The impact of the English national health inequalities strategy on inequalities in mortality at age 65: a time-trend analysis.

BACKGROUND: During the 1997-2010 Labour government, several policies were implemented to narrow health inequalities as part of a national health inequalities strategy. Many of these policies are likely to have had a disproportionately large impact on people aged 65 and over. We aimed to understand the association between the health inequalities strategy period and inequalities in mortality at age 65-69. METHODS: We use population at risk and mortality data covering 1991-2019 to calculate mortality rate at age 65-69 at the Local Authority level. We use the 2019 Index of Multiple Deprivation to examine geographical inequalities. We employ segmented linear regression models with marginal spline terms for the strategy period and interact these with an indicator of deprivation to understand how inequalities changed before, during and after the strategy. The reporting of this study adheres to STROBE guidelines. RESULTS: Mortality rates in each deprivation quintile improved continuously throughout the period of study. Prior to the programme (1991-9) there was no significant change in absolute inequalities. However, during the strategy (2000-10) there was a significant decrease in absolute inequalities of -9.66 (-17.48 to -1.84). The period following the strategy (2011-19) was associated with a significant increase in absolute inequalities of 12.84 (6.60 to 19.08). Our results were robust to a range of sensitivity tests. CONCLUSION: The English health inequalities strategy was associated with a significant reduction in absolute inequality in mortality age 65-69. Future strategies to address inequalities in ageing populations may benefit from adopting a similar approach.

Online compassion-based self-help for depression in people with skin conditions: a feasibility study.

BACKGROUND: There is a need to develop psychological interventions for depression in people with skin conditions. This study aimed to investigate the acceptability, feasibility, and effects of an online compassion-based self-help intervention for depression in people with skin conditions. METHODS: Adult participants (n = 34) with skin conditions and mild-moderate depressive symptoms were invited to undertake a six-week, compassion-based online intervention for depression with email support. Engagement with the intervention was monitored, along with time spent facilitating the intervention, and participant feedback was collected each week and post-intervention. Pre-post changes in depression, self-compassion and dermatological quality of life were also assessed. RESULTS: The intervention was started by 25 participants and completed by 13. Feedback scores indicated that the website was evaluated positively and that the sessions had positive impacts on participants. Participants appreciated the skin-specific aspects of the intervention but varied as to which of the compassion-based exercises they found helpful. The online intervention was feasible to provide and facilitate, and treatment completers showed improvements in depression, quality of life and self-compassion. CONCLUSIONS: The online compassion-based intervention holds promise as a treatment for depression in people with skin conditions. Recommendations are made for future research and further development of the intervention. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on 21 October 2019, NCT04132973.

High-resolution KIR and HLA genotyping in three Chinese ethnic minorities reveals distinct origins.

Polymorphism of killer-cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands impacts the effector activity of cytotoxic NK cell and T cell subsets. Therefore, understanding the extent and implications of KIR and HLA class I genetic polymorphism across various populations is important for immunological and medical research. In this study, we conducted a high-resolution investigation of KIR and HLA class I diversity in three distinct Chinese ethnic minority populations. We studied the She, Yugur, and Tajik, and compared them with the Zhejiang Han population (Zhe), which represents the majority Southern Han ethnicity. Our findings revealed that the Tajik population exhibited the most diverse KIR copy number, allele, and haplotype diversity among the four populations. This diversity aligns with their proposed ancestral origin, closely resembling that of Iranian populations, with a relatively higher presence of KIR-B genes, alleles, and haplotypes compared with the other Chinese populations. The Yugur population displayed KIR distributions similar to those of the Tibetans and Southeast Asians, whereas the She population resembled the Zhe and other East Asians, as confirmed by genetic distance analysis of KIR. Additionally, we identified 12.9% of individuals across the three minority populations as having KIR haplotypes characterized by specific gene block insertions or deletions. Genetic analysis based on HLA alleles yielded consistent results, even though there were extensive variations in HLA alleles. The observed variations in KIR interactions, such as higher numbers of 2DL1-C2 interactions in Tajik and Yugur populations and of 2DL3-C1 interactions in the She population, are likely shaped by demographic and evolutionary mechanisms specific to their local environments. Overall, our findings offer valuable insights into the distribution of KIR and HLA diversity among three distinct Chinese ethnic minority populations, which can inform future clinical and population studies.

