycInfo, and Web of Science were searched until March 1, 2024, to retrieve network meta-analyses including RCTs of pharmacotherapies for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision mental disorders.

STUDY SELECTION: RCTs that recruited people of any age with a diagnosis of a mental disorder and that tested the efficacy of any pharmacologic intervention vs any control arm.

DATA EXTRACTION AND SYNTHESIS: Random-effects logit-transformed proportion meta-analyses were used to estimate prevalence rates of race and ethnicity groups and their temporal trends across RCTs and to compare US RCT prevalence rates with US Census data. The Preferred Reporting Items for Overviews of Reviews was used to report our review.

MAIN OUTCOMES AND MEASURES: Reporting of data and percentages of race and ethnicity. The year of publication, type of RCT, geographic location, age group, and sample size were also included. There were no deviations that occurred from the original protocol.

RESULTS: Data were obtained from 1683 RCTs (375 120 participants in total). Of these, 1363 (91.7% of participants) included participants aged 18 years or older; 680 RCTs (36.0% of participants) were from the US, 404 (17.1% of participants) were from Europe, and 293 (29.9% of participants) were from multiple geographic locations. Race and ethnicity were reported in 39.2% of RCTs; reporting was the highest in US-based RCTs (58.7%) and lowest in Central and South America (8.7%) and Asia and the Middle East (12.4%). Among participants, 2.7% (95% CI, 2.1%-3.5%) self-reported as Asian, 9.0% (95% CI, 8.1%-10.0%) as Black, 11.0% (95% CI, 9.1%-13.3%) as Hispanic among White, 80.2% (95% CI, 78.8%-81.5%) as White including Hispanic, and 5.8% (95% CI, 5.2%-6.4%) as other race or ethnicity, multiracial, or multiethnic. There was more frequent reporting of race and ethnicity in US RCTs (log odds increased by 0.066 each year) and less frequent reporting in non-US RCTs (log odds increased by 0.023 each year). Studies reporting race and ethnicity did not generally include larger sample sizes (mean sample size, 263.7 [95% CI, 15.0-860.3] participants) compared with those not reporting such data (mean sample size, 196.6 [95% CI, 12.0-601.3] participants), albeit not in all locations. In US RCTs, adults in the other or multiracial and multiethnic category were historically overrepresented, while adults in Asian, Black, Hispanic among White, and White including Hispanic categories were underrepresented; Asian, Black, and Hispanic among White children and adolescents are still currently underrepresented.

CONCLUSIONS AND RELEVANCE: The findings of this meta-analysis suggest that differences in reporting race and ethnicity across geographic locations and underrepresentation of certain racial and ethnic groups in US-based RCTs highlight the need for international guidelines to ensure equitable recruitment and reporting in clinical trials.

PMID:40332916 | DOI:10.1001/jamapsychiatry.2025.0666

Invest Ophthalmol Vis Sci. 2025 May 1;66(5):17. doi: 10.1167/iovs.66.5.17.

ABSTRACT

PURPOSE: Amid efforts to understand spaceflight associated neuro-ocular syndrome (SANS), uncovering the role of the choroid in its etiology is challenged by the accuracy of image segmentation. The present study extended deep learning-based choroid quantification from optical coherence tomography (OCT) to the characterization of pulsatile and topological changes in the macular plane and investigated changes in response to prolonged microgravity exposure.

METHODS: We analyzed OCT macular videos and volumes acquired from astronauts before, during, and after long-duration spaceflight. Deep learning models were fine-tuned for choroid segmentation and combined with further image processing toward vascularity quantification. Statistical analysis was performed to determine changes in time-dependent and spatially averaged variables from preflight baseline.

RESULTS: For 12 astronauts with a mean age of 47 ± 9 years, there were significant increases in choroid thickness and luminal area (LA) averaged over OCT macular video segments. There was also a significant increase in pulsatile LA. For a subgroup of six astronauts for whom inflight imaging was available, choroid volume, luminal volume, and the choroidal vascularity index over the macular region all increased significantly during spaceflight.

CONCLUSIONS: The findings suggest that localized choroid pulsatile changes occur following prolonged microgravity exposure. They show that the choroid vessels expand in a manner similar to the choroid layer across the macular region during spaceflight, with a relative increase in the space they occupy. The methods developed provide new tools and avenues for studying and establishing effective countermeasures to risks associated with long-duration spaceflight.

PMID:40332907 | DOI:10.1167/iovs.66.5.17

JAMA Cardiol. 2025 May 7. doi: 10.1001/jamacardio.2025.0945. Online ahead of print.

ABSTRACT

IMPORTANCE: Innate immunity, particularly neutrophil activation, plays a crucial role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). The potential of calprotectin, a biomarker of neutrophil activation, as a mechanistically informed biomarker for ASCVD in an ethnically diverse population requires further investigation.

