Transcriptomic analysis of the human habenula in schizophrenia.

Importance: Habenula (Hb) pathophysiology is involved in many neuropsychiatric disorders, including schizophrenia. Deep brain stimulation and pharmacological targeting of the Hb are emerging as promising therapeutic treatments. However, little is known about the cell type-specific transcriptomic organization of the human Hb or how it is altered in schizophrenia. Objective: To define the molecular neuroanatomy of the human habenula and identify transcriptomic changes in individuals with schizophrenia compared to neurotypical controls. Design Setting and Participants: This study utilized Hb-enriched postmortem human brain tissue. Single nucleus RNA-sequencing (snRNA-seq) and single molecule fluorescent in situ hybridization (smFISH) experiments were conducted to identify molecularly defined Hb cell types and map their spatial location (n=3-7 donors). Bulk RNA-sequencing and cell type deconvolution were used to investigate transcriptomic changes in Hb-enriched tissue from 35 individuals with schizophrenia and 33 neurotypical controls. Gene expression changes associated with schizophrenia in the Hb were compared to those previously identified in the dorsolateral prefrontal cortex (DLPFC), hippocampus, and caudate. Main Outcomes and Measures: Semi-supervised snRNA-seq cell type clustering. Transcript visualization and quantification of smFISH probes. Bulk RNA-seq cell type deconvolution using reference snRNA-seq data. Schizophrenia-associated gene differential expression analysis adjusting for Hb and thalamus fractions, RNA degradation-associated quality surrogate variables, and other covariates. Cross-brain region schizophrenia-associated gene expression comparison. Results: snRNA-seq identified 17 cell type clusters across 16,437 nuclei, including 3 medial and 7 lateral Hb populations. Cell types were conserved with those identified in a rodent model. smFISH for cell type marker genes validated snRNA-seq Hb cell types and depicted the spatial organization of subpopulations. Bulk RNA-seq analyses yielded 45 schizophrenia-associated differentially expressed genes (FDR < 0.05), with 32 (71%) unique to Hb-enriched tissue. Conclusions: These results identify topographically organized cell types with distinct molecular signatures in the human Hb. They further demonstrate unique transcriptomic changes in the epithalamus associated with schizophrenia, thereby providing molecular insights into the role of Hb in neuropsychiatric disorders.

TrkB-dependent regulation of molecular signaling across septal cell types.

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning, and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.

Breathe.

This is a personal essay about breasts. It focuses on my experiences as a young girl, moving through adolescence to a history of breast cancer in my family, including my mother's breast cancer diagnosis. As a physician, patient, and wife, I reflect on the choices that I have to make and what this means for my identity as a woman and mother.

Evaluation of noninvasive biospecimens for transcriptome studies.

Transcriptome studies disentangle functional mechanisms of gene expression regulation and may elucidate the underlying biology of disease processes. However, the types of tissues currently collected typically assay a single post-mortem timepoint or are limited to investigating cell types found in blood. Noninvasive tissues may improve disease-relevant discovery by enabling more complex longitudinal study designs, by capturing different and potentially more applicable cell types, and by increasing sample sizes due to reduced collection costs and possible higher enrollment from vulnerable populations. Here, we develop methods for sampling noninvasive biospecimens, investigate their performance across commercial and in-house library preparations, characterize their biology, and assess the feasibility of using noninvasive tissues in a multitude of transcriptomic applications. We collected buccal swabs, hair follicles, saliva, and urine cell pellets from 19 individuals over three to four timepoints, for a total of 300 unique biological samples, which we then prepared with replicates across three library preparations, for a final tally of 472 transcriptomes. Of the four tissues we studied, we found hair follicles and urine cell pellets to be most promising due to the consistency of sample quality, the cell types and expression profiles we observed, and their performance in disease-relevant applications. This is the first study to thoroughly delineate biological and technical features of noninvasive samples and demonstrate their use in a wide array of transcriptomic and clinical analyses. We anticipate future use of these biospecimens will facilitate discovery and development of clinical applications.

TrkB-dependent regulation of molecular signaling across septal cell types.

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.

Hospital readmissions after stroke in patients with and without dementia and undergone gastrostomy tube placement.

INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) in stroke patients is associated with high hospital readmission rates. The impact of dementia on hospital readmission rates in stroke patients who underwent PEG is unknown. We aimed to assess if stroke patients with dementia who undergo PEG are at risk for readmission. METHODS: We conducted a retrospective, observational study using the National Readmission Database from Healthcare Cost and Utilization Project (HCUP) from 2013 to 2014. Patients 65 years or older admitted with stroke and who had gastrostomy in the same hospital admission were included. We compared readmission rates at 30 and 60 days between patients with and without dementia and assessed the five most common readmission diagnosis. The association of dementia and hospital readmission was analyzed. RESULTS: Out of 492,727 patients over 65 who had stroke/PEG, 45,477 (9 %) had dementia. Patients with dementia underwent PEG placement more frequently than those without dementia (4.3% vs. 3.3%, respectively). There was no significant difference in the 30 and 60 days readmission rates between those with dementia and those without. Septicemia, aspiration pneumonitis and complications from the procedure were among top five readmission diagnosis. Dementia was not significantly associated with 30-day (odds ratio (OR) 0.99, 95% CI 0.87-1.13) or 60-day (OR 1, 95% CI 0.89-1.12) readmissions. CONCLUSIONS: Risks and benefits of gastrostomy in older adults with stroke and dementia should be honestly discussed with patients and their families since it exposes them to a higher risk of hospital readmission due to aspiration pneumonitis and complications from PEG.

Impact of Fall Risk and Direct Oral Anticoagulant Treatment on Quality-Adjusted Life-Years in Older Adults with Atrial Fibrillation: A Markov Decision Analysis.

BACKGROUND AND OBJECTIVE: The decision to initiate anticoagulation in older adults with atrial fibrillation is complicated by the benefit of ischemic stroke prevention vs the risk of falls resulting in major bleeds. The objective of this study was to assess the impact of different treatments including direct oral anticoagulants on quality-adjusted life-years (QALYs) in patients aged 75 years and older with atrial fibrillation in the context of falls. METHODS: A Markov decision process was constructed for older patients with atrial fibrillation taking no anti-thrombotic, aspirin, warfarin, rivaroxaban, and apixaban. Input probabilities for clinical events were estimated from the available literature. One-way and two-way sensitivity analyses were performed by measuring the impact of varying input probabilities of clinical events on QALY outcomes. RESULTS: The base-case scenario estimated that older adults treated with no anti-thrombotic, aspirin, warfarin, rivaroxaban, and apixaban had QALYs of 8.03, 8.69, 10.38, 11.02, and 11.56, respectively. The sensitivity analysis estimated that an older adult would need to fall over 45 (rivaroxaban) and 458 (apixaban) times per year for the QALY of a direct oral anticoagulant to be lower than that of aspirin. CONCLUSIONS: Older adults with atrial fibrillation benefit from stroke protection of anticoagulants, especially direct oral anticoagulants, even if they are at high risk of falls. Clinicians should not consider fall risk as a deciding factor for withholding anticoagulation in this population of patients.

Delirium Among Hospitalized Older Adults With Acute Heart Failure Exacerbation.

BACKGROUND: Delirium among older adults hospitalized with acute heart failure is associated with increased mortality. However, studies concomitantly assessing the association of delirium with both clinical and economic outcomes in this population, such as mortality, hospital cost, or length of stay, are lacking. METHODS AND RESULTS: We conducted a retrospective observational study using National Inpatient Sample data from 2011 to 2014. Using multivariable logistic regression, we assessed the association of delirium with in-hospital mortality, then estimated the incremental hospital cost and excessive length of stay adjusting for demographic and clinical factors using multivariable generalized linear regression. The association of other medical complications on clinical and economic outcomes was also assessed. A total of 568,565 (weighted N = 2,826,131) hospitalizations of patients 65 years or older with acute heart failure from 2011 to 2014 were included in the final analysis. The reported prevalence of delirium was 4.53%. After multivariable adjustment, delirium was associated with a 2.35-fold increase in the odds of in-hospital mortality (95% confidence interval [CI] 2.23-2.47), which was lower than the odds ratio for sepsis/septicemia (5.36; 95% CI, 5.02-5.72) or respiratory failure (4.53; 95% CI, 4.38-4.69), but similar to that for acute kidney injury (2.39; 95% CI, 2.31-2.48) and higher than for non-ST elevation myocardial infarct (1.57; 95% CI, 1.46-1.68). Delirium increased the total hospital cost by $4,262 (95% CI, $4,002-4,521) and the length of stay by 1.73 days (95% CI, 1.68-1.78), which was slightly lower than, but similar to, acute kidney injury ($4,771; 95% CI, $4,644-4,897) and 1.82 days (95% CI, 1.79-1.84), and higher than non-ST elevation myocardial infarct ($1,907; 95% CI, $1,629-2,185) and 0.31 days (95% CI, 0.25-0.37). CONCLUSIONS: Delirium was associated with increased in-hospital mortality, total hospital cost, and length of stay, and the magnitude of the effect was similar to that for acute kidney injury. Enhanced efforts to prevent delirium are needed to decrease its adverse impact on clinical and economic outcomes for hospitalized older adults with acute heart failure.