Applications of Artificial Intelligence in Emergency Departments to Improve Wait Times: Protocol for an Integrative Living Review.

BACKGROUND: Long wait times in the emergency department (ED) are a major issue for health care systems all over the world. The application of artificial intelligence (AI) is a novel strategy to reduce ED wait times when compared to the interventions included in previous research endeavors. To date, comprehensive systematic reviews that include studies involving AI applications in the context of EDs have covered a wide range of AI implementation issues. However, the lack of an iterative update strategy limits the use of these reviews. Since the subject of AI development is cutting edge and is continuously changing, reviews in this area must be frequently updated to remain relevant. OBJECTIVE: This study aims to provide a summary of the evidence that is currently available regarding how AI can affect ED wait times; discuss the applications of AI in improving wait times; and periodically assess the depth, breadth, and quality of the evidence supporting the application of AI in reducing ED wait times. METHODS: We plan to conduct a living systematic review (LSR). Our strategy involves conducting continuous monitoring of evidence, with biannual search updates and annual review updates. Upon completing the initial round of the review, we will refine the search strategy and establish clear schedules for updating the LSR. An interpretive synthesis using Whittemore and Knafl's framework will be performed to compile and summarize the findings. The review will be carried out using an integrated knowledge translation strategy, and knowledge users will be involved at all stages of the review to guarantee applicability, usability, and clarity of purpose. RESULTS: The literature search was completed by September 22, 2023, and identified 17,569 articles. The title and abstract screening were completed by December 9, 2023. In total, 70 papers were eligible. The full-text screening is in progress. CONCLUSIONS: The review will summarize AI applications that improve ED wait time. The LSR enables researchers to maintain high methodological rigor while enhancing the timeliness, applicability, and value of the review. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52612.

Donor KIR2DL1 Allelic Polymorphism Influences Posthematopoietic Progenitor Cell Transplantation Outcomes in the T Cell Depleted and Reduced Intensity Conditioning Setting.

The majority of established KIR clinical assessment algorithms used for donor selection for hematopoietic progenitor cell transplantation (HPCT) evaluate gene content (presence/absence) of the KIR gene complex. In comparison, relatively little is known about the impact of KIR allelic polymorphism. By analyzing donors of T cell depleted (TcD) reduced intensity conditioning (RIC) HPCT, this study investigated the influence on post-transplant outcome of 2 polymorphic residues of the inhibitory KIR2DL1. The aim of this study was to expand upon existing research into the influence of KIR2DL1 allelic polymorphism upon post-transplant outcome. The effects of allele groups upon transplant outcomes were investigated within a patient cohort using a defined treatment protocol of RIC with TcD. Using phylogenetic data, KIR2DL1 allelic polymorphism was categorized into groups on the basis of variation within codons 114 and 245 (positive or negative for the following groups: KIR2DL1*002/001g, KIR2DL1*003, KIR2DL1*004g) and the identification of null alleles. The influence of these KIR2DL1 allele groups in hematopoietic progenitor cell transplantation (HPCT) donors was assessed in the post-transplant data of 86 acute myelogenous leukemia patients receiving RIC TcD HPCT at a single center. KIR2DL1 allele groups in the donor significantly impacted upon 5-year post-transplant outcomes in RIC TcD HPCT. Donor KIR2DL1*003 presented the greatest influence upon post-transplant outcomes, with KIR2DL1*003 positive donors severely reducing 5-year post-transplant overall survival (OS) compared to those receiving a transplant from a KIR2DL1*003 negative donor (KIR2DL1*003 pos versus neg: 27.0% versus 60.0%, P = .008, pc = 0.024) and disease-free survival (DFS) (KIR2DL1*003 pos versus neg: 23.5% versus 60.0%, P = .004, pc = 0.012), and increasing 5-year relapse incidence (KIR2DL1*003 pos versus neg: 63.9% versus 27.2%, P = .009, pc = 0.027). KIR2DL1*003 homozygous and KIR2DL1*003 heterozygous grafts did not present significantly different post-transplant outcomes. Donors possessing the KIR2DL1*002/001 allele group were found to significantly improve post-transplant outcomes, with donors positive for the KIR2DL1*004 allele group presenting a trend towards improvement. KIR2DL1*002/001 allele group (KIR2DL1*002/001g) positive donors improved 5-year OS (KIR2DL1*002/001g pos versus neg: 56.4% versus 27.2%, P = .009, pc = 0.024) and DFS (KIR2DL1*002/001g pos versus neg: 53.8% versus 25.5%, P = .018, pc = 0.036). KIR2DL1*004 allele group (KIR2DL1*004g) positive donors trended towards improving 5-year OS (KIR2DL1*004g pos versus neg: 53.3% versus 35.5%, P = .097, pc = 0.097) and DFS (KIR2DL1*004g pos versus neg: 50.0% versus 33.9%, P = .121, pc = 0.121), and reducing relapse incidence (KIR2DL1*004g pos versus neg: 33.1% versus 54.0%, P = .079, pc = 0.152). The presented findings suggest donor selection algorithms for TcD RIC HPCT should consider avoiding KIR2DL1*003 positive donors, where possible, and contributes to the mounting evidence that KIR assessment in donor selection algorithms should reflect the conditioning regime protocol used.

