Loss of Obstetric Services in Rural Appalachia: A Qualitative Study of Community Perceptions

Background: As rural hospitals across the United States increasingly downsize or close, the availability of inpatient obstetric services continues to decline in rural areas. In rural Appalachia, the termination of obstetric services threatens to exacerbate the existing risk of adverse birth outcomes for women and infants, yet less is known about how the cessation of these services affects the broader community. Purpose: The purpose of this paper is to explain how the loss of local obstetric services affects perceptions of healthcare among multi-generational residents of a remote, rural Appalachian community in western North Carolina. Methods: An interdisciplinary team of researchers conducted a thematic analysis of health-related oral history interviews (n=14) that were collected from local residents of a rural, western North Carolina community during the summer of 2019. Results: The closure of a local hospital’s labor and delivery department fostered 1) frustration with the decline in hospital services, 2) perceived increases in barriers to accessing healthcare, and 3) increased medical mistrust. Implications: Findings suggest that the loss of obstetric services in this rural Appalachian community could have broad, negative health implications for all residents, regardless of their age, sex, or ability to bear children. Community-specific strategies are needed to foster trust in the remaining healthcare providers and to increase access to care for local residents. Results serve as formative research to support the development of interventions and policies that effectively respond to all community members’ needs and concerns following the loss of obstetric services in remote Appalachian communities

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.This work was supported in part by grants from the Instituto de Salud Carlos III (ISCIII) (PI15/01551, PI17/01941 and CB16/11/00432 to P.G-P. and L.A-P.), the Spanish Ministry of Economy and Competitiveness (SAF2015-71863-REDT to P.G-P.), the John S. LaDue Memorial Fellowship at Harvard Medical School (Y.K.), Wellcome Trust (107469/Z/15/Z to J.S.W.), Medical Research Council (intramural awards to S.A.C. and J.S.W; MR/M003191/1 to U.T), National Institute for Health Research Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College London (P.J.B., S.A.C., J.S.W.), National Institute for Health Research Biomedical Research Centre at Imperial College London Healthcare National Health Service Trust and Imperial College London (D.O.R., S.A.C., S.P., J.S.W.), Sir Henry Wellcome Postdoctoral Fellowship (C.N.T.), Rosetrees and Stoneygate Imperial College Research Fellowship (N.W.), Fondation Leducq (S.A.C., C.E.S., J.G.S.), Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health (UK; HICF-R6-373; S.A.C., P.J.B., J.S. W.), the British Heart Foundation (NH/17/1/32725 to D.O.R.; SP/10/10/28431 to S.A.C), Alex’s Lemonade Stand Foundation (K.G.), National Institutes of Health (R.A.: U01CA097452, R01CA133881, and U01CA097452; Z.A.: R01 HL126797; B.K.: R01 HL118018 and K23-HL095661; J.G.S. and C.E.S.: 5R01HL080494, R01HL084553), and the Howard Hughes Medical Institute (C.E.S.). The Universitario Puerta de Hierro and Virgen de la Arrixaca Hospitals are members of the European Reference Network on Rare and Complex Diseases of the Heart (Guard-Heart; http://guard-heart.ern-net.eu). This publication includes independent research commissioned by the Health Innovation Challenge Fund (HICF), a parallel funding partnership between the Department of Health and Wellcome Trust. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Ministry of Economy, Industry and Competitiveness and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from ISCIII and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016 – European Regional Development Fund (FEDER) “A way of making Europe”.S

Natural Killer Lysis Receptor (NKLR)/NKLR-Ligand Matching as a Novel Approach for Enhancing Anti-Tumor Activity of Allogeneic NK Cells

