Donor KIR B Genotype Improves Progression-Free Survival of Non-Hodgkin Lymphoma Patients Receiving Unrelated Donor Transplantation

Donor killer immunoglobulin-like receptor (KIR) genotypes are associated with relapse protection and survival after allotransplantation for acute myelogenous leukemia. We examined the possibility of a similar effect in a cohort of 614 non-Hodgkin lymphoma (NHL) patients receiving unrelated donor (URD) T cell-replete marrow or peripheral blood grafts. Sixty-four percent (n = 396) of donor-recipient pairs were 10/10 allele HLA matched and 26% were 9/10 allele matched. Seventy percent of donors had KIR B/x genotype; the others had KIR A/A genotype. NHL patients receiving 10/10 HLA-matched URD grafts with KIR B/x donors experienced significantly lower relapse at 5 years (26%; 95% confidence interval [CI], 21% to 32% versus 37%; 95% CI, 27% to 46%; P = .05) compared with KIR A/A donors, resulting in improved 5-year progression-free survival (PFS) (35%; 95% CI, 26% to 44% versus 22%; 95% CI, 11% to 35%; P = .007). In multivariate analysis, use of KIR B/x donors was associated with significantly reduced relapse risk (relative risk [RR], .63, P = .02) and improved PFS (RR, .71, P = .008). The relapse protection afforded by KIR B/x donors was not observed in HLA-mismatched transplantations and was not specific to any particular KIR-B gene. Selecting 10/10 HLA-matched and KIR B/x donors should benefit patients with NHL receiving URD allogeneic transplantation

Trends in Use of Medication to Treat Opioid Use Disorder During the COVID-19 Pandemic in 10 State Medicaid Programs

Federal and state agencies granted temporary regulatory waivers to prevent disruptions in access to medication for opioid use disorder (MOUD) during the COVID-19 pandemic, including expanding access to telehealth for MOUD. Little is known about changes in MOUD receipt and initiation among Medicaid enrollees during the pandemic.To examine changes in receipt of any MOUD, initiation of MOUD (in-person vs telehealth), and the proportion of days covered (PDC) with MOUD after initiation from before to after declaration of the COVID-19 public health emergency (PHE).This serial cross-sectional study included Medicaid enrollees aged 18 to 64 years in 10 states from May 2019 through December 2020. Analyses were conducted from January through March 2022.Ten months before the COVID-19 PHE (May 2019 through February 2020) vs 10 months after the PHE was declared (March through December 2020).Primary outcomes included receipt of any MOUD and outpatient initiation of MOUD via prescriptions and office- or facility-based administrations. Secondary outcomes included in-person vs telehealth MOUD initiation and PDC with MOUD after initiation.Among a total of 8 167 497 Medicaid enrollees before the PHE and 8 181 144 after the PHE, 58.6% were female in both periods and most enrollees were aged 21 to 34 years (40.1% before the PHE; 40.7% after the PHE). Monthly rates of MOUD initiation, representing 7% to 10% of all MOUD receipt, decreased immediately after the PHE primarily due to reductions in in-person initiations (from 231.3 per 100 000 enrollees in March 2020 to 171.8 per 100 000 enrollees in April 2020) that were partially offset by increases in telehealth initiations (from 5.6 per 100 000 enrollees in March 2020 to 21.1 per 100 000 enrollees in April 2020). Mean monthly PDC with MOUD in the 90 days after initiation decreased after the PHE (from 64.5% in March 2020 to 59.5% in September 2020). In adjusted analyses, there was no immediate change (odds ratio [OR], 1.01; 95% CI, 1.00-1.01) or change in the trend (OR, 1.00; 95% CI, 1.00-1.01) in the likelihood of receipt of any MOUD after the PHE compared with before the PHE. There was an immediate decrease in the likelihood of outpatient MOUD initiation (OR, 0.90; 95% CI, 0.85-0.96) and no change in the trend in the likelihood of outpatient MOUD initiation (OR, 0.99; 95% CI, 0.98-1.00) after the PHE compared with before the PHE.In this cross-sectional study of Medicaid enrollees, the likelihood of receipt of any MOUD was stable from May 2019 through December 2020 despite concerns about potential COVID-19 pandemic–related disruptions in care. However, immediately after the PHE was declared, there was a reduction in overall MOUD initiations, including a reduction in in-person MOUD initiations that was only partially offset by increased use of telehealth

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development

Allele-Independent Turnover of Human Leukocyte Antigen (HLA) Class Ia Molecules.

