Citations

Abstract Background: Pharmacogenomic studies on antidepressant treatment outcomes could be conducted using previously collected data from electronic health record (EHR)-linked biobanks. However, absence of EHR based outcome measures is an unmet need in designing such studies We aimed to define EHR-derived antidepressant outcome measures and explore their utility in showing associations between treatment outcomes and Cytochrome P450 (CYP) metabolizer phenotypes in a proof-of-concept study. Methods: Using data from the EHR-linked cohort, Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT 10K) Study, we collected prescription data and patient health questionnaire 9 (PHQ-9) scores to compute 3 proxy measures for antidepressant response, efficacy, and acceptability: change in PHQ-9 scores, longest treatment interval with a single antidepressant, and antidepressant non-refill. Subsequently, we tested the association of both prescription-based outcomes with DNA-predicted CYP metabolizer phenotypes in European-ancestry participants. Results: We identified 3920 RIGHT 10K participants with at least 1 antidepressant prescription and European-ancestry. Participants had a mean age of 61 years and 72% were women. Implementation of the PHQ-9 outcome was not feasible because of missingness. Of both prescription-based outcomes, antidepressant non-refill reproduced several known antidepressant-CYP interactions. However, the pilot was limited by small subgroups of participants with non-normal metabolizer phenotypes. Conclusions: Derived from structured data, antidepressant non-refill is a promising outcome measure for EHR-linked biobanks that partially reproduced antidepressant-CYP interactions. However, testing on larger datasets is necessary to understand whether it would be a useful for pharmacogenomic research.

Background and Objectives: Stroke is a leading cause of disability worldwide. Recent studies have suggested the feasibility and potential utility of remotely supervised transcranial direct current stimulation (RS-tDCS) to improve different types of impairments in various neurological conditions. This scoping review provides a critical appraisal of RS-tDCS as an adjunct therapy to enhance recovery after stroke. Materials and Methods: A comprehensive literature review was systematically conducted using PubMed through Nested Knowledge software. A supplementary search was conducted in Google Scholar. Two independent authors screened and identified related studies investigating RS-tDCS in patients with stroke from inception to February 2025. Results: Studies showed that RS-tDCS was safe, with only mild side effects. Additionally, it was feasible, with high adherence rates likely due to ease of use. Regarding efficacy, RS-tDCS preliminarily yielded improvements in upper- and lower-limb motor functions and increased language and cognitive performance. However, the studies were underpowered and heterogeneous, limiting generalization of findings. Conclusions: RS-tDCS is safe and feasible, affording beneficial effects in the motor, language, and cognitive functions of patients with post-stroke impairments. RS-tDCS has the potential to improve access and reduce disparities for post-stroke experimental treatments. However, adequately powered randomized trials are needed to further investigate the efficacy.

Importance Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. Objective To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). Design, Setting, and Participants This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2 -positive (formerly HER2 -positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Intervention Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. Main Outcome Measures The primary outcome was ipsilateral breast tumor recurrence. Results Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2 -positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. Conclusions and Relevance The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02945579

Importance Completion of the Human Genome Project prompted predictions that genomics would transform medicine, including through genomic screening that identifies potentially medically actionable findings that could prevent disease, detect it earlier, or treat it better. However, genomic screening remains anchored in research and largely unavailable as part of routine care. Objective To summarize 11 years of experience with genomic screening and explore the landscape of genomic screening efforts. Design, Setting, and Participants This cohort study was based in Geisinger’s MyCode Community Health Initiative, a genomic screening program in a rural Pennsylvania health care system in which patient-participants exomes are analyzed. Main Outcomes and Measures Genomic screen-positive rates were evaluated and stratified by condition type (cancer, cardiovascular, other) and US Centers for Disease Control and Prevention (CDC) Tier 1 designation. The proportion of participants previously unaware of their genomic result was assessed. Other large-scale population-based genomic screening efforts with genomic results disclosure were compiled from public resources. Results A total of 354 957 patients participated in Geisinger’s genomic screening program (median [IQR] age, 54 [36-69] years; 194 037 [59.7%] assigned female sex at birth). As of June 2024, 175 500 participants had exome sequencing available for analysis, and 5934 participants (3.4%) had a pathogenic variant in 81 genes known to increase risk for disease. Between 2013 and July 2024, 5119 results were disclosed to 5052 eligible participants, with 2267 (44.2%) associated with risk for cardiovascular disease, 2031 (39.7%) with risk for cancer, and 821 (16.0%) with risk for other conditions. Most results (3040 [59.4%]) were in genes outside of those with a CDC Tier 1 designation. Nearly 90% of participants (4425 [87.6%]) were unaware of their genomic risk prior to disclosure. In a survey of large-scale biobanks with genomic and electronic health record (EHR) data, only 25.0% (6 of 24) disclosed potentially actionable genomic results. Conclusions and Relevance In this large, genomics-informed cohort study from a single health system, 1 in 30 participants had a potentially actionable genomic finding. However, nearly 90% were unaware of their risk prior to screening, demonstrating the utility of genomic screening in identifying at-risk individuals. Most large-scale biobanks with genomic and EHR data did not return genomic results with potential medical relevance, missing opportunities to significantly improve genomic risk ascertainment for these individuals and to perform longitudinal studies of clinical and implementation outcomes in diverse settings.

