Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are ...limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC p = 8.8x10-15 in African populations, rs11549407 with lower HGB p = 1.5x10-12 and HCT p = 8.8x10-10 in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with pulmonary hypertension (PH), ...yet their role remains incompletely understood.
We studied 482 participants with chronic dyspnoea who underwent clinically indicated cardiopulmonary exercise testing (CPET) with invasive haemodynamic monitoring. We performed comprehensive profiling of 888 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry, and examined associations with PH (mean pulmonary arterial pressure (mPAP) >20 mmHg), PH subtypes and physiological correlates, including transpulmonary metabolite gradients.
Among 482 participants (mean±sd age 56±16 years, 62% women), 200 had rest PH. We found 48 eicosanoids and eicosanoid-related metabolites that were associated with PH. Specifically, prostaglandin (11β-dhk-PGF2α), linoleic acid (12,13-EpOME) and arachidonic acid derivatives (11,12-DiHETrE) were associated with higher odds of PH (false discovery rate q<0.05 for all). By contrast, epoxide (8(9)-EpETE), α-linolenic acid (13(
)-HOTrE(γ)) and lipokine derivatives (12,13-DiHOME) were associated with lower odds. Among PH-related eicosanoids, 14 showed differential transpulmonary metabolite gradients, with directionality suggesting that metabolites associated with lower odds of PH also displayed pulmonary artery uptake. In individuals with exercise PH, eicosanoid profiles were intermediate between no PH and rest PH, with six metabolites that differed between rest and exercise PH.
Our findings highlight the role of specific eicosanoids, including linoleic acid and epoxide derivatives, as potential regulators of inflammation in PH. Of note, physiological correlates, including transpulmonary metabolite gradients, may prioritise future studies focused on eicosanoid-related pathways as important contributors to PH pathogenesis.
Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 ...T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7+SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy.
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•Single-cell RNA/TCR-seq with deep intra-patient, regional resolution in NSCLC•TFH, Treg, and CD8+ T cell subsets undergo progressive exhaustion with tumor proximity•LN TCF7+ progenitor exhausted T cells are clonally linked to tumor exhausted T cells•Tumor-specific T cells in aggregate persist after ICB
Pai et al. report a single T cell lung cancer dataset allowing for the lineage tracing of T cells across tumor regions, lymph nodes, and peripheral blood. This resource reveals clonal linkage of antigen-specific TCF7+SELL+ progenitor exhausted cells in the lymph node and their exhausted counterparts in the tumor, and long-term peripheral persistence of these cells after checkpoint blockade.
In allogeneic hematopoietic stem cell transplantation, donor αβ T cells attack recipient tissues, causing graft-versus-host disease (GVHD), a major cause of morbidity and mortality. A central ...question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation. The current model for GVHD holds that disease is maintained through the continued recruitment of alloreactive effectors from blood into affected tissues. Here, we show, using multiple approaches including parabiosis of mice with GVHD, that GVHD is instead primarily maintained locally within diseased tissues. By tracking 1,203 alloreactive T cell clones, we fitted a mathematical model predicting that within each tissue a small number of progenitor T cells maintain a larger effector pool. Consistent with this, we identified a tissue-resident TCF-1+ subpopulation that preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer. These results suggest that therapies targeting affected tissues and progenitor T cells within them would be effective.
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•During early GVHD, alloreactive T cell clones enter target tissues broadly but unevenly•Late-phase GVHD is maintained within affected tissues with only minor input from blood•Tissue-resident TCF-1+ T cells maintain effector cells within most affected tissues
Alloreactive T cells cause graft-versus-host disease (GVHD), but how GVHD is maintained once established is unclear. Using T cell clone tracking, parabiosis of GVHD mice and computational modeling, Sacirbegovic et al. demonstrate that progenitor-like T cells within affected tissues maintain GVHD locally, mostly independent of blood-derived T cells.
To determine overall response (OR) and complete response (CR) rates, response duration, progression-free (PFS) and overall survival and safety with the tositumomab and iodine-131 tositumomab ((131)I ...tositumomab) therapeutic regimen in patients with indolent, follicular large-cell, or transformed B-cell lymphoma, progressive after rituximab.
From July 1998 to November 1999, 40 patients (24 rituximab nonresponders: 11 with response < 6 months, and five with response > or = 6 months) received a therapeutic dose (0.65 to 0.75 Gy per platelet count) of (131)I tositumomab based on total-body dosimetry in this prospective phase II study. The median number of prior treatments was four; 59% of patients were chemotherapy-resistant.
