A subset of HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44.

Natural killer (NK) cells can recognize virus-infected and stressed cells1 using activating and inhibitory receptors, many of which interact with HLA class I. Although early studies also suggested a functional impact of HLA class II on NK cell activity2,3, the NK cell receptors that specifically recognize HLA class II molecules have never been identified. We investigated whether two major families of NK cell receptors, killer-cell immunoglobulin-like receptors (KIRs) and natural cytotoxicity receptors (NCRs), contained receptors that bound to HLA class II, and identified a direct interaction between the NK cell receptor NKp44 and a subset of HLA-DP molecules, including HLA-DP401, one of the most frequent class II allotypes in white populations4. Using NKp44ζ+ reporter cells and primary human NKp44+ NK cells, we demonstrated that interactions between NKp44 and HLA-DP401 trigger functional NK cell responses. This interaction between a subset of HLA-DP molecules and NKp44 implicates HLA class II as a component of the innate immune response, much like HLA class I. It also provides a potential mechanism for the described associations between HLA-DP subtypes and several disease outcomes, including hepatitis B virus infection5-7, graft-versus-host disease8 and inflammatory bowel disease9,10.

Human herpesvirus diversity is altered in HLA class I binding peptides.

Herpesviruses are ubiquitous, genetically diverse DNA viruses, with long-term presence in humans associated with infrequent but significant pathology. Human leukocyte antigen (HLA) class I presents intracellularly derived peptide fragments from infected tissue cells to CD8+ T and natural killer cells, thereby directing antiviral immunity. Allotypes of highly polymorphic HLA class I are distinguished by their peptide binding repertoires. Because this HLA class I variation is a major determinant of herpesvirus disease, we examined if sequence diversity of virus proteins reflects evasion of HLA presentation. Using population genomic data from Epstein­Barr virus (EBV), human cytomegalovirus (HCMV), and Varicella­Zoster virus, we tested whether diversity differed between the regions of herpesvirus proteins that can be recognized, or not, by HLA class I. Herpesviruses exhibit lytic and latent infection stages, with the latter better enabling immune evasion. Whereas HLA binding peptides of lytic proteins are conserved, we found that EBV and HCMV proteins expressed during latency have increased peptide sequence diversity. Similarly, latent, but not lytic, herpesvirus proteins have greater population structure in HLA binding than nonbinding peptides. Finally, we found patterns consistent with EBV adaption to the local HLA environment, with less efficient recognition of EBV isolates by high-frequency HLA class I allotypes. Here, the frequency of CD8+ T cell epitopes inversely correlated with the frequency of HLA class I recognition. Previous analyses have shown that pathogen-mediated natural selection maintains exceptional polymorphism in HLA residues that determine peptide recognition. Here, we show that HLA class I peptide recognition impacts diversity of globally widespread pathogens.

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.

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.

The impact of HLA polymorphism on herpesvirus infection and disease.

Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural selection by pathogens. Of these pathogens, human herpesviruses have a uniquely ancient relationship with our species, where coevolution likely has reciprocating impact on HLA and viral genomic diversity. Consistent with this notion, genetic variation at multiple HLA loci is strongly associated with modulating immunity to herpesvirus infection. Here, we synthesize published genetic associations of HLA with herpesvirus infection and disease, both from case/control and genome-wide association studies. We analyze genetic associations across the eight human herpesviruses and identify HLA alleles that are associated with diverse herpesvirus-related phenotypes. We find that whereas most HLA genetic associations are virus- or disease-specific, HLA-A*01 and HLA-A*02 allotypes may be more generally associated with immune susceptibility and control, respectively, across multiple herpesviruses. Connecting genetic association data with functional corroboration, we discuss mechanisms by which diverse HLA and cognate receptor allotypes direct variable immune responses during herpesvirus infection and pathogenesis. Together, this review examines the complexity of HLA-herpesvirus interactions driven by differential T cell and Natural Killer cell immune responses.

Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1.

Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data. We designed the model to represent a substantial component of human genetic diversity. Our Global imputation model is effective at genotyping KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians, with mean specificity of 99% and sensitivity of 95% for alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 with HLA-A and -B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable.