Abstract Studies assessing genetic associations with neuropathological features in Lewy body disease (LBD) have been limited to candidate gene investigations, and therefore, information is lacking regarding the genetic architecture of the neuropathology of LBD. In the current study, we examined a large series of neuropathologically confirmed LBD cases (n = 980 in the discovery series, n = 503 in the replication series) and performed genome-wide association studies of 11 different neuropathological outcome measures. The 11 neuropathological outcomes included Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, LBD subtype, Lewy body (LB) counts in five different brain regions, dorsolateral and ventromedial putaminal tyrosine hydroxylase immunoreactivity and neuronal loss in the ventrolateral part of the substantia nigra. Associations between variants and outcomes were assessed using regression models appropriate for the nature of the given neuropathological outcome and that were adjusted for age at death, sex and top principal components of genetic data. In the discovery series, APOE rs429358 (i.e. APOE ε4) was associated with a greater severity of each of Braak NFT stage [odds ratio (OR) = 3.07, P = 2.34 × 10−32], Thal amyloid phase (OR = 3.57, P = 3.28 × 10−29) and LBD subtype (OR = 1.78, P = 9.85 × 10−9), with similar findings observed in the independent replication series (Braak NFT stage, OR = 2.30, P = 2.70 × 10−11; Thal amyloid phase, OR = 3.17, P = 6.39 × 10−18; LBD subtype, OR = 2.68, P = 3.85 × 10−10). In the subgroup of cases with lower levels of Alzheimer's disease pathology (Braak NFT stage ≤ III and Thal amyloid phase ≤2), there was a strong association between APOE rs429358 and LBD subtype even when adjusting for Braak stage and Thal phase in the discovery series (n = 218, OR = 2.47, P = 0.007) and the replication series (n = 141, OR = 3.60, P = 0.006). Although additional genome-wide significant associations were identified in the discovery series between LINC01581/MCTP2 rs547411734 and lower middle frontal LB counts, between TLE3 rs3743309 and lower cingulate LB counts, and between GRIN2A/ATF7IP2 rs1097915 and lower parahippocampal LB counts, these findings were not observed in the replication series. Our results indicate that the APOE ε4 allele is the most prominent genetic determinant of severity of neuropathology in LBD. These findings represent a key step forward in our understanding of genetic drivers of neuropathological features in LBD. Future studies utilizing meta-analytical approaches will be important to more precisely assess other associations that were not quite genome-wide significant in the discovery series.

AbstractINTRODUCTIONParkinsonism in patients with Alzheimer's disease (AD) is often attributed to Lewy‐related pathology, given its high comorbidity. In the era of anti‐amyloid therapy, recognizing parkinsonism caused by AD pathology is needed to optimize the treatment.METHODSThis study aimed to quantitatively characterize parkinsonism and nigral neuropathology in AD without Lewy bodies (LB). Nigral neurons were counted automatically. Fine‐tuned ChatGPT collected structured clinical data.RESULTSAmong 635 AD patients without LB, 62 (9.7%) presented parkinsonism, which correlated with reduced nigral neuron density (p < 0.01). Tau burden did not explain the nigral neuronal loss. TAR DNA‐binding protein 43 (TDP‐43) pathology correlated with reduced nigral pigmented neuron density (p = 0.03).DISCUSSIONOur findings suggest that parkinsonism in AD without LB is related to nigral neuronal loss in association with TDP‐43 pathology. Recognition of parkinsonism in AD without LB is crucial for appropriate therapy.Highlights One in 10 Alzheimer's disease (AD) patients without Lewy bodies had parkinsonism. Parkinsonism in AD was correlated with reduced nigral neuron density. TAR DNA‐binding protein 43 pathology was associated with nigral degeneration in AD. AD should be included in the differential diagnosis of dementia with parkinsonism.