In the United States, the number and proportion of HIV/AIDS cases among black/African Americans continue to highlight the need for new biomedical prevention interventions, including an HIV vaccine, microbicide, or new antiretroviral (ARV) prevention strategies such as pre-exposure prophylaxis (PrEP) to complement existing condom usage, harm reduction methods, and behavioral change strategies to stem the HIV epidemic. Although black/African Americans are disproportionately impacted by HIV/AIDS, their participation in HIV clinical research continues to have unique challenges. We theorize that interaction among multilevel factors creates ideal alignment for minority participation in HIV clinical studies. Thus, we initially set out to test an extended model of reasoned action with 362 participants to understand the interplay of sociopsychological and network-level considerations influencing minority participation in HIV prevention research efforts. In this study, we linked the intrapersonal dimensions of attitudes, beliefs, and normative concerns to community-level components, appraisal of involvement with the clinical research organization, an entity which operates within a networked structure of community partner agencies, and identification with coalition advocacy aims. Various participatory outcomes were explored including involvement in future HIV vaccine community functions, participation in community promotion of HIV vaccine research, and community mobilization. Three-stage least squares estimates indicated similar findings across three models. Significant effects demonstrate the importance of positive attitudes toward HIV vaccine research, favorable health research beliefs, perceived social support for participation, HIV/AIDS issue engagement, and perceived relevance of the clinical research site’s mission and values. Identification of these nuanced pathway effects provides implications for tailored community program development.
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James J Kohler;
Seyed H. Hosseini;
Elgin Green;
Amy Hoying-Brandt;
Ioan Cucoranu;
Chad P. Haase;
Rodney Russ;
Jaya Srivastava;
Kristopher Ivey;
Tomika Ludaway;
Victor Kapoor;
Allison Abuin;
Alexsey Shapoval;
Robert Santoianni;
Ann Saada;
Orly Elpeleg;
William Lewis
Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (pol γ) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol γ and mtDNA replication. Cardiac “dominant negative” murine transgenes (TGs; Pol γ Y955G, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in “2 × 2” studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs (∼50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass (≈50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.
This paper discusses how the arrival of born-digital content into archives operating systems and complex digital collections, archives must build upon practices developed over recent decades in the handling of electronic records while also radically reconsidering the extent of acquisition and approaches to access. These changes are discussed within the context of the manuscripts and computers that comprise Salman Rushdie’s personal literary “papers,” which are housed in Emory University’s Manuscript, Archives, and Rare Book Library (MARBL). Early in the development of the Rushdie project, the library made a commitment to approach the material as holistically as possible, to prioritize the integration of paper and digital, and to balance the needs of donors with those of researchers. The paper will outline how the library developed researcher tools that allow concurrent exploration of the paper material and the born-digital material via emulation and item-level, database-driven searches.
Background
This study determined the reliability of topographic motor cortical maps and MEP characteristics in the extensor digitorum communis (EDC) evoked by single-pulse TMS among patients with chronic stroke.
Methods
Each of ten patients was studied on three occasions. Measures included location of the EDC hotspot and center of gravity (COG), threshold of activation and average amplitude of the hotspot, number of active sites, map volume, and recruitment curve (RC) slope.
Results
Consistent intrahemispheric measurements were obtained for the three TMS mapping sessions for all measured variables. No statistically significant difference was observed between hemispheres for the number of active sites, COG distance or the RC slope. The magnitude and range of COG movement between sessions were similar to those reported previously with this muscle in able-bodied individuals. The average COG movement over three sessions in both hemispheres was 0.90 cm. The average COG movement in the affected hemisphere was 1.13 (± 0.08) cm, and 0.68 (± 0.04) cm) for the less affected hemisphere. However, significant interhemispheric variability was seen for the average MEP amplitude, normalized map volume, and resting motor threshold.
Conclusion
The physiologic variability in some TMS measurements of EDC suggest that interpretation of TMS mapping data derived from hemiparetic patients in the chronic stage following stroke should be undertaken cautiously. Irrespective of the muscle, potential causes of variability should be resolved to accurately assess the impact of pharmacological or physical interventions on cortical organization as measured by TMS among patients with stroke.
Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate motile processes. Motility of these processes is guided by local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. Here we identified a molecular pathway in mouse and human microglia that converts ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A2A adenosine receptor coincident with P2Y12 downregulation. Thus, A2A receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.
An important challenge in prostate cancer research is to develop effective predictors of tumor recurrence following surgery to determine whether immediate adjuvant therapy is warranted. To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed, paraffin-embedded radical prostatectomy specimens with known long-term outcomes to perform DASL expression profiling with a custom panel that we designed of 522 prostate cancer–relevant genes. We identified a panel of 10 protein-coding genes and two miRNA genes (RAD23B, FBP1, TNFRSF1A, CCNG2, NOTCH3, ETV1, BID, SIM2, LETMD1, ANXA1, miR-519d, and miR-647) that could be used to separate patients with and without biochemical recurrence (P < 0.001), as well as for the subset of 42 Gleason score 7 patients (P < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of biochemical recurrence for all cases (P = 0.013) and for a subset of 19 Gleason score 7 cases (P = 0.010), both of which were adjusted for relevant clinical information including T-stage, prostate-specific antigen, and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason score 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.
Based on Micah Vandegrift’s article What is digital humanities and what’s it doing in the library? and Stewart Varner’s response to that piece, this article offers an overview of the foundational ideals where libraries and digital humanities overlap. The authors lay out practical ways for libraries to involve themselves in this evolving area, especially focused on current strengths of many libraries including commitments to resource accessibility and project development. Finally, this article proposes that the role of the research librarian is evolving in order to effectively integrate the library as a partner in the scholarship of digital humanities.
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Mark B Powers;
Megan E Douglas;
Simon Driver;
Seema Sikka;
Rita Hamilton;
Chad Swank;
Librada Callender;
Christa Ochoa;
Monica Bennett;
Neil Stewart;
Gregory V Chauvin;
Barbara Rothbaum;
Ann Marie Warren
Background: Scant research has focused on posttraumatic stress disorder (PTSD) in the SCI population, despite high prevalence estimates. Fortunately, prolonged exposure therapy (PE) is a well-researched and highly effective treatment for PTSD. Our recent clinical trial showed that standard 12-session PE was effective for PTSD treatment among inpatients with SCI. Early intervention with brief PE (3-sessions) delivered in the emergency department has also been effective for PTSD prevention, but has not been tested among people post-SCI. Thus, we aim to conduct the first test of the Brief PE intervention to prevent PTSD among patients with SCI. Methods: Adults who have experienced a SCI (N = 200) will be randomly assigned during inpatient rehabilitation to either: (a) 3 60-min sessions of Brief PE (intervention group) or (b) treatment as usual (control group). Results: The primary outcome measure (PTSD symptoms measured by the PSSI-5) and secondary outcome measures (depression, anxiety, pain, quality of life, sleep disturbance, and resilience) will be assessed at baseline, 1-month, 3-months, and 6-months. Hierarchical linear modeling (HLM) will be used to evaluate the effectiveness of the PE intervention on PTSD and secondary outcomes. Descriptive statistics will examine feasibility and will include the number of participants enrolled, the number of sessions completed, fidelity of Brief PE delivery, and average scores for difficulty and helpfulness of the intervention scales for those randomized to intervention. Conclusions: Successful completion of this study will provide an evidence-based program to alleviate posttraumatic distress post spinal cord injury and prevent long-term development of PTSD.