Development and validation of the perceived approval of Risky Drinking Inventory in undergraduate students.

OBJECTIVE: Undergraduates frequently engage in risky drinking (i.e., drinking alcohol in ways that may result in problems). The reasoned action approach identifies injunctive norms (i.e., perceptions that others approve of risky drinking) as central in predicting engagement in risky drinking. However, research linking injunctive norms and risky drinking is equivocal, possibly because of extensive variability in the operationalization of injunctive norms across studies. This study describes the development and validation of the Perceived Approval of Risky Drinking Inventory (PARDI), designed according to best practice guidelines in questionnaire development. METHOD: Undergraduate students (N = 1,313) participated in one of the three phases of data collection, including focus group interviews for item generation (n = 31), self-report questionnaires for scale refinement (n = 407), and self-report questionnaires for scale validation (n = 875). RESULTS: Exploratory and confirmatory factor analyses supported a 20-item four-factor solution (Heavy Drinking, Drinking-Related Problems, Coping-Related Drinking, and Sexual-Risk Taking) across the three assessed referent groups (friends, parents, and typical students), all of which present satisfactory estimates of scale score and composite reliability. The results also provided preliminary support for the convergent validity of scores obtained on the PARDI, as demonstrated through correlations with other measures of perceived norms, alcohol use, alcohol-related problems, and coping-motivated drinking. Finally, the results supported the generalizability of the PARDI factor structure by demonstrating its measurement invariance across gender and drinking status (i.e., alcohol use and problems). CONCLUSIONS: The PARDI represents a reliable, valid, yet nuanced measure of injunctive norms that can be used to support further theory development and intervention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exceptional diversity of KIR and HLA class I in Egypt.

Genetically determined variation of killer cell immunoglobulin like receptors (KIR) and their HLA class I ligands affects multiple aspects of human health. Their extreme diversity is generated through complex interplay of natural selection for pathogen resistance and reproductive health, combined with demographic structure and dispersal. Despite significant importance to multiple health conditions of differential effect across populations, the nature and extent of immunogenetic diversity is under-studied for many geographic regions. Here, we describe the first high-resolution analysis of KIR and HLA class I combinatorial diversity in Northern Africa. Analysis of 125 healthy unrelated individuals from Cairo in Egypt yielded 186 KIR alleles arranged in 146 distinct centromeric and 79 distinct telomeric haplotypes. The most frequent haplotypes observed were KIR-A, encoding two inhibitory receptors specific for HLA-C, two that are specific for HLA-A and -B, and no activating receptors. Together with 141 alleles of HLA class I, 75 of which encode a KIR ligand, we identified a mean of six distinct interacting pairs of inhibitory KIR and HLA allotypes per individual. We additionally characterize 16 KIR alleles newly identified in the study population. Our findings place Egyptians as one of the most highly diverse populations worldwide, with important implications for transplant matching and studies of immune-mediated diseases.

HLA-DPB1*13:01 associates with enhanced, and KIR2DS4*001 with diminished protection from developing severe COVID-19.

