Intolerance of uncertainty as a predictor of anxiety severity and trajectory during the COVID-19 pandemic.

BACKGROUND: Efforts to identify risk and resilience factors for anxiety severity and course during the COVID-19 pandemic have focused primarily on demographic rather than psychological variables. Intolerance of uncertainty (IU), a transdiagnostic risk factor for anxiety, may be a particularly relevant vulnerability factor. METHOD: N = 641 adults with pre-pandemic anxiety data reported their anxiety, IU, and other pandemic and mental health-related variables at least once and up to four times during the COVID-19 pandemic, with assessments beginning in May 2020 through March 2021. RESULTS: In preregistered analyses using latent growth models, higher IU at the first pandemic timepoint predicted more severe anxiety, but also a sharper decline in anxiety, across timepoints. This finding was robust to the addition of pre-pandemic anxiety and demographic predictors as covariates (in the full sample) as well as pre-pandemic depression severity (in participants for whom pre-pandemic depression data were available). Younger age, lower self/parent education, and self-reported history of COVID-19 illness at the first pandemic timepoint predicted more severe anxiety across timepoints with strong model fit, but did not predict anxiety trajectory. CONCLUSIONS: IU prospectively predicted more severe anxiety but a sharper decrease in anxiety over time during the pandemic, including after adjustment for covariates. IU therefore appears to have unique and specific predictive utility with respect to anxiety in the context of the COVID-19 pandemic.

Novel approaches to functional lateralization: Assessing information in activity patterns across hemispheres and more accurately identifying structural homologues.

Functional lateralization is typically measured by comparing activation levels across the right and left hemispheres of the brain. Significant additional information, however, exists within distributed multi-voxel patterns of activity - a format not detectable by traditional activation-based analysis of functional magnetic resonance imaging (fMRI) data. We introduce and test two methods -one anatomical, one functional- that allow hemispheric information asymmetries to be detected. We first introduce and apply a novel tool that draws on brain 'surface fingerprints' to pair every location in one hemisphere with its hemispheric homologue. We use anatomical data to show that this approach is more accurate than the common distance-from-midline method for comparing bilateral regions. Next, we introduce a complementary analysis method that quantifies multivariate laterality in functional data. This new 'multivariate Laterality Index' (mLI) reflects both quantitative and qualitative information-differences across homologous activity patterns. We apply the technique here to functional data collected as participants viewed faces and non-faces. Using the previously generated surface fingerprints to pair-up homologous searchlights in each hemisphere, we use the novel multivariate laterality technique to identify face-information asymmetries across right and left counterparts of the fusiform gyrus, inferior temporal gyrus, superior parietal lobule, and early visual areas. The typical location of the fusiform face area has greater information asymmetry for faces than for shapes. More generally, we argue that the field should consider an information-based approach to lateralization.

The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

A five-factor model of perseverative thought.

Like diagnostic status, clinically relevant thought remains overwhelmingly conceptualized in terms of discrete categories (e.g., worry, rumination, obsessions). However, definitions can vary widely. The area of perseverative thought (or clinically relevant thought more broadly) would benefit substantially from a consensus-based, empirically grounded taxonomy similar to the Hierarchical Taxonomy of Psychopathology (Kotov et al., 2017) or the Big Five for personality. This article addresses three major barriers to establishing such a taxonomy: (a) a lack of research explicitly comparing categorical (subtype) versus dimensional models, (b) primary reliance on between-person measures rather than modeling at the level of the thought (within person), and (c) insufficient emphasis on replication and refinement. Participants included an unselected crowdsourced sample (790 observations from 286 participants) and an independent anxious-depressed replication sample (808 observations from 277 participants). Participants made dimensional ratings for three idiographic clinically relevant thoughts on a range of features. Multilevel latent class analysis and multilevel exploratory factor analysis were applied to identify and extract natural patterns of covariation among features at the level of the thought, controlling for person-level tendencies. A consistent five-dimension solution emerged across both samples and reliably outperformed the best-fitting categorical solution in terms of fit, replicability, and explanatory power. Identified dimensions were dyscontrol, self-focus, valence, interpersonal, and uncertainty. Findings support a five-factor latent structure of perseverative thought. Theoretical, empirical, and clinical implications and future directions are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Barts Health NHS Trust COVID-19 cohort: characteristics, outcomes and risk scoring of patients in East London.