Background: Total Marrow and Lymphoid Irradiation (TMLI) is a promising component of the preparative regimen for hematopoietic cell transplantation in patients with high-risk acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Extramedullary (EM) relapse after TMLI is comparable to TBI and non-TBI conditioning regimens. This study evaluates outcomes of patients treated with radiotherapy (RT) with EM relapse previously treated with TMLI. Methods: A retrospective analysis of five prospective TMLI trials was performed. TMLI targeted bones and major lymphoid tissues using image-guided tomotherapy, with total dose ranging from 12 to 20 Gy. EM recurrences were treated at the discretion of the hematologist and radiation oncologist using RT ± chemotherapy. Descriptive statistics and survival analysis were then performed on this cohort. Results: In total, 254 patients with refractory or relapsed AML or ALL were treated with TMLI at our institution. Twenty-one patients were identified as receiving at least one subsequent course of radiation. A total of 67 relapse sites (median=2 sites/patient, range=1-16) were treated. Eleven relapsed patients were initially treated with curative intent. Following the initial course of subsequent RT, 1-year, 3-year and 5-year estimates of OS were 47.6%, 32.7% and 16.3%, respectively. OS was significantly better in patients treated with curative intent, with median OS of 50.7 months vs 1.6 months (p<0.001). 1-year, 3-year and 5-year estimates of PFS were 23.8%, 14.3% and 14.3%, respectively. PFS was significantly better in patients treated with curative intent, with median PFS of 6.6 months vs 1.3 months (p<0.001). Following RT, 86.6% of the sites had durable local control. Conclusions: RT is an effective modality to treat EM relapse in patients with acute leukemia who relapse after HCT achieving high levels of local control. In patients with limited relapse amenable to curative intent, radiation confers favorable long-term survival. Radiation as salvage treatment for EM relapse after HCT warrants further evaluation.
Numerous radiation oncology residents and junior attendings have identified common weaknesses in residency training that hinder the transition from training to independent practice. Recurrent themes include not only general autonomy but also proficiency in technical skills, such as treatment plan review and image verification, and nontechnical skills, such as leadership, mentorship, and education. While multiple strategies to address these deficiencies have been investigated, many are not widely available or may be difficult to implement. We aim to summarize the frequently cited challenges in the transition to independent radiation oncology practice as well as the pertinent interventions that have been explored.
Behavior polymorphisms underlying alternative mating tactics can evolve due to genetic inversions, especially when inversions capture sets of genes involved in hormonal regulation. In the three-morph system of the ruff (Calidris pugnax), two alternative morphs (Satellites and Faeders) with distinct behaviors and low circulating testosterone are genetically determined by an inverted region on an autosomal chromosome. Here, we discuss recent findings on the ruff and present novel insights into how an inversion that poses drastic constraints on testosterone production might lead to morph-specific differences in brain areas that regulate social behavior. A gene responsible for converting testosterone to androstenedione (HSD17B2) is located inside the inverted region and is a promising candidate. We identify a single missense mutation in the HSD17B2 gene of inverted alleles that is responsible for a 350–500% increase in testosterone to androstenedione conversion, when mutated in the human HSD17B2 protein. We discuss new evidence of morph differences in neural HSD17B2 expression in embryos and circulating androgens in sexually-immature juveniles. We suggest processes that shape morph differences in behavior likely begin early in ontogeny. We propose that the organization of behaviorally relevant neuron cell types that are canonically sexually dimorphic, such as subpopulations of aromatase and vasotocin neurons, should be particularly affected due to the life-long condition of low circulating testosterone in inversion morphs. We further emphasize how HSD17B2 catalytic activity extends beyond androgens, and includes estradiol oxidation into estrone and progesterone synthesis. Lastly, we underscore dimerization of HSD17B2 as an additional layer of complexity that merits consideration.
