Nevin Manimala

JAMA Netw Open. 2024 Aug 1;7(8):e2425593. doi: 10.1001/jamanetworkopen.2024.25593.

ABSTRACT

IMPORTANCE: Precise estimation of a patient’s drug metabolism capacity is important for antiseizure dose personalization.

OBJECTIVE: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.

DATA SOURCES: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.

STUDY SELECTION: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.

DATA EXTRACTION AND SYNTHESIS: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.

MAIN OUTCOMES AND MEASURES: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.

RESULTS: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.

CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

PMID:39115847 | DOI:10.1001/jamanetworkopen.2024.25593

JAMA Netw Open. 2024 Aug 1;7(8):e2425987. doi: 10.1001/jamanetworkopen.2024.25987.

ABSTRACT

IMPORTANCE: Depression is a leading cause of disability. The timing and persistence of depression may be differentially associated with long-term mental health and psychosocial outcomes.

OBJECTIVE: To examine if depression symptoms during early and middle childhood and adolescence and persistent depression symptoms are associated with impaired young adult outcomes independent of early risk factors.

DESIGN, SETTING, AND PARTICIPANTS: Data for this prospective, longitudinal cohort study were from the Québec Longitudinal Study of Child Development, a representative population-based Canadian birth cohort. The cohort consists of infants born from October 1, 1997, to July 31, 1998. This is an ongoing study; data are collected annually or every 2 years and include those ages 5 months to 21 years. The end date for the data in this study was June 30, 2019, and data analyses were performed from October 4, 2022, to January 3, 2024.

EXPOSURES: Depression symptoms were assessed using maternal reports in early childhood (ages 1.5 to 6 years) from 1999 to 2004, teacher reports in middle childhood (ages 7 to 12 years) from 2005 to 2010, and self-reports in adolescence (ages 13 to 17 years) from 2011 to 2015.

MAIN OUTCOMES AND MEASURES: The primary outcome was depression symptoms at age 20 years, and secondary outcomes were indicators of psychosocial functioning (binge drinking; perceived stress; not being in education, employment, or training; social support; and experiencing online harrasment) at age 21 years. All outcomes were self-reported. Adult outcomes were reported by participants at ages 20 and 21 years from 2017 to 2019. Risk factors assessed when children were aged 5 months old were considered as covariates to assess the independent associations of childhood and adolescent depression symptoms with adult outcomes.

RESULTS: The cohort consisted of 2120 infants. The analytic sample size varied from 1118 to 1254 participants across outcomes (56.85% to 57.96% female). Concerning the primary outcome, adjusting for early risk factors and multiple testing, depression symptoms during adolescence were associated with higher levels of depression symptoms (β, 1.08 [95% CI, 0.84-1.32]; P < .001 unadjusted and Bonferroni adjusted) in young adulthood. Concerning the secondary outcomes, depression symptoms in adolescence were only associated with perceived stress (β, 3.63 [95% CI, 2.66-4.60]; P < .001 unadjusted and Bonferroni adjusted), while both middle-childhood (β, -1.58 [95% CI, -2.65 to -0.51]; P = .003 unadjusted and P < .001 Bonferroni adjusted) and adolescent (β, -1.97 [95% CI, -2.53 to -1.41]; P < .001 unadjusted and Bonferroni adjusted) depression symptoms were associated with lower levels of social support. There were no associations for binge drinking; not being in education, employment, or training; or experiencing online harrasment.

CONCLUSIONS AND RELEVANCE: In this cohort study of Canadian children and adolescents, childhood and adolescent depression symptoms were associated with impaired adult psychosocial functioning. Interventions should aim to screen and monitor children and adolescents for depression to inform policymaking regarding young adult mental health and psychosocial outcomes.

PMID:39115846 | DOI:10.1001/jamanetworkopen.2024.25987

JAMA Netw Open. 2024 Aug 1;7(8):e2426590. doi: 10.1001/jamanetworkopen.2024.26590.

ABSTRACT

IMPORTANCE: Traumatic brain injury (TBI), seizures, and dementia increase with age. There is a gap in understanding the associations of TBI, seizures, and medications such as antiseizure and antipsychotics with the progression of cognitive impairment across racial and ethnic groups.