Following Transplantation for Acute Myelogenous Leukemia, Donor KIR Cen B02 Better Protects against Relapse than KIR Cen B01.

In the treatment of acute myelogenous leukemia with allogeneic hematopoietic cell transplantation, we previously demonstrated that there is a greater protection from relapse of leukemia when the hematopoietic cell transplantation donor has either the Cen B/B KIR genotype or a genotype having two or more KIR B gene segments. In those earlier analyses, KIR genotyping could only be assessed at the low resolution of gene presence or absence. To give the analysis greater depth, we developed high-resolution KIR sequence-based typing that defines all the KIR alleles and distinguishes the expressed alleles from those that are not expressed. We now describe and analyze high-resolution KIR genotypes for 890 donors of this human transplant cohort. Cen B01 and Cen B02 are the common CenB haplotypes, with Cen B02 having evolved from Cen B01 by deletion of the KIR2DL5, 2DS3/5, 2DP1, and 2DL1 genes. We observed a consistent trend for Cen B02 to provide stronger protection against relapse than Cen B01 This correlation indicates that protection depends on the donor having inhibitory KIR2DL2 and/or activating KIR2DS2, and is enhanced by the donor lacking inhibitory KIR2DL1, 2DL3, and 3DL1. High-resolution KIR typing has allowed us to compare the strength of the interactions between the recipient's HLA class I and the KIR expressed by the donor-derived NK cells and T cells, but no clinically significant interactions were observed. The trend observed between donor Cen B02 and reduced relapse of leukemia points to the value of studying ever larger transplant cohorts.

Behavioural Change Techniques in Health Coaching-Based Interventions for Type 2 Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND: Given the high rates globally of Type 2 Diabetes Mellitus (T2DM), there is a clear need to target health behaviours through person-centred interventions. Health coaching is one strategy that has been widely recognised as a tool to foster positive behaviour change. However, it has been used inconsistently and has produced mixed results. This systematic review sought to explore the use of behaviour change techniques (BCTs) in health coaching interventions and identify which BCTs are linked with increased effectiveness in relation to HbA1C reductions. METHODS: In line with the PICO framework, the review focused on people with T2DM, who received health coaching and were compared with a usual care or active control group on HbA1c levels. Studies were systematically identified through different databases including Medline, Web of science, and PsycINFO searches for relevant randomised controlled trials (RCTs) in papers published between January 1950 and April 2022. The Cochrane collaboration tool was used to evaluate the quality of the studies. Included papers were screened on the reported use of BCTs based on the BCT taxonomy. The effect sizes obtained in included interventions were assessed by using Cohen's d and meta-analysis was used to estimate sample-weighted average effect sizes (Hedges' g). RESULTS: Twenty RCTs with a total sample size of 3222 were identified. Random effects meta-analysis estimated a small-sized statistically significant effect of health coaching interventions on HbA1c reduction (g+ = 0.29, 95% CI: 0.18 to 0.40). A clinically significant HbA1c decrease of ≥5 mmol/mol was seen in eight studies. Twenty-three unique BCTs were identified in the reported interventions, with a mean of 4.5 (SD = 2.4) BCTs used in each study. Of these, Goal setting (behaviour) and Problem solving were the most frequently identified BCTs. The number of BCTs used was not related to intervention effectiveness. In addition, there was little evidence to link the use of specific BCTs to larger reductions in HbA1c across the studies included in the review; instead, the use of Credible source and Social reward in interventions were associated with smaller reductions in HbA1c. CONCLUSION: A relatively small number of BCTs have been used in RCTs of health coaching interventions for T2DM. Inadequate, imprecise descriptions of interventions and the lack of theory were the main limitations of the studies included in this review. Moreover, other possible BCTs directly related to the theoretical underpinnings of health coaching were absent. It is recommended that key BCTs are identified at an early stage of intervention development, although further research is needed to examine the most effective BCTs to use in health coaching interventions. TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228567 .

Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men.

BACKGROUND: The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. OBJECTIVE: To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men. DESIGN: Cohort study. SETTING: UK Biobank prospective cohort. PARTICIPANTS: Community-dwelling men aged 40 to 69 years. MEASUREMENTS: Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. RESULTS: Of 210 700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). LIMITATION: Observational study; single baseline measurement of testosterone and SHBG. CONCLUSION: Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. PRIMARY FUNDING SOURCE: Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

Trends in the incidence, surgical management and outcomes of type B aortic dissections in Australia over the last decade.

