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Background: Previous epidemiological research has linked posttraumatic stress disorder (PTSD) with specific physical health problems, but the comprehensive landscape of medical conditions associated with PTSD remains uncharacterized. Electronic health records provide an opportunity to overcome clinical knowledge gaps and uncover associations with biological relevance that potentially vary by sex., Methods: PTSD was defined among biobank participants ( N  = 145,959) in 3 major healthcare systems using 2 ICD code-based definitions: broad (≥1 PTSD or acute stress codes vs. 0; n cases  = 16,706) and narrow (≥2 PTSD codes vs. 0; n cases  = 3325). Using a phenome-wide association study design, we tested associations between each PTSD definition and all prevalent disease umbrella categories, i.e., phecodes. We also conducted sex-stratified phenome-wide association study analyses including a sex × diagnosis interaction term in each logistic regression., Results: A substantial number of phecodes were significantly associated with PTSD Narrow (61%) and PTSD Broad (83%). While the strongest associations were shared between the 2 definitions, PTSD Broad captured 334 additional phecodes not significantly associated with PTSD Narrow and exhibited a wider range of significantly associated phecodes across various categories, including respiratory, genitourinary, and circulatory conditions. Sex differences were observed in that PTSD Broad was more strongly associated with osteoporosis, respiratory failure, hemorrhage, and pulmonary heart disease among male patients and with urinary tract infection, acute pharyngitis, respiratory infections, and overweight among female patients., Conclusions: This study provides valuable insights into a diverse range of comorbidities associated with PTSD, including both known and novel associations, while highlighting the influence of sex differences and the impact of defining PTSD using electronic health records., (© 2024 The Authors.)

Background: Chronic pain affects one fifth of American adults, contributing significant public health burden. Chronic pain mechanisms can be further understood through investigating brain gene expression., Methods: We tested differentially expressed genes (DEGs) in chronic pain, migraine, lifetime fentanyl and oxymorphone use, and with chronic pain genetic risk in four brain regions (dACC, DLPFC, MeA, BLA) and imputed cell type expression data from 304 postmortem donors. We compared findings across traits and with independent transcriptomics resources, and performed gene-set enrichment., Results: We identified two chronic pain DEGs: B4GALT and VEGFB in bulk dACC. We found over 2000 (primarily BLA microglia) chronic pain cell type DEGs. Findings were enriched for mouse microglia pain genes, and for hypoxia and immune response. Cross-trait DEG overlap was minimal., Conclusions: Chronic pain-associated gene expression is heterogeneous across cell type, largely distinct from that in pain-related traits, and shows BLA microglia are a key cell type.

Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric syndrome with genetic and environmental influences. In addition to neuroanatomical and circuit-level disturbances, dysregulation of the brain transcriptome is a key phenotypic signature of MDD. Postmortem brain gene expression data are uniquely valuable resources for identifying this signature and key genomic drivers in human depression; however, the scarcity of brain tissue limits our capacity to observe the dynamic transcriptional landscape of MDD. It is therefore crucial to explore and integrate depression and stress transcriptomic data from numerous, complementary perspectives to construct a richer understanding of the pathophysiology of depression. In this review, we discuss multiple approaches for exploring the brain transcriptome reflecting dynamic stages of MDD: predisposition, onset, and illness. We next highlight bioinformatic approaches for hypothesis-free, genome-wide analyses of genomic and transcriptomic data and their integration. Last, we summarize the findings of recent genetic and transcriptomic studies within this conceptual framework., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a substantial public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that are heavily implicated in CUD, the nucleus accumbens and caudate nucleus, from men suffering from CUD and matched controls. Weighted gene coexpression analyses identified CUD-specific gene networks enriched in ionotropic receptors and linked to lowered neuroinflammation, contrasting the proinflammatory responses found in opioid use disorder. Integration of comprehensive transcriptomic datasets from mouse cocaine self-administration models revealed evolutionarily conserved gene networks in CUD that implicate especially D1 medium spiny neurons as drivers of cocaine-induced plasticity.

Regions of hypoxia are common in solid tumors and drive changes in gene expression that increase risk of cancer metastasis. Tumor cells must respond to the stress of hypoxia by activating genes to modify cell metabolism and antioxidant response to improve survival. The goal of the current study was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in metastatic (metM-Wnt lung ) compared with nonmetastatic (M-Wnt) murine mammary cancer cell lines. We show that hypoxia induced a greater suppression of glutamine to glutamate conversion in metastatic cells (13% in metastatic cells compared to 7% in nonmetastatic cells). We also show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to nonmetastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Interestingly, hypoxia increased the mRNA level of the transaminase glutamic pyruvic transaminase 2 (Gpt2, 7.7-fold) only in metM-Wnt lung cells. The change in Gpt2 expression was accompanied by transcriptional (4.2-fold) and translational (6.5-fold) induction of the integrated stress response effector protein activating transcription factor 4 (ATF4). Genetic depletion ATF4 demonstrated importance of this molecule for survival of hypoxic metastatic cells in detached conditions. These findings indicate that more aggressive, metastatic cancer cells utilize hypoxia for metabolic reprogramming and induction of antioxidant defense, including activation of ATF4, for survival in detached conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kiesel, Sheeley, Hicks, Andolino, Donkin, Wendt, Hursting and Teegarden.)

Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large transcriptome studies are essential. Here we describe the transcriptome analysis of 255 primary human microglial samples isolated at autopsy from multiple brain regions of 100 individuals. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region and aging. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, finding associations with microglial expression of USP6NL for Alzheimer's disease and P2RY12 for Parkinson's disease. We have built the most comprehensive catalog to date of genetic effects on the microglial transcriptome and propose candidate functional variants in neurological and psychiatric disorders., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aims and Objectives: To describe the spirituality and religiosity of 30 non-directed (altruistic) living kidney donors in the USA and explore how they may have affected their motivations to donate and donation process experiences., Background: The rise in non-directed donors and their ability to initiate kidney chains offer a novel approach to help alleviate the overextended kidney transplant wait list in the USA. However, little is known about the non-directed donors' motivations, characteristics and experiences., Design: We conducted a qualitative-dominant study and used a grounded theory approach to analyse data., Methods: Thirty participants completed in-depth interviews between April 2013-April 2015. Three analysts independently read and coded interview transcripts. Grounded theory techniques were used to develop descriptive categories and identify topics related to the non-directed donors donation experience., Results: Sixteen of the 30 non-directed donorss discussed the topic of spirituality and religiosity when describing their donation experiences, regardless of whether they were actively practising a religion at the time of donation. Specifically, three themes were identified within spirituality and religiosity: motivation to donate, support in the process, and justification of their donation decisions postdonation., Conclusions: Findings from this study are the first to describe how spirituality and religiosity influenced the experiences of U.S. non-directed donorss and may help improve non-directed donors educational resources for future spiritual or religious non-directed donors, and the overall non-directed donors donation experience in efforts to increase the living donor pool., Relevance to Clinical Practice: Spirituality and religiosity are often overlooked yet potentially influential factors in Western medicine, as demonstrated through the experiences of Jehovah's Witnesses and their religious restrictions while undergoing surgery and the beliefs of Christian Scientists against taking medications and receiving medical procedures. Understanding needs of non-directed donors specifically with spirituality and religiosity can better position kidney transplant centres and teams to improve predonation screening of non-directed donor candidates and provide support services during the donation process., (© 2017 John Wiley & Sons Ltd.)

The disparity between kidney transplant candidates and donors necessitates innovations to increase organ availability. Transporting kidneys allows for living donors and recipients to undergo surgery with a familiar transplant team, city, friends, and family. The effect of shipping kidneys and prolonged cold ischemia time (CIT) with living donor transplantation outcomes is not clearly known. This retrospective matched (age, gender, race, and year of procedure) cohort study compared allograft outcomes for shipped live donor kidney transplants and nonshipped living donor kidney transplants. Fifty-seven shipped live donor kidneys were transplanted from 31 institutions in 26 cities. The mean shipping distance was 1634 miles (range 123-2811) with mean CIT of 12.1 ± 2.8 h. The incidence of delayed graft function in the shipped cohort was 1.8% (1/57) compared to 0% (0/57) in the nonshipped cohort. The 1-year allograft survival was 98% in both cohorts. There were no significant differences between the mean serum creatinine values or the rates of serum creatinine decline in the immediate postoperative period even after adjusted for gender and differences in recipient and donor BMI. Despite prolonged CITs, outcomes for shipped live donor kidney transplants were similar when compared to matched nonshipped living donor kidney transplants., (© 2014 Steunstichting ESOT.)

Purpose/objectives: To investigate how familial communication about prostate cancer (PCa) risk and screening affects sons of men with PCa., Research Approach: Qualitative grounded theory., Setting: Southern California., Participants: 17 Latino sons of PCa survivors., Methodologic Approach: The team conducted semistructured interviews and follow-up interviews. Therefore, the sample includes 25 transcripts. Data were analyzed with a mix of a priori topical codes and grounded theory techniques., Findings: Sons were in need of information about familial risk and screening options. They became sensitized to PCa, desired information, and held protective intentions. Hopeful intentions came up against cultural taboos around sex, reproductive health, and intimacy that limited discussions between fathers and sons. Fathers were a valued source of information but play various roles, which affect sons' screening intentions. Open communication between father and son promoted awareness of screening and familial risk., Conclusions: Uncertainty about familial risk and screening options, especially early detection strategies, was exacerbated by cultural taboos around PCa. Fathers could have been primary and credible advocates for shared decision making, but sons had difficulty learning from their fathers' experience., Interpretation: FINDINGS from the study can help inform community-based interventions with Latino families, help to culturally tailor health messaging, and sensitize clinicians to a group that needs concerted counseling about PCa risk and screening.