OBJECTIVE: To investigate the association of TBI and seizures with the risk of cognitive impairment among cognitively normal older adults and the role of medications in moderating the association.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study was a secondary analysis of the Uniform Data Set collected between June 1, 2005, and June 30, 2020, from the National Alzheimer’s Coordination Center. Statistical analysis was performed from February 1 to April 3, 2024. Data were collected from participants from 36 Alzheimer’s Disease Research Centers in the US who were 65 years or older at baseline, cognitively normal at baseline (Clinical Dementia Rating of 0 and no impairment based on a presumptive etiologic diagnosis of AD), and had complete information on race and ethnicity, age, sex, educational level, and apolipoprotein E genotype.

EXPOSURE: Health history of TBI, seizures, or both conditions.

MAIN OUTCOMES AND MEASURES: Progression to cognitive impairment measured by a Clinical Dementia Rating greater than 0.

RESULTS: Among the cohort of 7180 older adults (median age, 74 years [range, 65-102 years]; 4729 women [65.9%]), 1036 were African American or Black (14.4%), 21 were American Indian or Alaska Native (0.3%), 143 were Asian (2.0%), 332 were Hispanic (4.6%), and 5648 were non-Hispanic White (78.7%); the median educational level was 16.0 years (range, 1.0-29.0 years). After adjustment for selection basis using propensity score weighting, seizure was associated with a 40% higher risk of cognitive impairment (hazard ratio [HR], 1.40; 95% CI, 1.19-1.65), TBI with a 25% higher risk of cognitive impairment (HR, 1.25; 95% CI, 1.17-1.34), and both seizure and TBI were associated with a 57% higher risk (HR, 1.57; 95% CI, 1.23-2.01). The interaction models indicated that Hispanic participants with TBI and seizures had a higher risk of cognitive impairment compared with other racial and ethnic groups. The use of antiseizure medications (HR, 1.23; 95% CI, 0.99-1.53), antidepressants (HR, 1.32; 95% CI, 1.17-1.50), and antipsychotics (HR, 2.15; 95% CI, 1.18-3.89) was associated with a higher risk of cognitive impairment, while anxiolytic, sedative, or hypnotic use (HR, 0.88; 95% CI, 0.83-0.94) was associated with a lower risk.

CONCLUSIONS AND RELEVANCE: This study highlights the importance of addressing TBI and seizures as risk factors for cognitive impairment among older adults. Addressing the broader social determinants of health and bridging the health divide across various racial and ethnic groups are essential for the comprehensive management and prevention of dementia.

PMID:39115844 | DOI:10.1001/jamanetworkopen.2024.26590

JAMA Netw Open. 2024 Aug 1;7(8):e2426790. doi: 10.1001/jamanetworkopen.2024.26790.

ABSTRACT

IMPORTANCE: Climate change is a fundamental threat to human health, and industries, including health care, must assess their respective contribution to this crisis.

OBJECTIVE: To assess the change in knowledge of clinicians who completed a quality incentive program (QIP) measure on climate change and health care sustainability and to examine clinician attitudes toward climate change and their perception of clinical and individual relevance.

DESIGN, SETTING, AND PARTICIPANTS: The participants in this survey study included employed physicians and psychologists who were part of a hospital physician organization in an academic medical center (AMC) in Boston, Massachusetts. The hospital physician organization provides a QIP with different measures every 6 months and provides incentive payments on completion. The study is based on a survey of participants on completion of a QIP measure focused on climate change and health care sustainability offered from July 2023 through September 2023 at the AMC.

EXPOSURE: Structured educational video modules.

MAIN OUTCOMES AND MEASURES: After completion of the modules, the participants reported their baseline and postintervention knowledge on climate change impacts on health and health care sustainability, perceived relevance of the material, and attitudes toward the modules using 5-point Likert scales and free-text comments. Data were analyzed using univariate and multivariable analyses including participant age, gender, and practice specialty.