OBJECTIVES: This study aims to investigate the incidence and in-hospital outcomes of surgical repair for type B aortic dissection (TBAD) in Australia. METHODS: Data were obtained from the Australasian Vascular Audit (AVA) and the Australian Institute of Health and Welfare (AIHW). The former is a total practice audit mandated for all members of the Australian and New Zealand Society for Vascular Surgery (ANZSVS) while the latter is an independent government agency which records all healthcare data in Australia. All cases of TBAD which underwent surgical intervention (endovascular or open repair) between 2010 and 2019 were identified using prospectively recorded data from the AVA (New Zealand data was excluded). The primary outcomes were temporal trends in procedures and hospital mortality; secondary outcomes were complications and risk factors for mortality. All admissions and procedures for, and hospital deaths from, TBAD in Australia were identified in AIHW datasets using the relevant diagnosis and procedure codes, with age-standardized rates calculated for the period 2000-01 to 2018-19. RESULTS: A total of 567 cases of TBAD underwent vascular surgical intervention (AVA data, Australia). Of these, 96.3% were treated by endovascular repair. There was an increase in the annual procedure number from 45 in 2010 to 88 in 2019. In-hospital mortality was 4.8% for endovascular repair and 19% for open repair (p = 0.021). From 2000-01 to 201819, the age-standardized procedure rates for TBAD (Australia) doubled, the proportion of admitted patients undergoing a procedure rose from 28% to 43%, and in-hospital deaths fell by 25%. CONCLUSION: There has been an increasing incidence of vascular surgical intervention for TBAD in Australia. The majority of patients received endovascular therapy while the mortality from surgically managed TBAD appears to be falling.

Investigating ethnic inequalities in hearing aid use in England and Wales: a cross-sectional study.

OBJECTIVE: To establish whether ethnic inequalities exist in levels of self-reported hearing difficulty and hearing aid use among middle-aged adults. DESIGN: Cross-sectional data from the UK Biobank resource. STUDY SAMPLE: 164,460 participants aged 40-69 who answered hearing questions at an assessment centre in England or Wales. RESULTS: After taking into account objectively assessed hearing performance and a corresponding correction for bias in non-native English speakers, as well as a range of correlates including demographic, socioeconomic, and health factors, there were lower levels of hearing aid use for people from Black African (OR 0.36, 95% CI 0.17-0.77), Black Caribbean (OR 0.38, 95% CI 0.22-0.65) and Indian (OR 0.60, 95% CI 0.41-0.86) ethnic groups, compared to the White British or Irish group. Men from most ethnic minority groups and women from Black African, Black Caribbean and Indian groups were less likely to report hearing difficulty than their White British or Irish counterparts. CONCLUSIONS: For equivalent levels of hearing loss, the use of hearing aids is lower among ethnic minority groups. Inequalities are partly due to lower levels of self-reported hearing difficulty among minority groups. However, even when self-reported hearing difficulty is considered, hearing aid use remains lower among many ethnic minority groups.

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.

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B, and -C genes, we show that the Chinese Southern Han (CHS) are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the CHS KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the CHS represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.

Analysis of Genomic DNA from Medieval Plague Victims Suggests Long-Term Effect of Yersinia pestis on Human Immunity Genes.

Pathogens and associated outbreaks of infectious disease exert selective pressure on human populations, and any changes in allele frequencies that result may be especially evident for genes involved in immunity. In this regard, the 1346-1353 Yersinia pestis-caused Black Death pandemic, with continued plague outbreaks spanning several hundred years, is one of the most devastating recorded in human history. To investigate the potential impact of Y. pestis on human immunity genes, we extracted DNA from 36 plague victims buried in a mass grave in Ellwangen, Germany in the 16th century. We targeted 488 immune-related genes, including HLA, using a novel in-solution hybridization capture approach. In comparison with 50 modern native inhabitants of Ellwangen, we find differences in allele frequencies for variants of the innate immunity proteins Ficolin-2 and NLRP14 at sites involved in determining specificity. We also observed that HLA-DRB1*13 is more than twice as frequent in the modern population, whereas HLA-B alleles encoding an isoleucine at position 80 (I-80+), HLA C*06:02 and HLA-DPB1 alleles encoding histidine at position 9 are half as frequent in the modern population. Simulations show that natural selection has likely driven these allele frequency changes. Thus, our data suggest that allele frequencies of HLA genes involved in innate and adaptive immunity responsible for extracellular and intracellular responses to pathogenic bacteria, such as Y. pestis, could have been affected by the historical epidemics that occurred in Europe.