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Tao Qing;
Thomas Karn;
Mariya Rozenblit;
Julia Foldi;
Michal Marczyk;
Naing Lin Shan;
Kim Blenman;
Uwe Holtrich;
Kevin Kalinsky;
Funda Meric-Bernstam;
Lajos Pusztai
The RxPONDER and TAILORx trials demonstrated benefit from adjuvant chemotherapy in patients age ≤ 50 with node-positive breast cancer and Recurrence Score (RS) 0–26, and in node-negative disease with RS 16–25, respectively, but no benefit in older women with the same clinical features. We analyzed transcriptomic and genomic data of ER+/HER2− breast cancers with in silico RS < 26 from TCGA (n = 530), two microarray cohorts (A: n = 865; B: n = 609), the METABRIC (n = 867), and the SCAN-B (n = 1636) datasets. There was no difference in proliferation-related gene expression between age groups. Older patients had higher mutation burden and more frequent ESR1 copy number gain, but lower frequency of GATA3 mutations. Younger patients had higher rate of ESR1 copy number loss. In all datasets, younger patients had significantly lower mRNA expression of ESR1 and ER-associated genes, and higher expression of immune-related genes. The ER- and immune-related gene signatures showed negative correlation and defined three subpopulations in younger women: immune-high/ER-low, immune-intermediate/ER-intermediate, and immune-low/ER-intermediate. We hypothesize that in immune-high cancers, the cytotoxic effect of chemotherapy may drive the benefit, whereas in immune-low/ER-intermediate cancers chemotherapy induced ovarian suppression may play important role.
Objectives: We evaluated changes in priority indicators of child growth from 2006 to 2021 and examined the role of human development measures in these changes. Methods: We estimated cumulative and annualized changes in state- and district-level child growth indicators using 3 rounds of National Family Health Surveys (2005–2006, 2015–2016, 2019–2021) in 36 states. Outcomes included stunting, underweight, wasting, and overweight. Human development was measured using a principal components analysis of 9 ecological indicators. We contrasted expected versus observed changes in district-level growth outcomes between 2016 and 2021 based on changes in development indicators using 2-way Blinder Oaxaca decomposition. Results: From 2006 to 2021, the prevalence of stunting, underweight, and wasting decreased by 12.3, 10.3, and 0.7 percentage points, respectively, while the prevalence of overweight increased by 1.9 percentage points. The annualized rate of within-state change for stunting was lower from 2016 to 2021 compared with the 2006 to 2016 period, while the rate of change in overweight was higher. Simultaneously, all 9 human development indicators improved between 2006 and 2021. A unit increase between 2016 and 2021 in the human development score predicted a -5.1 percentage point (95% confidence interval=-5.8, -4.4) change in stunting, yet observed stunting declined by just -2.5 percentage points. Conclusions: From 2016 to 2021, population-level reduction in child stunting has slowed and the rise in child overweight has accelerated, relative to the 10 years preceding this period.
Gestational epigenetic age (GEA) acceleration and deceleration can indicate developmental risk and may help elucidate how prenatal exposures lead to offspring outcomes. Depression and neighbourhood conditions during pregnancy are well-established determinants of birth and child outcomes. Emerging research suggests that maternal depression may contribute to GEA deceleration. It is unknown whether prenatal neighbourhood adversity would likewise influence GEA deceleration. This study examined whether maternal depression and neighbourhood conditions independently or jointly contributed to GEA deceleration, and which social and environmental neighbourhood conditions were associated with GEA. Participants were from the Albany Infant and Mother Study (n = 204), a prospective non-probability sampled cohort of higher risk racial/ethnic diverse mother/infant dyads. GEA was estimated from cord blood. Depressive symptoms and census-tract level neighbourhood conditions were assessed during pregnancy. Maternal depression (β = −0.03, SE = 0.01, p = 0.008) and neighbourhood adversity (β = −0.32, SE = 0.14, p = 0.02) were independently associated with GEA deceleration, controlling for all covariates including antidepressant use and cell type proportions. Neighbourhood adversity did not modify the association of maternal depression and GEA (β = 0.003, SE = 0.03, p = 0.92). igher levels of neighbourhood poverty, public assistance, and lack of healthy food access were each associated with GEA deceleration; higher elementary school test scores (an indicator of community tax base) were associated with GEA acceleration (all p < 0.001). The results of this study indicated that maternal depression and neighbourhood conditions were independently and cumulatively associated GEA in this diverse population.