RESULTS: Of the 2559 eligible clinicians, 2417 (94.5%) (mean [SD] age, 48.9 [11.5] years; range, 29-85 years; 1244 males [51.5%]) participated in the measure and completed the survey. Among these participants, 1767 (73.1%) thought the modules were relevant or very relevant to their lives and 1580 (65.4%) found the modules relevant or very relevant to their clinical practice. Age was not associated with responses. Practitioners in specialties classified as climate facing were more likely to think that the education was relevant to their clinical practice compared with those in non-climate-facing specialties (mean [SD] score, 3.76 [1.19] vs 3.61 [1.26]; P = .005). Practitioners identifying as female were also more likely to consider this education as relevant to their clinical practice compared with male practitioners (mean [SD] score, 3.82 [1.17] vs 3.56 [1.27]; P < .001).

CONCLUSIONS AND RELEVANCE: In this survey study, a high proportion of clinicians expressed positive attitudes toward education in climate change and health and health care sustainability, with some demographic and specialty variability. These data support that climate and health education in AMCs provides information that practitioners see as relevant and important.

PMID:39115843 | DOI:10.1001/jamanetworkopen.2024.26790

JAMA Netw Open. 2024 Aug 1;7(8):e2426795. doi: 10.1001/jamanetworkopen.2024.26795.

ABSTRACT

IMPORTANCE: Evidence on the association of early intervention services (EISs) with self-harm and suicide among patients with first-episode schizophrenia (FES) at older than 25 years is lacking.

OBJECTIVE: To examine changes in self-harm and suicide rates among patients with FES before and after the implementation of an EIS program.

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study conducted among 37 040 patients aged 15 to 64 years with FES between January 1, 2001, and March 31, 2020, used electronic medical records from the Hong Kong Clinical Data Analysis and Reporting System. All patients were followed up from the first diagnosis of schizophrenia (the index date) until the date of their death or the end of the study period (March 31, 2021), whichever came first. Statistical analysis was performed from July to November 2023.

EXPOSURE: The EIS extended the Early Assessment Service for Young People With Early Psychosis (EASY) program from patients aged 15 to 25 years to those aged 15 to 64 years (EASY Plus). The exposure was the implementation of the EASY Plus program in April 2011. The exposure period was defined as between April 2012 and March 2021 for the 1-year-time-lag analysis.

MAIN OUTCOMES AND MEASURES: The outcomes were monthly rates of self-harm and suicide among patients with FES before and after the implementation of the EASY Plus program. Interrupted time series analysis was used for the main analysis.

RESULTS: This study included 37 040 patients with FES (mean [SD] age at onset, 39 [12] years; 82.6% older than 25 years; 53.0% female patients). The 1-year-time-lag analysis found an immediate decrease in self-harm rates among patients aged 26 to 44 years (rate ratio [RR], 0.77 [95% CI, 0.59-1.00]) and 45 to 64 years (RR, 0.70 [95% CI, 0.49-1.00]) and among male patients (RR, 0.71 [95% CI, 0.56-0.91]). A significant long-term decrease in self-harm rates was found for all patients with FES (patients aged 15-25 years: RR, 0.98 [95% CI, 0.97-1.00]; patients aged 26-44 years: RR, 0.98 [95% CI, 0.97-0.99]; patients aged 45-64 years: RR, 0.97 [95% CI, 0.96-0.98]). Suicide rates decreased immediately after the implementation of the EASY Plus program among patients aged 15 to 25 years (RR, 0.33 [95% CI, 0.14-0.77]) and 26 to 44 years (RR, 0.38 [95% CI, 0.20-0.73]). Compared with the counterfactual scenario, the EASY Plus program might have led to 6302 fewer self-harm episodes among patients aged 26 to 44 years.

CONCLUSIONS AND RELEVANCE: This cohort study of the EASY Plus program suggests that the extended EIS was associated with reduced self-harm and suicide rates among all patients with FES, including those older than 25 years. These findings emphasize the importance of developing tailored interventions for patients across all age ranges to maximize the benefits of EISs.

PMID:39115842 | DOI:10.1001/jamanetworkopen.2024.26795

Transl Vis Sci Technol. 2024 Aug 1;13(8):12. doi: 10.1167/tvst.13.8.12.

ABSTRACT

PURPOSE: Compare the use of optic disc and macular optical coherence tomography measurements to predict glaucomatous visual field (VF) worsening.