Proximal false lumen thrombosis is associated with low false lumen pressure and fewer complications in type B aortic dissection.

BACKGROUND: Improved risk stratification is a key priority for type B aortic dissection (TBAD). Partial false lumen thrombus morphology is an emerging predictor of complications. However, partial thrombosis is poorly defined, and its evaluation in clinical studies has been inconsistent. Thus, we aimed to characterize the hemodynamic pressure in TBAD and determine how the pressure relates to the false lumen thrombus morphology and clinical events. METHODS: The retrospective admission computed tomography angiograms of 69 patients with acute TBAD were used to construct three-dimensional computational models for simulation of cyclical blood flow and calculation of pressure. The patients were categorized by the false lumen thrombus morphology as minimal, extensive, proximal or distal thrombosis. Linear regression analysis was used to compare the luminal pressure difference between the true and false lumen for each morphology group. The effect of morphology classification on the incidence of acute complications within 14 days was studied using logistic regression adjusted for clinical parameters. A survival analysis for adverse aortic events at 1 year was also performed using Cox regression. RESULTS: Of the 69 patients, 44 had experienced acute complications and 45 had had an adverse aortic event at 1 year. The mean ± standard deviation age was 62.6 ± 12.6 years, and 75.4% were men. Compared with the patients with minimal thrombosis, those with proximal thrombosis had a reduced false lumen pressure by 10.1 mm Hg (95% confidence interval [CI], 4.3-15.9 mm Hg; P = .001). The patients who had not experienced an acute complication had had a reduced relative false lumen pressure (-6.35 mm Hg vs -0.62 mm Hg; P = .03). Proximal thrombosis was associated with fewer acute complications (odds ratio, 0.17; 95% CI, 0.04-0.60; P = .01) and 1-year adverse aortic events (hazard ratio, 0.36; 95% CI, 0.16-0.80; P = .01). CONCLUSIONS: We found that proximal false lumen thrombosis was a marker of reduced false lumen pressure. This might explain how proximal false lumen thrombosis appears to be protective of acute complications (eg, refractory hypertension or pain, aortic rupture, visceral or limb malperfusion, acute expansion) and adverse aortic events within the first year.

High-throughput Interpretation of Killer-cell Immunoglobulin-like Receptor Short-read Sequencing Data with PING.

The killer-cell immunoglobulin-like receptor (KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.

Does Temporal Stability Moderate Reasoned Action Approach Relations With Covid-19 Preventive Behaviors?

BACKGROUND: Preventive behaviors continue to play an important role in reducing the spread of the SARS-CoV-2 virus. PURPOSE: This study aimed to apply the reasoned action approach (RAA) to predict Covid-19 preventive intentions and behavior and to test whether temporal stability moderates relations between RAA constructs and behavior. METHODS: A representative sample of UK adults (N = 603) completed measures of RAA variables (i.e., experiential attitudes, instrumental attitudes, injunctive norms, descriptive norms, capacity, autonomy and intention) in relation to six Covid-19 preventive behaviors (i.e., wearing face coverings, social distancing, hand sanitizing, avoiding the three Cs [closed spaces, crowded places, and close contacts], cleaning surfaces, and coughing/sneezing etiquette) at baseline (December 2020) and after 1 month. Self-reported behavior was assessed at baseline and after 1 and 2 months. RESULTS: The RAA was predictive of Covid-19 preventive intentions at time 1 and time 2; instrumental attitudes, descriptive norms, and capability were the strongest predictors at each time point. The RAA also predicted subsequent behavior across time points with intention, descriptive norms, and capability the strongest/most consistent predictors. Temporal stability moderated a number of RAA-behavior relationships including those for intention, descriptive norms, and capability. In each case, the relationships became stronger as temporal stability increased. CONCLUSIONS: Health cognitions as outlined in the RAA provide appropriate targets for interventions to promote Covid-19 preventive intentions and behavior. Moreover, given that continued performance of Covid-19 preventive behaviors is crucial for reducing transmission of the SARS-CoV-2 virus, the results highlight the need for consistent messaging from governments and public health organizations to promote positive intentions and maintain preventive behavior.