BACKGROUND: Barts Health National Health Service Trust (BHNHST) serves a diverse population of 2.5 million people in London, UK. We undertook a health services assessment of factors used to evaluate the risk of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection.METHODS: Patients with confirmed polymerase chain reaction (PCR) test results admitted between 1 March and 1 August 2020 were included, alongwith clinician-diagnosed suspected cases. Prognostic factors from the 4C Mortality score and 4C Deterioration scores were extracted from electronic health records and logistic regression was used to quantify the strength of association with 28-day mortality and clinical deterioration using national death registry linkage.RESULTS: Of 2783 patients, 1621 had a confirmed diagnosis, of whom 61% were male and 54% were from Black and Minority Ethnic groups; 26% died within 28 days of admission. Mortality was strongly associated with older age. The 4C mortality score had good stratification of risk with a calibration slope of 1.14 (95% CI 1.01-1.27). It may have under-estimated mortality risk in those with a high respiratory rate or requiring oxygen.CONCLUSION: Patients in this diverse patient cohort had similar mortality associated with prognostic factors to the 4C score derivation sample, but survival might be poorer in those with respiratory failure.

A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson's disease: a study protocol for a randomised controlled trial.

BACKGROUND: Parkinson's disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals' needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. METHODS/DESIGN: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. PRIMARY OUTCOME: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson's Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. DISCUSSION: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016.

Worry alters speed-accuracy tradeoffs but does not impair sustained attention.

Worry has been experimentally linked to a range of cognitive consequences, including impairments in working memory, inhibition, and cognitive control. However, findings are mixed, and the effects of worry on other phenomenologically-relevant constructs, such as sustained attention, have received less attention. Potential confounds such as speed-accuracy tradeoffs have also received little attention, as have psychometric and related design considerations, and potential moderators beyond trait worry. The present study investigated the effects of experimentally-induced worry versus a neutral control condition on speed-accuracy tradeoff-corrected performance on a validated measure of sustained attention (88 participants; within-subjects). Moderation by trait worry and trait mindfulness was probed in confirmatory and exploratory analyses, respectively. Worry led to faster and less accurate responding relative to the neutral comparison condition. There was no main effect of condition or trait worry on sustained attention after accounting for speed-accuracy tradeoffs. In exploratory analyses, higher trait mindfulness was robustly related to better post-worry performance, including after controlling for trait worry, general distress, and post-neutral performance, and correction for multiple comparisons. Follow-up analyses exploring dissociable mindfulness facets found a robust relationship between present-moment attention and post-worry performance. Future research should experimentally manipulate mindfulness facets to probe causality and inform treatment development.

No Effect of Commercial Cognitive Training on Brain Activity, Choice Behavior, or Cognitive Performance.