METHODS: Machine learning and statistical models were trained on 924 eyes (924 patients) with circumpapillary retinal nerve fiber layer (cp-RNFL) or ganglion cell inner plexiform layer (GC-IPL) thickness measurements. The probability of 24-2 VF worsening was predicted using both trend-based and event-based progression definitions of VF worsening. Additionally, the cp-RNFL and GC-IPL predictions were combined to produce a combined prediction. A held-out test set of 617 eyes was used to calculate the area under the curve (AUC) to compare cp-RNFL, GC-IPL, and combined predictions.

RESULTS: The AUCs for cp-RNFL, GC-IPL, and combined predictions with the statistical and machine learning models were 0.72, 0.69, 0.73, and 0.78, 0.75, 0.81, respectively, when using trend-based analysis as ground truth. The differences in performance between the cp-RNFL, GC-IPL, and combined predictions were not statistically significant. AUCs were highest in glaucoma suspects using cp-RNFL predictions and highest in moderate/advanced glaucoma using GC-IPL predictions. The AUCs for the statistical and machine learning models were 0.63, 0.68, 0.69, and 0.72, 0.69, 0.73, respectively, when using event-based analysis. AUCs decreased with increasing disease severity for all predictions.

CONCLUSIONS: cp-RNFL and GC-IPL similarly predicted VF worsening overall, but cp-RNFL performed best in early glaucoma stages and GC-IPL in later stages. Combining both did not enhance detection significantly.

TRANSLATIONAL RELEVANCE: cp-RNFL best predicted trend-based 24-2 VF progression in early-stage disease, while GC-IPL best predicted progression in late-stage disease. Combining both features led to minimal improvement in predicting progression.

PMID:39115839 | DOI:10.1167/tvst.13.8.12

Phytopathology. 2024 Aug 8. doi: 10.1094/PHYTO-05-24-0167-R. Online ahead of print.

ABSTRACT

A protein-expressing citrus tristeza virus (CTV)-based vector construct, pT36CA-V1.3, obtained from a California isolate of the T36 strain (T36CA), was retooled into a virus induced gene silencing (VIGS) system intended for use with studies of California citrus. VIGS constructs engineered with a truncated Citrus macrophylla (Cm) PHYTOENE DESATURASE (PDS) gene sequence in the sense or anti-sense orientation worked equally well to silence the endogenous CmPDS gene. In a parallel effort to optimize vector performance, two non-synonymous nucleotides in open reading frame 1a of pT36CA-V1.3 were replaced with those conserved in the reference sequences from the T36CA cDNA library. The resulting viruses, T36CA-V1.4 (with one amino acid modification: D760N) and T36CA-V1.5 (with two amino acid modifications: D760N and P1174L), along with T36CA-V1.3 were individually propagated in Nicotiana benthamiana and C. macrophylla plants. Enzyme-linked immunosorbent assay (ELISA) measurements of extracts of the newly emerged leaves suggested that all three viruses accumulated to similar levels in N. benthamiana plants at 5 week-post-inoculation. ELISA values of T36CA-V1.4- and -V1.5-infected C. macrophylla samples were significantly higher than that of T36CA-V1.3-infected samples within an 8 to 12 month-post-inoculation (mpi) window, suggesting a higher accumulation of T36CA-V1.4 and -V1.5 than T36CA-V1.3. However, at 36 mpi, the ELISA values suggested that all three viruses accumulated to similar levels. When C. macrophylla plants infected with each of the three viruses were grafted to commercial citrus varieties, a limited number of receptor plants became infected, demonstrating a weak but nonetheless (the first) successful delivery of T36CA to California-grown commercial citrus.

PMID:39115802 | DOI:10.1094/PHYTO-05-24-0167-R

J Cancer Surviv. 2024 Aug 8. doi: 10.1007/s11764-024-01651-x. Online ahead of print.

ABSTRACT

PURPOSE: Rehabilitation services are recommended by clinical practice guidelines following breast cancer treatment, yet little is known about how utilization may vary by patient-level characteristics which we aimed to study using SEER-Medicare data.

METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database was used to identify non-metastatic breast cancer survivors aged ≥ 66 years diagnosed between 2011 and 2016. Rehabilitation services delivered 0-11 months post-diagnosis were identified via outpatient or physician visit claims. Descriptive statistics and associations between patient characteristics and rehabilitation services were calculated using modified Poisson models estimating relative risk (RR) and corresponding 95% confidence intervals (CIs).