Mechanisms of Action in a Behavioral Weight-Management Program: Latent Growth Curve Analysis.

BACKGROUND: A greater understanding of the mechanisms of action of weight-management interventions is needed to inform the design of effective interventions. PURPOSE: To investigate whether dietary restraint, habit strength, or diet self-regulation mediated the impact of a behavioral weight-management intervention on weight loss and weight loss maintenance. METHODS: Latent growth curve analysis (LGCA) was conducted on trial data in which adults (N = 1,267) with a body mass index (BMI) ≥28 kg/m2 were randomized to either a brief intervention (booklet on losing weight), a 12 week weight-management program or the same program for 52 weeks. LGCA estimated the trajectory of the variables over four time points (baseline and 3, 12 and 24 months) to assess whether potential mechanisms of action mediated the impact of the weight-management program on BMI. RESULTS: Participants randomized to the 12 and 52 week programs had a significantly greater decrease in BMI than the brief intervention. This direct effect became nonsignificant when dietary restraint, habit strength, and autonomous diet self-regulation were controlled for. The total indirect effect was significant for both the 12 (estimate = -1.33, standard error [SE] = 0.41, p = .001) and 52 week (estimate = -2.13, SE = 0.52, p < .001) program. Only the individual indirect effect for dietary restraint was significant for the 12 week intervention, whereas all three indirect effects were significant for the 52 week intervention. CONCLUSIONS: Behavior change techniques that target dietary restraint, habit strength, and autonomous diet self-regulation should be considered when designing weight loss and weight loss maintenance interventions. Longer interventions may need to target both deliberative and automatic control processes to support successful weight management.

Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease.

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (p c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/HLA-Bw4i from gait difficulties (p c = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (pc = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.

Does it matter how we measure the health of older people in places for associations with labour market outcomes? A cross-sectional study.

BACKGROUND: Inequalities between different areas in the United Kingdom (UK) according to health and employment outcomes are well-documented. Yet it is unclear which health indicator is most closely linked to labour market outcomes, and whether associations are restricted to the older population. METHODS: We used the Office for National Statistics (ONS) Longitudinal Study (LS) to analyse which measures of health-in-a-place were cross-sectionally associated with three employment outcomes in 2011: not being in paid work, working hours (part-time, full-time), and economic inactivity (unemployed, retired, sick/disabled, other). Seven health indicators from local-authority census and vital records data were chosen to represent the older working age population (self-rated health 50-74y, long-term illness 50-74y, Age-specific mortality rate 50-74y, avoidable mortality, life expectancy at birth and 65 years, disability-free life expectancy at 50 years, and healthy life expectancy at 50 years). An additional two health indicators (life expectancy at birth and infant mortality rate) were included as test indicators to determine if associations were limited to the health of older people in a place. These nine health indicators were then linked with the LS sample aged 16-74y with data on employment outcomes and pertinent demographic and individual health information. Interactions by gender and age category (16-49y vs. 50-74y) were also tested. FINDINGS: For all health-in-a-place measures, LS members aged 16-74 who resided in the tertile of local authorities with the 'unhealthiest' older population, had higher odds of not being in paid work, including all four types of economic inactivity. The strongest associations were seen for the health-in-a-place measures that were self-reported, long-term illness (Odds Ratio 1.60 [95% Confidence Intervals 1.52, 1.67]) and self-rated health (1.60 [1.52, 1.68]). Within each measure, associations were slightly stronger for men than women and for the 16-49y versus 50-74y LS sample. In models adjusted for individual self-rated health and gender and age category interactions, health-in-a-place gradients were apparent across all economic inactivity's. However, these same gradients were only apparent for women in part-time work and men in full-time work. CONCLUSION: Improving health of older populations may lead to wider economic benefits for all.