Extreme polymorphism of HLA and killer-cell immunoglobulin-like receptors (KIR) differentiates immune responses across individuals. Additional to T cell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that possession of the activating KIR2DS4*001 allotype is associated with severe disease, requiring hospitalization (OR = 1.48, 95% CI 1.20-1.85, pc = 0.017), and this effect is greater in individuals homozygous for KIR2DS4*001 (OR = 3.74, 95% CI 1.75-9.29, pc = 0.003). We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from severe disease (OR = 0.49, 95% CI 0.33-0.74, pc = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-α associated with COVID-19 severity were detected in 26% of 156 hospitalized patients tested. HLA-C*08:02 was more frequent in patients with IFN-α autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN-α antibodies. These findings suggest that KIR and HLA polymorphism is integral in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.

Does Intention Strength Moderate the Intention-Health Behavior Relationship for Covid-19 Protection Behaviors?

BACKGROUND AND PURPOSE: The present research tests whether intention strength moderates intention-health behavior relations and the extent to which this is accounted for by the moderating effects of intention stability, goal priority, and goal conflict. METHODS: In a prospective multi-behavior study, a representative sample of UK adults (N = 503) completed measures of past behavior, intention, intention strength, goal priority, and goal conflict in relation to eight Covid-19 protection behaviors at time 1. Intention and self-reported behavior were assessed at time 2 (2 months later). Intention stability was assessed over 2 months. RESULTS: Intention strength was a significant moderator of the intention-behavior relationship (controlling for past behavior). Controlling for the moderating effects of intention stability attenuated the moderating effect of intention strength, while also controlling for the moderating effects of goal priority and goal conflict reduced the moderating effects of intention strength to nonsignificance. CONCLUSIONS: The present findings indicate that intention strength is a significant moderator of the intention-health behavior relationship. They also suggest that the moderating effect of intention strength is explained by effects on intention stability, goal priority, and goal conflict. Tests of interventions to manipulate intention strength as a means to strengthen intention stability and intention-behavior relations are warranted.

Predictors of engaging in eight Covid-19 protection behaviors (e.g., wearing face coverings, social distancing) were examined in a representative sample of adults in the UK in November 2021. Intentions to engage in these behaviors (e.g., "I will try to wear a face covering in public places in the next two months") were a strong predictor of self-reported engagement 2 months later, even when taking account of people's past behavior. Importantly, people's intentions were more predictive of behavior when intentions were judged to be strong (e.g., important, based on a lot of thought). Further analyses revealed that the enhanced effect of strong intentions on behavior was due to strong intentions being more stable over time, and being given greater priority over, and not conflicting with, other goals. Increasing the strength of people's intentions may be a useful and novel way to increase performance of health-protection behaviors.

High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis.

Background: The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods. Methods: We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls. Results: We identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk. Results: The results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

Unraveling the Phenotypic States of Human innate-like T Cells: Comparative Insights with Conventional T Cells and Mouse Models.

The "innate-like" T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity, having the ability to mount rapid responses following activation. In mice, this ability is acquired during thymic development. We explored the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single cell RNA sequencing and flow cytometry. We reveal that in human blood, the majority of Tinn cells, including iNKT, MAIT, and Vδ2+Vγ9+ T cells, share an effector program characterized by the expression of unique chemokine and cytokine receptors, and cytotoxic molecules. This program is driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type I/type III effector potential. To conduct a comprehensive cross-species analysis, we constructed a murine Tinn developmental atlas and uncovered additional species-specific distinctions, including the absence of type II Tinn cells in humans, which implies distinct immune regulatory mechanisms across species. The study provides insights into the development and functionality of Tinn cells, emphasizing their role in immune responses and their potential as targets for therapeutic interventions.

The effectiveness of mindfulness-based cognitive therapy for social anxiety symptoms in people living with alopecia areata: a single-group case-series design.

BACKGROUND: Alopecia areata (AA) is an immunological disorder characterised by hair loss. Individuals with AA report high levels of social anxiety. One intervention that holds potential for reducing social anxiety in individuals with AA is mindfulness-based cognitive therapy (MBCT). AIMS: Our key aim was to investigate whether MBCT reduces social anxiety in individuals with AA. The study also investigated whether MBCT reduces depression, general anxiety, and increases quality of life and increases trait mindfulness in individuals with AA. METHOD: Five participants with AA took part in an 8-session in-person MBCT intervention. A multiple-baseline single-group case series design was adopted. Idiographic measures of social anxiety were measured each day from baseline, through intervention, to follow-up. Standardised questionnaires of trait mindfulness, social anxiety, depression, anxiety, and quality of life were completed at baseline, post-intervention, and at 4-week follow-up. RESULTS: All participants completed the MBCT course, but one participant was excluded from the idiographic analysis due to a high amount of missing data. The remaining four participants demonstrated reductions in idiographic measures of social anxiety from baseline to follow-up. These effects were larger between baseline and follow-up, than between baseline and post-intervention. Two participants demonstrated significant improvement in standardised measures of wellbeing from baseline to follow-up - they also practised mindfulness most regularly at home between sessions. CONCLUSION: MBCT may be effective in reducing social anxiety and improving wellbeing in individuals with AA, although this might be dependent on the extent to which participants regularly practise mindfulness exercises.

