Association of serum vitamin D with diagnosis and growth of abdominal aortic aneurysm.

Objective: We examined the associations between 25-hydroxy vitamin D (25(OH)D3) concentration and the diagnosis and growth of abdominal aortic aneurysm (AAA). Methods: AAA cases and healthy controls were recruited from vascular centers or the community. A subset of participants with AAA were monitored by repeat ultrasound examination to assess AAA growth. Serum 25(OH)D3 concentration was measured using a validated mass spectrometry method and categorized into guideline-recommended cut-points after deseasonalization. The associations between deseasonalized 25(OH)D3 concentration and AAA diagnosis and growth were examined using logistic regression and linear mixed effects modeling. Results: A total of 4673 participants consisting of 873 (455 controls and 418 cases) from Queensland and 3800 (3588 controls and 212 cases) from Western Australia were recruited. For every 1 standard deviation increase in 25(OH)D3 concentration, odds of AAA diagnosis was significantly reduced in both Queensland (adjusted odds ratio: 0.81; 95% confidence interval [CI]: 0.69-0.95; P = .009) and Western Australia (adjusted odds ratio: 0.80; 95% CI: 0.68-0.94; P = .005) cohorts. A subset of 310 eligible participants with small AAA from both regions were followed for a median of 4.2 (interquartile range: 2.0-5.8) years. Compared with vitamin D sufficient participants (50 to ˂75 nmol/L), annual mean AAA growth was significantly greater in those with higher vitamin D (≥75 nmol/L) (adjusted mean difference: 0.1 mm/y, 95% CI: 0.1-0.2; P < .001). Conclusions: High 25(OH)D3 concentration was paradoxically associated with a lower likelihood of AAA diagnosis and faster AAA growth. Further research is needed to resolve these conflicting findings.

The acceptability of early psychological interventions for adults with appearance concerns after burns.

INTRODUCTION: Appearance concerns are common following burns. However, there is a lack of research investigating early psychological interventions for appearance concerns. This qualitative study explored the acceptability of early psychological interventions for appearance concerns after burns. METHODS: Fifteen adults (nine female; 18-56 years) with appearance concerns were interviewed within three months post-burn to explore their views about the acceptability of early psychological interventions for these concerns. Interviews were audio-recorded and transcribed. Template analysis informed data collection and analysis. RESULTS: Three themes represented participants' views about the acceptability of early psychological interventions for appearance concerns: (1) early psychological interventions are absent; (2) early psychological interventions are acceptable within a therapeutic relationship (to manage upsetting emotions and thoughts about appearance, with therapists who are experienced in supporting burns patients); and (3) ambivalence and obstacles exist (e.g., difficulties accepting help, minimising injuries or concerns, and time restrictions following hospital discharge). CONCLUSION: Early psychological interventions for appearance concerns following burns are likely to be acceptable for some patients. However, ambivalence and potential barriers remain to be addressed. Embedding early psychological interventions for appearance concerns into routine burn care could increase acceptability through normalisation.

A qualitative study of the barriers and facilitators impacting the implementation of a quality improvement program for emergency departments: SurgeCon.

BACKGROUND: The implementation of intervention programs in Emergency Departments (EDs) is often fraught with complications due to the inherent complexity of the environment. Hence, the exploration and identification of barriers and facilitators prior to an implementation is imperative to formulate context-specific strategies to ensure the tenability of the intervention. OBJECTIVES: In assessing the context of four EDs prior to the implementation of SurgeCon, a quality improvement program for ED efficiency and patient satisfaction, this study identifies and explores the barriers and facilitators to successful implementation from the perspective of the healthcare providers, patients, researchers, and decision-makers involved in the implementation. SETTINGS: Two rural and two urban Canadian EDs with 24/7 on-site physician support. METHODS: Data were collected prior to the implementation of SurgeCon, by means of qualitative and quantitative methods consisting of semi-structured interviews with 31 clinicians (e.g., physicians, nurses, and managers), telephone surveys with 341 patients, and structured observations from four EDs. The interpretive description approach was utilized to analyze the data gathered from interviews, open-ended questions of the survey, and structured observations. RESULTS: A set of five facilitator-barrier pairs were extracted. These key facilitator-barrier pairs were: (1) management and leadership, (2) available resources, (3) communications and networks across the organization, (4) previous intervention experiences, and (5) need for change. CONCLUSION: Improving our understanding of the barriers and facilitators that may impact the implementation of a healthcare quality improvement intervention is of paramount importance. This study underscores the significance of identifing the barriers and facilitators of implementating an ED quality improvement program and developing strategies to overcome the barriers and enhance the facilitators for a successful implementations. We propose a set of strategies for hospitals when implementing such interventions, these include: staff training, champion selection, communicating the value of the intervention, promoting active engagement of ED staff, assigning data recording responsibilities, and requiring capacity analysis. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04789902. 10/03/2021.