Background: Human and animal exposure to bisphenol A (BPA) has been associated with adverse developmental and reproductive effects. The molecular mechanisms by which BPA exposure exerts its effects are not well-understood, even less known about its analogues bisphenol F (BPF). To address these knowledge gaps, we conducted an untargeted metabolome-wide association study (MWAS) to identify metabolic perturbations associated with BPA/BPF exposures in a pregnant African American cohort. Methods: From a subset of study participants enrolled in the Atlanta African American Maternal-Child cohort, we collected both urine samples, for targeted exposure assessment of BPA (N = 230) and BPF (N = 48), and serum samples, for high-resolution metabolomics (HRM) profiling (N = 230), during early pregnancy (8–14 weeks’ gestation). Using an established untargeted HRM workflow consisting of MWAS modeling, pathway enrichment analysis, and chemical annotation and confirmation, we investigated the potential metabolic pathways and features associated with BPA/BPF exposures. Results: The geometric mean creatinine-adjusted concentrations of urinary BPA and BPF were 0.85 ± 2.58 and 0.70 ± 4.71 µg/g creatinine, respectively. After false positive discovery rate correction at 20 % level, 264 and 733 unique metabolic features were significantly associated with urinary BPA and BPF concentrations, representing 10 and 12 metabolic pathways, respectively. Three metabolic pathways, including steroid hormones biosynthesis, lysine and lipoate metabolism, were significantly associated with both BPA and BPF exposure. Using chemical standards, we have confirmed the chemical identity of 16 metabolites significantly associated with BPA or BPF exposure. Conclusions: Our findings support that exposure to BPA and BPF in pregnant women is associated with the perturbation of aromatic amino acid metabolism, xenobiotics metabolism, steroid biosynthesis, and other amino acid metabolism closely linked to stress responses, inflammation, neural development, reproduction, and weight regulation.
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Michael G Levin;
Noah L Tsao;
Pankhuri Singhal;
Chang Liu;
Ha My T Vy;
Ishan Paranjpe;
Joshua D Backman;
Tiffany R Bellomo;
William P Bone;
Kiran J Biddinger;
Qin Hui;
Ozan Dikilitas;
Benjamin A Satterfield;
Yifan Yang;
Michael P Morley;
Yuki Bradford;
Megan Burke;
Nosheen Reza;
Brian Charest;
Renae L Judy;
Megan J Puckelwartz;
Hakon Hakonarson;
Atlas Khan;
Leah C Kottyan;
Iftikhar Kullo;
Yuan Luo;
Elizabeth M McNally;
Laura J Rasmussen-Torvik;
Sharlene M Day;
Ron Do;
Lawrence Phillips;
Patrick T Ellinor;
Girish N Nadkarni;
Marylyn D Ritchie;
Zoltan Arany;
Thomas P Cappola;
Kenneth B Margulies;
Krishna G Aragam;
Christopher M Haggerty;
Jacob Joseph;
Yan Sun;
Benjamin F Voight;
Scott M Damrauer
Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.
Purpose To assess hospitalized COVID-19 inpatients for the prevalence of retinopathy and tear film SARS-CoV-2 RNA, and associated risk factors for their detection. Methods Hospitalized COVID-19 patients underwent dilated ophthalmic examination and fundus photography. Conjunctival swabs were assessed for SARS-CoV-2 RT-PCR via a triple target assay. We assessed the relationships of retinopathy with clinical outcomes, systemic risk factors and laboratory data. Results The median age was 59.5 years and 29 (48%) were female. Retinopathy associated with COVID-19 was observed in 12 of 60 patients (20%). The median age of patients with COVID-19 retinopathy was 51.5 compared to 62.5 years in individuals without retinopathy (p = 0.01). Median BMI was 34.3 in patients with retinopathy versus 30.9 in those without retinopathy (p = 0.04). Fifteen of 60 patients (25%) tested SARS-CoV-2 RNA-positive in their tear film without a relationship with timing of illness and hospitalization. The N2 gene was particularly sensitive with 18 of 19 eyes (94.7%) showing N2-positivity, including 2 patients with alpha variant-positivity (B.1.1.7). Conclusion Retinopathy was observed in 20% of patients hospitalized for COVID-19. Patients with retinopathy were more likely to be younger and have higher BMI than hospitalized patients without retinopathy. Tear film SARS-CoV-2 RNA was detected in 25% of patients. The relationship of obesity and age with retinopathy requires further investigation.