Contrasting socio-economic influences on colorectal cancer incidence and survival in England and Wales.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world and second most common cause of cancer death. The relationship between socio-economic deprivation and CRC incidence is unclear and previous findings have been inconsistent. There is stronger evidence of an association between area-level deprivation and CRC survival; however, few studies have investigated the association between individual-level socio-economic status (SES) and CRC survival. Data from the Office for National Statistics Longitudinal Study (LS) in England and Wales was used. LS members aged 50+ were stratified by individual-level educational attainment, social class, housing tenure and area deprivation quintile, measured at the 2001 Census. Time-to-event analysis examined associations between indicators of SES and CRC incidence and survival (all-cause and CRC death), over a 15-year follow-up period. Among 178116 LS members, incidence of CRC was lower among those with a degree, compared to those with no degree and higher among those employed in manual occupations compared to non-manual occupations. No clear relationship was observed between CRC incidence and the area-based measure of deprivation. Disparities were greater for survival. Among 5016 patients diagnosed with CRC aged 50+, probability of death from all-causes was lower among those with a degree, compared to no degree and higher among those employed in manual occupations, compared to non-manual occupations and among those living in social-rented housing, compared to owner-occupiers. Individual indicators of SES were also associated with probability of death from CRC. Those living in the most deprived areas had a higher probability of death (from all-causes and CRC) compared to those in the least deprived areas. Both individual and area-based indicators of SES were associated with CRC survival, and the relationships were stronger than those observed for CRC incidence. These findings could help inform more effective targeting of public health interventions for CRC.

Cohort profile: Evaluation of the Methods and Management of Acute Coronary Events (EMMACE) Longitudinal Cohort.

AIMS: The Evaluation of the Methods and Management of Acute Coronary Events (EMMACE) longitudinal cohort study aims to investigate health trajectories of individuals following hospitalization for myocardial infarction (MI). METHODS AND RESULTS: EMMACE is a linked multicentre prospective cohort study of 14 899 patients with MI admitted to 77 hospitals in England who participated in the EMMACE-3 and -4 studies between 1st November 2011 and 24th June 2015. Long-term follow-up of the EMMACE cohorts was conducted through the EMMACE-XL (27th September 2020 to 31st March 2022) and EMMACE-XXL (1st July 2021 to 1st July 2023) studies. EMMACE collected individual participant data for health-related quality of life (HRQoL) measured by three-level EuroQol five-dimension and visual analogy scale at admission, 1 month, 6 months, 12 months, and 10 years follow-up, as well as medications, medication adherence, beliefs about medicines, Satisfaction with Information about Medicines Scale, and illness perceptions. Participant data were deterministically linked to the Myocardial Infarction National Audit Project (MINAP) for information on baseline treatments and comorbidities, Hospital Episode Statistics Admitted Patient Care (for cause-specific hospitalization data), and the Office for National Statistics (for mortality data) up to 2020. CONCLUSION: EMMACE is a nationwide prospective cohort that will provide unique insights into fatal and non-fatal outcomes, medication adherence, and HRQoL following MI.Trial registration: ClinicalTrials.gov NCT01808027 and NCT01819103.

Antithrombotic therapy after heart valve intervention: review of mechanisms, evidence and current guidance.