RESULTS: Of 55,539 breast cancer survivors, 33% (n = 18,244) had received any type of rehabilitative services. Survivors were a mean age of 75 years (SD 6.7), 88% White, 86% urban-dwelling, and 21% Medicare/Medicaid dually enrolled. In adjusted models, patients aged > 75 vs. ≤ 75 were 6% (RR 0.94, 95% CI 0.92-0.96) less likely to have received rehabilitative services. Survivors in an area with greater educational attainment vs. less educational attainment, White vs. non-White, or living in a rural vs. urban area were 26% (1.26, CI 1.22-1.30), 6% (1.06, CI 1.02-1.11), and 6% (1.06, CI 1.02-1.10) more likely to have received rehabilitative services, respectively.

CONCLUSION: The largest differences in rehabilitation utilization were observed for survivors of differing educational and treatment statuses.

IMPLICATIONS FOR CANCER SURVIVORS: Further research is needed on barriers, access, and delivery of rehabilitation services, specifically for breast cancer survivors who are older-aged, non-White, or Medicare/Medicaid dual eligible.

PMID:39115791 | DOI:10.1007/s11764-024-01651-x

J Clin Psychol Med Settings. 2024 Aug 8. doi: 10.1007/s10880-024-10028-2. Online ahead of print.

ABSTRACT

Prevalence rates of perinatal mood disorders range from 5 to 25%. Furthermore, suicide is a leading cause of death in postpartum women. Various factors have been associated with an increased risk of suicide in postpartum women, including co-occurring mental health disorders, lack of mental health care, and substance use. It is important for mental health screening and psychological assessment used within OB-GYN clinics to be current with regard to postpartum mood dysfunction and suicide risk assessment. We collected data from a sample of 78 postpartum women (0-6-month post-delivery), focusing specifically on patterns of emotional/internalizing dysfunction, using three different screening measures as predictors. Contrary to hypotheses, our sample did not produce significant elevations on target criterion scales of the Minnesota multiphasic personality inventory-3 (MMPI-3). Although the multidimensional behavioral health screen (MBHS) was better at differentially capturing MMPI-3 elevations when compared to the Edinburgh postnatal depression scale (EDPS) and patient health questionnaire-9 (PHQ-9), two of the three comparisons were not statistically significant. Statistical analyses were challenged by our extremely low base rate for elevated suicide risk. Despite this, the MBHS performed better than the EPDS and PHQ-9 at accurately capturing elevated suicide risk.

PMID:39115760 | DOI:10.1007/s10880-024-10028-2

World J Urol. 2024 Aug 8;42(1):476. doi: 10.1007/s00345-024-05186-9.

ABSTRACT

OBJECTIVES: To comprehensively investigate the potential association between prostate cancer (PCa) and the G84E mutation within the Homeobox Protein B13 (HOXB13) gene among individuals of Turkish descent, our study aims to undertake a prospective examination.

METHODS: We evaluated 300 patients (150 diagnosed with prostate cancer, 150 controls) who presented in our clinic. Data collected were prospectively examined. DNA isolation was performed using an isolation kit. The HOXB13-G84E mutation (rs138213197) was analyzed in the obtained samples. Data encoding and statistical analysis were performed.

RESULTS: The pathological allele for the G84E mutation was T. According to the findings, no mutations were detected in the control group, while the G84E mutation was detected in 17 patients in the patient group, all of whom had the TC genotype. The analysis showed that having the CC genotype reduced the risk of prostate cancer by 0.47 times (OR=0.47, CI=0.415-0.532). Our results did not support a trend toward family history or earlier-onset disease in comparisons between carriers and non-carriers of HOXB13 G84E mutation. Individuals with a positive family history exhibited a higher frequency of the G84E mutation.

CONCLUSIONS: We concluded that HOXB13 gene mutation is indeed linked to PCa in Turkish men. However, we did not find a relationship between the HOXB13 gene G84E mutation carrier status and either early-onset PCa or familial PCa in Turkish men.

PMID:39115757 | DOI:10.1007/s00345-024-05186-9