Increased preference for immediate over delayed rewards and for risky over certain rewards has been associated with unhealthy behavioral choices. Motivated by evidence that enhanced cognitive control can shift choice behavior away from immediate and risky rewards, we tested whether training executive cognitive function could influence choice behavior and brain responses. In this randomized controlled trial, 128 young adults (71 male, 57 female) participated in 10 weeks of training with either a commercial web-based cognitive training program or web-based video games that do not specifically target executive function or adapt the level of difficulty throughout training. Pretraining and post-training, participants completed cognitive assessments and functional magnetic resonance imaging during performance of the following validated decision-making tasks: delay discounting (choices between smaller rewards now vs larger rewards in the future) and risk sensitivity (choices between larger riskier rewards vs smaller certain rewards). Contrary to our hypothesis, we found no evidence that cognitive training influences neural activity during decision-making; nor did we find effects of cognitive training on measures of delay discounting or risk sensitivity. Participants in the commercial training condition improved with practice on the specific tasks they performed during training, but participants in both conditions showed similar improvement on standardized cognitive measures over time. Moreover, the degree of improvement was comparable to that observed in individuals who were reassessed without any training whatsoever. Commercial adaptive cognitive training appears to have no benefits in healthy young adults above those of standard video games for measures of brain activity, choice behavior, or cognitive performance.SIGNIFICANCE STATEMENT Engagement of neural regions and circuits important in executive cognitive function can bias behavioral choices away from immediate rewards. Activity in these regions may be enhanced through adaptive cognitive training. Commercial brain training programs claim to improve a broad range of mental processes; however, evidence for transfer beyond trained tasks is mixed. We undertook the first randomized controlled trial of the effects of commercial adaptive cognitive training (Lumosity) on neural activity and decision-making in young adults (N = 128) compared with an active control (playing on-line video games). We found no evidence for relative benefits of cognitive training with respect to changes in decision-making behavior or brain response, or for cognitive task performance beyond those specifically trained.

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.

BACKGROUND: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. METHODS: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. FINDINGS: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. INTERPRETATION: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. FUNDING: National Institutes of Health.

Differences between disease-associated endoplasmic reticulum aminopeptidase 1 (ERAP1) isoforms in cellular expression, interactions with tumour necrosis factor receptor 1 (TNF-R1) and regulation by cytokines.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) processes peptides for major histocompatibility complex (MHC) class I presentation and promotes cytokine receptor ectodomain shedding. These known functions of ERAP1 may explain its genetic association with several autoimmune inflammatory diseases. In this study, we identified four novel alternatively spliced variants of ERAP1 mRNA, designated as ΔExon-11, ΔExon-13, ΔExon-14 and ΔExon-15. We also observed a rapid and differential modulation of ERAP1 mRNA levels and spliced variants in different cell types pretreated with lipopolysaccharide (LPS). We have studied three full-length allelic forms of ERAP1 (R127-K528, P127-K528, P127-R528) and one spliced variant (ΔExon-11) and assessed their interactions with tumour necrosis factor receptor 1 (TNF-R1) in transfected cells. We observed variation in cellular expression of different ERAP1 isoforms, with R127-K528 being expressed at a much lower level. Furthermore, the cellular expression of full-length P127-K528 and ΔExon-11 spliced variant was enhanced significantly when co-transfected with TNF-R1. Isoforms P127-K528, P127-R528 and ΔExon-11 spliced variant associated with TNF-R1, and this interaction occurred in a region within the first 10 exons of ERAP1. Supernatant-derived vesicles from transfected cells contained the full-length and ectodomain form of soluble TNF-R1, as well as carrying the full-length ERAP1 isoforms. We observed marginal differences between TNF-R1 ectodomain levels when co-expressed with individual ERAP1 isoforms, and treatment of transfected cells with tumour necrosis factor (TNF), interleukin (IL)-1ß and IL-10 exerted variable effects on TNF-R1 ectodomain cleavage. Our data suggest that ERAP1 isoforms may exhibit differential biological properties and inflammatory mediators could play critical roles in modulating ERAP1 expression, leading to altered functional activities of this enzyme.

Facilitated acquisition of standard but not long delay classical eyeblink conditioning in behaviorally inhibited adolescents.