As the population ages and treatment options for heart valve disease increase, the number of patients with intracardiac valve prostheses is growing rapidly. Although all devices have the potential to cause thrombus formation, the propensity depends on the type of prosthesis as well as risk of the individual patient. Mechanical valve prostheses carry the highest (and persistent) risk of thromboembolism, and these patients require anticoagulation with vitamin K antagonists (warfarin). Required international normalised ratio levels are dependent on the location of the valve (mitral>aortic), type of valve (ball and cage vs bilealfet vs On-X bilealfet) and rhythm. The risk of tissue (biological) prosthesis is highest soon after surgery and is dependent on individual patient risk including age, valve location (mitral>aortic), history of thromboembolic events and rhythm. In patients with no other indication for anticoagulation, there is uncertainty on the benefits of anticoagulation versus antiplatelet therapy in patients with tissue prostheses or repaired native valves. Patients with an a priori indication for anticoagulation with a direct oral anticoagulant can continue taking this class of drug. Patients with transcatheter aortic valve implantation devices and no additional evidence-based indication for dual antiplatelet therapy or anticoagulation can be maintained on aspirin monotherapy. Patients undergoing transcatheter instrumentation in the mitral valve position should be anticoagulated, although there is currently no published evidence for antithrombotic management in this group of patients. Patients with thrombosed devices (commonly mitral mechanical) should preferably be treated surgically. Patients at high risk of thromboembolism (with mechanical prostheses) should undergo bridging therapy when undergoing surgery.

Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires.

The functionality of natural killer (NK) cells is tuned during education and is associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation in killer cell immunoglobulin-like receptor (KIR) and HLA, which is known to influence the functional strength of NK cells, fine-tunes the payload of effector molecules stored in secretory lysosomes. To address this possibility, we performed a high-resolution analysis of KIR and HLA class I genes in 365 blood donors and linked genotypes to granzyme B loading and functional phenotypes. We found that granzyme B levels varied across individuals but were stable over time in each individual and genetically determined by allelic variation in HLA class I genes. A broad mapping of surface receptors and lysosomal effector molecules revealed that DNAM-1 and granzyme B levels served as robust metric of the functional state in NK cells. Variation in granzyme B levels at rest was tightly linked to the lytic hit and downstream killing of major histocompatibility complex-deficient target cells. Together, these data provide insights into how variation in genetically hardwired receptor pairs tunes the releasable granzyme B pool in NK cells, resulting in predictable hierarchies in global NK cell function.

Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells.

Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8+ T cells rather than NK cells. These KIR3DL3-expressing cells are rare in the blood and thymus but more common in the lungs and digestive tract. High-resolution flow cytometry and single-cell transcriptomics showed that peripheral blood KIR3DL3+ T cells have an activated transitional memory phenotype and are hypofunctional. The T cell receptor (TCR) usage is biased toward genes from early rearranged TCR-α variable segments or Vδ1 chains. In addition, we show that TCR-mediated stimulation can be inhibited through KIR3DL3 ligation. Whereas we detected no impact of KIR3DL3 polymorphism on ligand binding, variants in the proximal promoter and at residue 86 can reduce expression. Together, we demonstrate that KIR3DL3 is up-regulated alongside unconventional T cell stimulation and that individuals may vary in their ability to express KIR3DL3. These results have implications for the personalized targeting of KIR3DL3/HHLA2 checkpoint inhibition.

Delivery of noninvasive ventilation to people living with motor neuron disease in the UK.

Objective: Noninvasive ventilation (NIV) improves survival and quality of life in motor neuron disease (MND), but many patients fail to receive effective ventilation. This study aimed to map the respiratory clinical care for MND patients at a service and individual healthcare professional (HCP) level to understand where attention may be needed to ensure all patients receive optimal care. Methods: Two online surveys of HCPs working with MND patients in the UK were conducted. Survey 1 targeted HCPs providing specialist MND care. Survey 2 targeted HCPs working in respiratory/ventilation services and community teams. Data were analysed using descriptive and inferential statistics. Results: Responses from 55 HCPs providing specialist MND care who worked at 21 MND care centres and networks and 13 Scotland Health Boards were analysed from Survey 1. Responses from 85 HCPs from respiratory/ventilation services and 73 HCPs from community teams, representing 97 services, were analysed from Survey 2. Significant differences in practice were identified at each stage of the respiratory care pathway as well as evidence of the need for improvement. This included when patients were referred to respiratory services, the time taken waiting to commence NIV, the availability of sufficient NIV equipment and provision of services, particularly out of hours. Conclusion: We have highlighted significant disparity in MND respiratory care practices. Increased awareness of the factors that influence NIV success and the performance of individuals and services is important for optimal practice.