OBJECTIVE: To examine the prospective association between circulating calprotectin and ASCVD in a diverse, population-based cohort while also exploring calprotectin’s mechanistic contributions to ASCVD in vitro.

DESIGN, SETTING, AND PARTICIPANTS: Circulating calprotectin was measured in plasma collected from 2412 participants during phase 2 of the Dallas Heart Study, a multiethnic, population-based cohort study. The median follow-up after plasma collection was 8 years.

MAIN OUTCOMES AND MEASURES: Associations with future ASCVD events (defined as first nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or death from a cardiovascular cause) were assessed using Cox proportional hazards models, adjusted for known cardiovascular disease risk factors as well as high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT).

RESULTS: Higher calprotectin levels were associated with older age, male sex, Black race, hypertension, diabetes, and smoking history. Individuals with higher calprotectin had higher hemoglobin A1c, very low-density lipoprotein cholesterol, and triglycerides, and lower high-density lipoprotein cholesterol and cholesterol efflux capacity. Log-transformed calprotectin levels were associated with an increased risk of ASCVD events over 8 years (hazard ratio [HR], 1.98 per log increase [95% CI, 1.54-2.53]). This association remained statistically significant after adjusting for prior ASCVD and traditional risk factors (HR, 1.61 [95% CI, 1.22-2.13]) and hs-CRP, NT-proBNP, and hs-cTnT (HR, 1.43 [95% CI, 1.04-1.96]). Higher calprotectin also correlated with higher coronary artery calcium scores (P < .001). In vitro studies revealed that calprotectin impaired coronary endothelial integrity, diminished nitric oxide production, and fostered endothelial to mesenchymal transition, providing potential mechanisms for ASCVD progression.

CONCLUSIONS AND RELEVANCE: The findings suggest that calprotectin may serve as a mechanistically informed biomarker for ASCVD, independent of traditional and contemporary cardiovascular risk factors and biomarkers. However, its clinical utility warrants further evaluation.

PMID:40332890 | DOI:10.1001/jamacardio.2025.0945

Int J Mol Sci. 2025 Apr 19;26(8):3883. doi: 10.3390/ijms26083883.

ABSTRACT

The adaptation of the body when exposed to a lower-than-usual temperature is a challenge that involves neuro-endocrine-immune mechanisms and affects the pharmacokinetics and/or pharmacodynamics of drugs taken before or after cold exposure. The experiments presented in this study clearly show differences in the analgesic effect of an exogenously introduced model substance (C-terminal fragment of calcium-binding protein, spermatid-specific 1) before and after cold exposure compared to its effect at an ambient temperature. The model substance used for the experiments is an octapeptide, TDIFELLK, which was synthesized via standard solid-phase peptide synthesis. Preliminary studies proved TDIFELLK’s analgesic activity. The ANOVA analysis performed showed statistically significant differences in the pain thresholds, measured by a paw pressure test, in 109 rats distributed among 14 groups and subjected to cold exposure according to different set-ups. Cold exposure immediately after TDIFELLK administration appears to enhance its analgesic effect, while cold exposure before administration reduces the effect. In some of the set-ups, antagonists of the most significant for analgesia receptors, i.e., opioid, cannabinoid, and serotonergic, were also introduced. The results showed that cold exposure had a modulating influence on the effect of the exogenously administered substances. The modulating effect was manifested differently depending on whether the intake occurred before or after cold exposure. The results also showed that the interaction with individual mediator systems was also subjected to differences depending on intake occurring before and after cold exposure.

PMID:40332811 | DOI:10.3390/ijms26083883

Insects. 2025 Mar 26;16(4):346. doi: 10.3390/insects16040346.

ABSTRACT

After eight generations of laboratory selection with β-cypermethrin, a P. okadai strain was cultivated that displayed a 10.04-fold increase in resistance (RS) relative to the susceptible strain (SS), with an estimation of heritability (h²) of 0.34. Compared with the SS, the developmental duration of the eggs was significantly prolonged (p < 0.05); however, the pupal stage duration was shorter, with no statistically significant difference. Moreover, the levels of GSTs, CarEs, and CYP450 activity were notably higher in the RS than in the SS. In addition, the level of CarE and CYP450 activity in the RS was significantly higher in the midgut (MG), fat body (FB), and Malpighian tubules (MTs) compared to the SS; however, the GSTs showed no statistically significant difference in the MTs. These results suggest that P. okadai‘s resistance to β-cypermethrin could be selected rapidly and the decreases in the intrinsic rate of increase (r) observed in the RS are likely due to mutations in the detoxification enzyme genes under the strong selection pressure exerted by β-cypermethrin. The increased activity of GSTs, CarEs, and CYP450 was associated with β-cypermethrin resistance in the RS of P. okadai. The data reported herein provide a foundation for future studies on the mechanisms responsible for β-cypermethrin resistance in P. okadai.

PMID:40332797 | DOI:10.3390/insects16040346