Adolescence is a key age in the development of anxiety disorders. The present study assessed the relationship between behavioral inhibition, a risk factor for anxiety typified by avoidance, and acquisition of the classically conditioned eyeblink response. 168 healthy high school students (mean age 15.7 years, 54% female) were given a battery of self-report measures including the Adult Measure of Behavioural Inhibition (AMBI). The study compared acquisition of three experimental training conditions. Two groups were given paired CS-US training: standard delay of 500-ms or long delay of 1000-ms with CS overlapping and co-terminating with a 50-ms airpuff US. A third group received unpaired training of 1000-ms CS and 50-ms airpuff US. Inhibited individuals showed greater acquisition of the conditioned eyeblink response in the 500-ms CS condition, but not in the paired 1000-ms condition. No differences in spontaneous blinks or reactivity to the stimulus were evident in the 1000-ms unpaired CS condition. Results support a relationship between associative learning and anxiety vulnerability that may be mediated by cerebellar functioning in inhibited individuals.

Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis.

AIMS/HYPOTHESIS: Multiple genetic variants are associated with type 2 diabetes-related traits in Europeans, but their role in South Asian populations needs further study. We hypothesised that genetic variants associated with diabetes-related traits in Europeans would explain a similar proportion of phenotypic variance in a Pakistani population and could be used in Mendelian randomisation analyses. METHODS: We used data from 2,131 individuals from the Control of Blood Pressure and Risk Attenuation Trial (COBRA) in Karachi, Pakistan. Individuals were aged 40 years or older. RESULTS: Combining information from multiple genetic variants showed that fasting glucose, BMI, triacylglycerol, and systolic and diastolic blood pressure variants explained 2.9%, 0.7%, 5.5%, 1.2% and 1.8% of the variance in those traits respectively. Genetic risk scores of fasting glucose, triacylglycerol, BMI, systolic blood pressure and diastolic blood pressure variants were associated with these traits, with per allele SD effects of 0.057 (95% CI 0.041, 0.074), p=3.44 × 10(-12), 0.130 (95% CI 0.105, 0.155), p=2.9 × 10(-21), 0.04 (95% CI 0.014, 0.072), p=0.004, 0.031 (95% CI 0.016, 0.047), p=7.9 × 10(-5), 0.028 (95% CI 0.015, 0.042), p = 5.5 × 10(-5), respectively. These effects are consistent with those observed in Europeans, except that the effect of triacylglycerol variants in South Asians was slightly lower. Mendelian randomisation provided evidence that genetically influenced, raised triacylglycerol levels do not causally affect type 2 diabetes risk to the extent predicted from observational data (p=0.0003 for difference between observed and instrumental variables correlations). CONCLUSIONS/INTERPRETATION: Genetic variants identified in Europeans are associated with type 2 diabetes-related traits in Pakistanis, with comparable effect sizes. Larger studies are needed to perform adequately powered Mendelian randomisation and help dissect the relationships between type 2 diabetes-related traits in diverse South Asian subgroups.

Development of a ubiquitous clinical monitoring solution to improve patient safety and outcomes.

This paper highlights the main findings of an integrated and ubiquitous remote wireless based vital signs monitoring solution as trialed in a clinical setting. Results demonstrate the feasibility of utilising a Wi-Fi based solution to monitor early-warning signs such as impedance-based respiration rate changes, heart rate/ECG events, temperature, and motion analysis in a clinical setting and act as an early warning system.

The questionable value of some science-based 'welfare' assessments in intensive animal farming: sow stalls as an illustrative example.

A recent review of the code of practice for pigs brought attention to the question of how to assess the impact of housing conditions on pig welfare. The stance adopted by the law-makers, which mirrors that of industry, is that the status quo should be maintained until there is irrefutable scientific evidence in favour of change. Sows in intensive pig farms are often confined in cages (sow stalls) that are little bigger than their body. Many people find this repellent and the question of whether keeping sows in stalls is detrimental to their welfare has become a major focus of debate. All animal welfare groups in Australia, including the RSPCA, oppose the use of sow stalls. This brief essay critically examines the rationale for refusing to sanction change unless supported by scientific evidence. We conclude that the criteria for assessing welfare should not be restricted to consideration of scientific evidence alone, but should be widened to encompass moral and ethical considerations.