NK cells are key players in anti tumor immune response, which can be employed in cell-based therapeutic modalities. One of the suggested ways to amplify their anti tumor effect, especially in the field of stem cell transplantation, is by selecting donor/recipient mismatches in specific HLA, to reduce the inhibitory effect of killer Ig-like receptors (KIRs). Here we suggest an alternative approach for augmentation of anti tumor effect of allogeneic NK cells, which is founded on profile matching of donor NK lysis receptors (NKLR) phenotype with tumor lysis-ligands.We show that an NKLR-mediated killing directly correlates with the NKLR expression intensity on NK cells. Considerable donor variability in the expression of CD16, NKp46, NKG2D and NKp30 on circulating NK cells, combined with the stability of phenotype in several independently performed tests over two months, indicates that NKLR-guided selection of donors is feasible. As a proof of concept, we show that melanoma cells are dominantly recognized by three NKLRs: NKG2D, NKp30 and NKp44. Notably, the expression of NKp30 on circulating NK cells among metastatic melanoma patients was significantly decreased, which diminishes their ability to kill melanoma cells. Ex vivo expansion of NK cells results not only in increased amount of cells but also in a consistently superior and predictable expression of NKG2D, NKp30 and NKp44. Moreover, expanded NK cultures with high expression of NKG2D or NKp30 were mostly derived from the corresponding NKG2D(high) or NK30(high) donors. These NK cultures subsequently displayed an improved cytotoxic activity against melanoma in a HLA/KIR-ligand mismatched setup, which was NKLR-dependent, as demonstrated with blocking anti-NKG2D antibodies.NKLR/NKLR-ligand matching reproducibly elicits enhanced NK anti-tumor response. Common NKLR recognition patterns of tumors, as demonstrated here in melanoma, would allow implementation of this approach in solid malignancies and potentially in hematological malignancies, either independently or in adjunction to other modalities

Demographic correlates of attenuated positive psychotic symptoms

It is now well established that the utilization of standardized clinical criteria can enhance prediction of psychosis. These criteria are primarily concerned with the presence and severity of attenuated positive symptoms. Because these symptom criteria are used to derive algorithms for designating clinical high risk (CHR) status and for maximizing prediction of psychosis risk, it is important to know whether the symptom ratings vary as a function of demographic factors that have previously been linked with symptoms in diagnosed psychotic patients. Using a sample of 356 CHR individuals from the NAPLS-II multi-site study, we examined the relation of three sex, age, and educational level, with the severity of attenuated positive symptom scores from the Scale of Prodromal Symptoms (SOPS). Demographic factors accounted for little of the variance in symptom ratings (5–6%). Older CHR individuals manifested more severe suspiciousness, and female CHR participants reported more unusual perceptual experiences than male participants. Contrary to prediction, higher educational level was associated with more severe ratings of unusual thought content, but less severe perceptual abnormalities. Overall, sex, age and education were modestly related to unusual thought content and perceptual abnormalities, only, suggesting minimal implication for designating CHR status and predicting psychosis-risk

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study

Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. Methods: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. Results: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. Conclusions: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

A Generation\u27s Experiment: Oberlin Womanhood, Coeducation, and The Ladies\u27 Board of Managers 1835-1879

No abstract available

"Far More than Just a Prescription": Focus Groups With U.S. Family Planning Providers and Staff About Integrating PrEP for HIV Prevention Into Their Work.

BackgroundCisgender women in the United States use pre-exposure prophylaxis (PrEP) for HIV prevention at lower rates relative to other groups. Advocacy groups and patients identify family planning clinics as the preferred sites to lead PrEP implementation for women in the United States. However, limited qualitative exploration exists of U.S. family planning practitioners' attitudes toward integrating PrEP into their work.MethodsWe conducted qualitative focus groups with a convenience sample of family planning clinicians, counselors, and clinic managers to explore barriers and facilitators to PrEP provision in U.S. family planning clinics.ResultsWe conducted six focus groups (total participants&nbsp;=&nbsp;37) with respondents who worked in family planning clinics in San Francisco, California; Kansas City, Missouri; and Philadelphia, Pennsylvania. Key themes emerged highlighting how PrEP at times runs contrary to other family planning agendas, including efficient clinic visits, condom promotion, and long-acting reversible contraception counseling. Throughout these discussions, participants expressed discomfort with HIV vulnerabilities rooted in social and structural determinants of health.ConclusionsFindings suggest that those seeking to implement PrEP for U.S. cisgender women may benefit from exploring 1) how to integrate patient/provider conversations about the structural determinants of health and their relationship to HIV and other sexual and reproductive health outcomes and 2) how to foster person-centered prevention conversations in the context of busy family planning visits