Confirmed OR (65%) and CR (38%) rates were not significantly associated with prior rituximab response. With a median follow-up of 3.3 years, the median PFS was 10.4 months, 24.5 months for responders, and not reached for CR patients. Among follicular grade 1 or 2 patients with tumors < or = 7 cm (n = 21), the OR and CR rates were 86% and 57%. Estimated 3-year PFS in this subgroup was 48%, compared with 11% for all others (P = .002). Transient grade 3 to 4 marrow toxicity was seen in 50% of patients. Two patients, one of whom received two subsequent chemotherapy regimens, developed secondary myelodysplasia.
(131)I tositumomab is effective in CD20-positive lymphoma progressive after rituximab, with a 65% OR rate and median PFS of 24.5 months for responders. Patients with follicular grade 1 or 2 histology and tumors < or = 7 cm achieved very high OR and CR rates, with 48% PFS at 3 years.
There is concern about the effect of the COVID-19 pandemic on psychosocial functioning among school-age children, who have faced unusual stressors during this time. Our goal was to assess mental ...health symptoms and social risks during COVID-19, compared to before the pandemic, for urban, racial and ethnic minority school-age children, and investigate the relationship between mental health and social risks.
We conducted a cohort study from September 2019 until January 2021 of children age 5-11 years old recruited from an urban safety net hospital-based pediatric primary care practice. We measured emotional and behavioral symptoms (including attention, internalizing, and externalizing symptoms) before and during the pandemic with the Pediatric Symptom Checklist (PSC-17). We measured social risks (including food and housing insecurity) before and during the pandemic with the THRIVE screener. We measured additional mid-pandemic COVID-related stressors with items on school participation, screens/media use, illness exposure, and caregiver mental health. We compared pre- and mid-pandemic PSC-17 symptom scores across 4 domains (total, attention, internalizing, and externalizing) and used path analysis to examine the relationship between mental health and social risks pre- and mid-pandemic.
Caregivers of 168 children (54% non-Hispanic Black, 29% Hispanic, and 22% non-English speaking) completed the study. Children had significantly higher levels of emotional and behavioral symptoms midpandemic- vs. pre-pandemic in all domains. Significantly more children had a positive PSC-17 total score (18% vs. 8%, p < 0.01) and internalizing (depression and anxiety) score (18% vs. 5%, p < 0.001) during the pandemic vs. before, indicating clinical concerns in these areas. Caregivers reported significantly more social risks during vs. before the pandemic (p < 0.001). Mental health symptoms significantly correlated with number of social risks before the pandemic, but not during the pandemic. Less school assignment completion, increased screen time, and caregiver depression were all significantly associated with worse mid-pandemic mental health in children.
The COVID-19 pandemic has led to a dramatic increase in depression/anxiety problems and social risks among urban, racial and ethnic minority school-age children compared to before the pandemic. More research is needed to understand if these changes will persist.
Background: Moral injury (MI) describes emotional, spiritual, and social suffering that can arise following psychological trauma. Prior research in military populations indicates the relevance of MI ...to adverse psychological outcomes, such as post-traumatic stress disorder (PTSD) and suicidal behaviours, and shows evidence for MI as a unique construct. Minimal studies of MI have been implemented in civilians, usually restricted to small samples with a specific set of traumatic experiences, despite the conceptual relevance of MI to non-military trauma reactions more broadly (e.g. feelings of betrayal towards a perpetrator of sexual abuse).
Objective: To address this problem, we assessed MI in trauma-exposed civilians to examine ways in which this construct was related to and distinct from trauma and traumatic stress-related problems, including PTSD and depression.
Method: We adapted an existing MI scale, Moral Injury Events Scale (MIES) and administered this measure to 81 men and women along with measures of trauma exposure, PTSD and depression, and also asked participants about past suicide attempts.
Results: We observed that both greater exposure and distress related to potentially morally injurious events were associated with higher trauma exposure, particularly childhood maltreatment, as well as post-traumatic and depressive psychopathology. However, even after accounting for current PTSD and depression symptoms, MI exposure (F = 6.05, p = .017) was significantly higher among participants who had previously attempted suicide.
Conclusions: These pilot data reveal the ways in which MI is associated with trauma exposure, PTSD and depression and highlight the salience of MI in civilians. Similarly, these data demonstrate the unique relevance of MI to suicide behaviours, independent of post-traumatic psychopathology, indicating that this construct may be an understudied contributor to suicide risk in civilians.
Moral injury (MI) describes emotional, spiritual, and social suffering emerging after psychological trauma.
Despite conceptual relevance to civilian trauma, it has been largely assessed in military populations.
We assessed MI in a sample of high trauma-exposed civilians, finding associations with interpersonal trauma, PTSD, and depression, as well as past suicide attempt.
Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic.
Cross-sectional survey using four ...validated instruments.
Sixty-two sites in Canada and the United States.
Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs.
None.
We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 55.6%) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 56.9%) and burnout (259 63.8%). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures.
Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.
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