NK and T cell repertoire is established early after allogeneic HSCT and is profoundly imprinted by CMV reactivation.

Besides genetic influences, non-genetic factors such as graft-versus-host disease (GvHD) and viral infections have been shown as important shapers of the immune reconstitution and diversification processes after hematopoietic stem cell transplantation (HSCT). However, the differential susceptibility to immune modulation by non-genetic factors is not fully understood. We determined to follow the reconstitution of the T cell receptor (TCR) repertoire through immune-sequencing, of natural killer (NK) cells using a 35-marker spectral flow cytometry panel, and in relation to clinical events. Longitudinal investigation was performed on samples derived from 54 HSCT recipients during the first-year post-HSCT. We confirmed a significant contraction in TCR repertoire diversity with a remarkable stability over time. CMV reactivation had the ability to significantly change TCR repertoire clonality and composition, with a long-lasting imprint. Our data further revealed skewing of NK cell reconstitution in CMV reactivated recipients, with an increased frequency of KIR2DL2L3S2+ adaptive, cytolytic and functional CD107a+ NK cells concomitant with a reduced pool of NKG2A+ NK cells. We provided support that CMV might act as one of the more important driver of peripheral homeostatic proliferation of circulating specific T and NK cells, which can be viewed as a compensatory mechanism to establish a new peripheral repertoire.

HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis.

Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

MHConstructor: A high-throughput, haplotype-informed solution to the MHC assembly challenge.

The extremely high levels of genetic polymorphism within the human major histocompatibility complex (MHC) limit the usefulness of reference-based alignment methods for sequence assembly. We incorporate a short read de novo assembly algorithm into a workflow for novel application to the MHC. MHConstructor is a containerized pipeline designed for high-throughput, haplotype-informed, reproducible assembly of both whole genome sequencing and target-capture short read data in large, population cohorts. To-date, no other self-contained tool exists for the generation of de novo MHC assemblies from short read data. MHConstructor facilitates wide-spread access to high quality, alignment-free MHC sequence analysis.

Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers.

PURPOSE: Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients. PATIENTS AND METHODS: We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days. RESULTS: In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0-17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1. CONCLUSIONS: Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib.

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.

Modelled impact of virtual fractional flow reserve in patients undergoing coronary angiography (VIRTU-4).

BACKGROUND: The practical application of 'virtual' (computed) fractional flow reserve (vFFR) based on invasive coronary angiogram (ICA) images is unknown. The objective of this cohort study was to investigate the potential of vFFR to guide the management of unselected patients undergoing ICA. The hypothesis was that it changes management in >10% of cases. METHODS: vFFR was computed using the Sheffield VIRTUheart system, at five hospitals in the North of England, on 'all-comers' undergoing ICA for non-ST-elevation myocardial infarction acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The cardiologists' management plan (optimal medical therapy, percutaneous coronary intervention (PCI), coronary artery bypass surgery or 'more information required') and confidence level were recorded after ICA, and again after vFFR disclosure. RESULTS: 517 patients were screened; 320 were recruited: 208 with ACS and 112 with CCS. The median vFFR was 0.82 (0.70-0.91). vFFR disclosure did not change the mean number of significantly stenosed vessels per patient (1.16 (±0.96) visually and 1.18 (±0.92) with vFFR (p=0.79)). A change in intended management following vFFR disclosure occurred in 22% of all patients; in the ACS cohort, there was a 62% increase in the number planned for medical management, and in the CCS cohort, there was a 31% increase in the number planned for PCI. In all patients, vFFR disclosure increased physician confidence from 8 of 10 (7.33-9) to 9 of 10 (8-10) (p<0.001). CONCLUSION: The addition of vFFR to ICA changed intended management strategy in 22% of patients, provided a detailed and specific 'all-in-one' anatomical and physiological assessment of coronary artery disease, and was accompanied by augmentation of the operator's confidence in the treatment strategy.

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.

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.

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.

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).

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.

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.

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.

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.

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.