Stemming the Tide of Elder Mistreatment: A Medical School-State Agency Collaborative.

In 1995, the Texas Department of Family and Protective Services: Adult Protective Service Agency began a partnership with the Baylor College of Medicine geriatrics program to form the Texas Elder Abuse and Mistreatment (TEAM) Institute. The medical school-state agency partners overcame institutional and bureaucratic barriers to work collaboratively on mutually beneficial projects, including research and publications. Interprofessional students gained first-hand experience about abuse and neglect cases. As of 2019, there are 4 divisions: Clinical and Forensic Evaluation, Education and Outreach, Research and Program Evaluation, and Senior Justice. TEAM members have published numerous articles and chapters, educated members from multiple disciplines, and served thousands of mistreated older patients. In 2017, TEAM launched the first statewide telecommunication program for elder mistreatment to improve practice for the entire state. Perseverance, teamwork, and dedication to the mission of the intervention and prevention of elder mistreatment have sustained this program for over 30 years. This article describes the steps to forming TEAM, the institute's early struggles, and the subsequent community and academic contributions of this medical school-state agency collaboration.

Bridging the Gap: Holistic Review to Increase Diversity in Graduate Medical Education.

PROBLEM: Racial and ethnic disparities in health outcomes remain pervasive in the U.S. health care system. Increasing the diversity of the physician workforce is recognized as an important component of addressing these disparities. Holistic review, which gives balanced consideration to applicants' academic metrics, experiences, and attributes, has gained popularity in undergraduate medical education and led to improvement in student diversity. Limited research has investigated how holistic review and other strategies can be implemented in graduate medical education to enhance diversity. APPROACH: The internal medicine (IM) residency program of the John P. and Kathrine G. McGovern Medical School implemented a pilot intervention in academic years (AY) 2016-2017 and 2017-2018 aimed at increasing the number of matriculating residents who are underrepresented in medicine (URM). The intervention included (1) using holistic review in the process of selecting applicants for interview, (2) standardizing the interview encounters, and (3) explicitly highlighting the program's commitment to diversity on interview days. OUTCOMES: From AY 2015-2016 (preintervention) to AY 2017-2018, the percentage of URM applications reviewed increased from 14.1% (180/1,276) to 20.4% (183/897), the proportion of URM applicants interviewed rose from 16.0% (60/374) to 24.5% (95/388), and the proportion of URM residents matriculating increased from 12.5% (5/40) to 31.7% (13/41). NEXT STEPS: Further efforts are needed to expand the pool of URM applicants at McGovern and elsewhere and to identify how holistic review can be widely employed in other IM residency programs and in other specialties.

Medication Regimen Complexity and Low Adherence in Older Community-Dwelling Adults With Substantiated Self-Neglect.

OBJECTIVE: Determine whether medication regimen complexity predicts medication adherence levels in a sample of community-dwelling adults 65 years and older with Adult Protective Services-substantiated self-neglect. METHODS: A cross-sectional analysis of baseline data ( N = 31 participants) from a pilot intervention to increase medication adherence among the target group was performed. The Medication Regimen Complexity Index (MRCI) and the 8-item Morisky Medication Adherence Scale (MMAS-8)™ were the primary independent and dependent measures, respectively. A multivariable linear regression analysis, adjusting for potential confounders, was conducted to estimate the association between complexity and adherence. RESULTS: Regimen complexity was high (mean MRCI = 19.6) and adherence was low (mean MMAS = 5.1). Even after controlling for confounders, increased complexity was significantly associated with lower adherence. DISCUSSION: Older community-dwelling adults who self-neglect have complex medication regimens that contribute to low medication adherence. Medication regimen complexity may be a modifiable contributor to low adherence that can be targeted by future interventions to reduce self-neglect and its consequences.

The Association Between Past Sexual Abuse and Depression in Older Adults From Colombia.

To explore the association between past sexual abuse and depression in elders living in Bogotá, Colombia, we used data from the SABE (Salud, Bienestar y Envejecimiento [Health, Well-being, and Aging]) Bogotá Study. Participants were 2000 community-dwelling adults aged 60 years and older in 2012. Sexual abuse was assessed by self-report. Depression was measured by the Geriatric Depression Scale. The weighted prevalence estimate was 2.6% for past sexual abuse and 23.4% for depression. Multivariate data analyses showed significantly higher odds of depression for past sexual abuse (odds ratio [OR] = 3.91, 95% confidence interval [CI]: 2.13-7.16). Other characteristics associated with depression were history of being displaced by violence (OR = 1.77, 95% CI: 1.30-2.40), low socioeconomic status, low education, poor self-rated health status, and poor self-rated memory. Thus, past sexual abuse and history of being displaced by violence were strongly associated with depression among Colombian elderly individuals.