Major histocompatibility complex class I (MHCI) glycoproteins present cytosolic peptides to CD8+ T cells and regulate NK cell activity. Their heavy chains (HC) are expressed from up to three MHC gene loci (human leukocyte antigen [HLA]-A, -B, and -C in humans), whose extensive polymorphism maps predominantly to the antigen-binding groove, diversifying the bound peptide repertoire. Codominant expression of MHCI alleles is thus functionally critical, but how it is regulated is not fully understood. Here, we have examined the effect of polymorphism on the turnover rates of MHCI molecules in cell lines with functional MHCI peptide loading pathways and in monocyte-derived dendritic cells (MoDCs). Proteins were labeled biosynthetically with heavy water (2H2O), folded MHCI molecules immunoprecipitated, and tryptic digests analysed by mass spectrometry. MHCI-derived peptides were assigned to specific alleles and isotypes, and turnover rates quantified by 2H incorporation, after correcting for cell growth. MHCI turnover half-lives ranged from undetectable to a few hours, depending on cell type, activation state, donor, and MHCI isotype. However, in all settings, the turnover half-lives of alleles of the same isotype were similar. Thus, MHCI protein turnover rates appear to be allele-independent in normal human cells. We propose that this is an important feature enabling the normal function and codominant expression of MHCI alleles

Development and Implementation of a Transdiagnostic, Stepped-Care Approach to Treating Emotional Disorders in Children via Telehealth

Stepped-care interventions may increase the accessibility of evidence-based treatments but remain relatively underexplored in the child mental health literature. Further, while the feasibility and efficacy of stepped-care interventions have been examined for specific diagnoses or classes or disorders, transdiagnostic stepped-care interventions have not yet been developed. We discuss the development and initial implementation of a transdiagnostic approach to emotional disorders using the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Children (UP-C; Ehrenreich-May et al., 2018). A case series is presented to illustrate the delivery of UP-C stepped care (UPC-SC) via telehealth, using a collaborative decision-making process to inform step-up/step-down decisions. Lessons learned are discussed to guide refinements of UPC-SC and inform a larger trial. •Reviewed the rationale for transdiagnostic, stepped-care approaches to treatment•Discussed development of a stepped-care Unified Protocol for Children (UPC-SC)•Illustrated the implementation of UPC-SC through presentation of three case examples•Discussed preliminary results, implementation challenges, and future direction

A distinct innate lymphoid cell population regulates tumor-associated T cells.

Antitumor T cells are subject to multiple mechanisms of negative regulation. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses led us to examine the regulatory potential of ILCs in the context of cancer. We identified a unique ILC population that inhibits tumor-infiltrating lymphocytes (TILs) from high-grade serous tumors, defined their suppressive capacity in vitro, and performed a comprehensive analysis of their phenotype. Notably, the presence of this CD56+CD3- population in TIL cultures was associated with reduced T cell numbers, and further functional studies demonstrated that this population suppressed TIL expansion and altered TIL cytokine production. Transcriptome analysis and phenotypic characterization determined that regulatory CD56+CD3- cells exhibit low cytotoxic activity, produce IL-22, and have an expression profile that overlaps with those of natural killer (NK) cells and other ILCs. NKp46 was highly expressed by these cells, and addition of anti-NKp46 antibodies to TIL cultures abrogated the ability of these regulatory ILCs to suppress T cell expansion. Notably, the presence of these regulatory ILCs in TIL cultures corresponded with a striking reduction in the time to disease recurrence. These studies demonstrate that a previously uncharacterized ILC population regulates the activity and expansion of tumor-associated T cells

MICB Genomic Variant Is Associated with NKG2D-mediated Acute Lung Injury and Death.

Rationale: Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. Objectives: To investigate the association of a common missense variant, MICBG406A, with ALI. Methods: We assessed MICBG406A genotypes within two multicenter observational study cohorts at risk for ALI: primary graft dysfunction (N = 619) and acute respiratory distress syndrome (N = 1,376). Variant protein functional effects were determined in cultured and ex vivo human samples. Measurements and Main Results: Recipients of MICBG406A-homozygous allografts had an 11.1% absolute risk reduction (95% confidence interval [CI], 3.2-19.4%) for severe primary graft dysfunction after lung transplantation and reduced risk for allograft failure (hazard ratio, 0.36; 95% CI, 0.13-0.98). In participants with sepsis, we observed 39% reduced odds of moderately or severely impaired oxygenation among MICBG406A-homozygous individuals (95% CI, 0.43-0.86). BAL NK cells were less frequent and less mature in participants with MICBG406A. Expression of missense variant protein MICBD136N in cultured cells resulted in reduced surface MICB and reduced NKG2D ligation relative to wild-type MICB. Coculture of variant MICBD136N cells with NK cells resulted in less NKG2D activation and less susceptibility to NK cell killing relative to the wild-type cells. Conclusions: These data support a role for MICB signaling through the NKG2D receptor in mediating ALI, suggesting a novel therapeutic approach