Reduced risk of cytomegalovirus infection in solid organ transplant recipients treated with sirolimus: a pooled analysis of clinical trials.

INTRODUCTION: Cytomegalovirus (CMV) is an opportunistic infection that causes substantial morbidity and mortality in transplant recipients. This pooled analysis of Wyeth clinical trials explored the incidence of CMV infection in solid organ transplant recipients treated with sirolimus versus comparator immunosuppressant drugs. METHODS: Wyeth-conducted, multicenter, randomized, comparative trials with at least one non-sirolimus-containing arm and at least 6 months' complete data were included. Cases of CMV were investigator-identified. The occurrence of CMV in sirolimus-treated patients was assessed versus all other comparator agents, versus antimetabolite agents, and versus calcineurin inhibitors. RESULTS: Nine trials in recipients of renal, liver, and cardiac transplants met the inclusion criteria; eight enrolled de novo allograft recipients, and one was a conversion trial. The primary pooled analysis revealed an odd ratio for CMV infection of 0.64 (95% confidence interval [CI] 0.42 to 1.0, P = .047) on sirolimus versus comparator immunosuppressant drugs. The subanalysis of sirolimus versus antimetabolites showed an odds ratio for CMV of 0.39 (95% CI 0.19 to 0.81, P = .012), and for sirolimus versus calcineurin inhibitors the odds ratio was 0.58 (95% CI 0.34 to 1.01, P = .054). CONCLUSION: This pooled analysis demonstrated a reduced risk of CMV infection among sirolimus-treated patients as compared to those receiving alternative forms of immunosuppression in Wyeth-sponsored clinical trials in solid organ transplantation. This risk reduction persisted in subgroup analyses stratified by class of comparator treatment.

Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine.

BACKGROUND: A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome. METHODS: The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA. RESULTS: VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old. CONCLUSIONS: The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.

Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study.

BACKGROUND: Aldosterone is an important cardiovascular hormone; 15% of hypertensive subjects have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of the aldosterone synthase gene (CYP11B2) have focused on a single nucleotide polymorphism in the 5'promoter region (-344 C/T). In normotensive subjects, the T allele associates with raised levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for 11beta-hydroxylase, encoded by the adjacent and homologous gene, CYP11B1. We have speculated that this altered 11beta-hydroxylase efficiency leads to increased ACTH drive to the adrenal gland to maintain cortisol production and reported herein the association between the -344 C/T single nucleotide polymorphism (SNP) and adrenal steroid production in subjects with essential hypertension. METHODS: The CYP11B2-344 C/T polymorphism was genotyped and urinary excretion of adrenal steroid metabolites was measured (by GCMS) in 511 unrelated hypertensives from the Medical Research Council (MRC) British Genetics of Hypertension (BRIGHT) study. RESULTS: Thirty-five per cent of subjects were homozygous for the -344T allele whilst 16% were CC homozygotes. There was no difference in cortisol excretion rate between the two genotype groups but the index of adrenal 11beta-hydroxylation (ratio of tetrahydrodeoxycortisol/total cortisol) was significantly higher in the TT group (P < 0.005) than in the CC group. Excretion rates of the major urinary metabolite of aldosterone (tetrahydroaldosterone) correlated strongly with the ACTH-regulated steroids, cortisol (r = 0.437, P < 0.0001) and total androgen metabolites (r = 0.4, P < 0.0001) in TT but not CC subjects. CONCLUSIONS: Hypertensives homozygous for the -344 T allele of CYP11B2 demonstrate altered 11beta-hydroxylase efficiency (CYP11B1); this is consistent with the hypothesis of a genetically determined increase in adrenal ACTH drive in these subjects. The correlation between excretion of aldosterone and cortisol metabolites and suggests that, in TT subjects, ACTH exerts an important common regulatory influence on adrenal corticosteroid production in subjects with hypertension.