The Impact of HIV and Antiretroviral Therapy on the Cardiovascular System of HIV-infected Children

Background Cardiovascular disease is increased in HIV-infected adults but the underlying aetiology is incompletely understood. Pre-clinical changes in cardiovascular structure and arterial stiffness in HIV-infected children are described in mainly middle to high-income countries with minimal longitudinal data available. Limited cross-sectional data is available from Africa in settings where 90% of HIV-infected children live. Methods ART-naïve and ART-experienced (on d4T+3TC+NNRTI for >2years, virologically suppressed at enrolment) HIV-infected children underwent serial assessment within the CHAPAS-3 trial (evaluating d4T vs ZDV vs ABC-based first line ART in Zambia/Uganda): extensive cardiovascular assessment of structure (carotid intimal medial thickness [cIMT] and arterial stiffness (pulse wave velocity [PWV]). Additionally markers of inflammation, disordered thrombogenesis, vascular damage and immune activation were measured. Age-matched HIV-uninfected controls had a single assessment. Baseline differences between ART-naïve/experienced children vs controls, and longitudinal changes in HIV-infected children were assessed. Results In 208 ART-naïve children with median age 2.9y (IQR 1.7–4.4), median CD4% 18% (11-23) and 209 HIV-uninfected controls median age 3.0y (2.1–4.1), mean(sd) cIMT was 0.46(0.04) v 0.44(0.04) mm respectively (p<0.001); PWV was 5.85(0.8) vs 5.67(0.74)m/sec respectively (p=0.05). Among 74 ART-experienced children on ART for a mean of 3.7y with a median age of 6.9y (5.9–8.50), median CD4% 33% (27-39) and 75 uninfected controls with median age 6.7y (5.6-8.6), the mean(sd) cIMT was 0.46(0.05) vs 0.45(0.04)mm respectively (p=0.09); PWV was 5.63(0.61) vs 5.69(0.68)m/s respectively (p=0.57). In ART naïve children IMT and PWV significantly decreased from baseline (ART initiation) to week 96 mean(sd) cIMT -0.02(0.04)mm (p<0.001), PWV -0.37(0.82)m/s (p<0.001). In contrast whereas cIMT had significantly reduced by mean -0.2(0.06)mm (p=0.01) at week 96 in the ART experienced group PWV increased by 0.34(0.62)m/s (p<0.001). There was no evidence that the changes in IMT or PWV over 96 weeks differed by randomisation ART in either ART naïve or ART experienced children (p≥0.27). Significant differences in a panel of 19 biomarkers and immunophenotyping (markers of activation and proliferation) were demonstrated between HIV infected ART naïve children and healthy age matched HIV uninfected children. No significant relationship between any of the biomarkers, immunophenotyping markers and IMT or PWV was demonstrated. Conclusion In this large study of arterial structural and stiffness in HIV-infected children in Africa, ART-naïve HIV-infected children had significantly poorer IMT and PWV than age-matched controls, with significant improvement seen after 96 weeks of ART. After a mean 3.7 years on ART, HIV-infected children had cIMT and PWV comparable to uninfected age-matched controls. IMT continued to improve after a further 96 weeks on ART. These findings illustrate that ART can reverse some of the structural/stiffness changes caused by HIV, strengthening the argument for early diagnosis and treatment of HIV-infected infants

Investigating the effect of relative time delay on companion screen experiences

Mobile devices are increasingly used while watching television, leading to the development of companion apps that complement the content of programmes. A concern for these applications is the extent to which companion app and television content need to be temporally aligned for live synchronisation. In this study, 18 participants watched a nature programme while being shown companion content on a tablet. Temporal synchronisation of content between the devices was varied. Participants completed questionnaires measuring immersion and affect and were tested on their recall for companion app content. While there were no statistically significant effects on these measures, qualitative interviews with participants after viewing consistently revealed that longer 10s delays in content synchronisation were frustrating. This suggests that poor content synchronisation can produce a negative companion experience for viewers and should be avoided

Perspective: Vitamin D deficiency and COVID‐19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis

Background SARS‐CoV‐2 coronavirus infection ranges from asymptomatic through to fatal COVID‐19 characterized by a ‘cytokine storm’ and lung failure. Vitamin D deficiency has been postulated as a determinant of severity. Objectives To review the evidence relevant to vitamin D and COVID‐19. Methods Narrative review. Results Regression modelling shows that more northerly countries in the Northern Hemisphere are currently (May 2020) showing relatively high COVID‐19 mortality, with an estimated 4.4% increase in mortality for each 1 degree latitude north of 28 degrees North (P = 0.031) after adjustment for age of population. This supports a role for ultraviolet B acting via vitamin D synthesis. Factors associated with worse COVID‐19 prognosis include old age, ethnicity, male sex, obesity, diabetes and hypertension and these also associate with deficiency of vitamin D or its response. Vitamin D deficiency is also linked to severity of childhood respiratory illness. Experimentally, vitamin D increases the ratio of angiotensin‐converting enzyme 2 (ACE2) to ACE, thus increasing angiotensin II hydrolysis and reducing subsequent inflammatory cytokine response to pathogens and lung injury. Conclusions Substantial evidence supports a link between vitamin D deficiency and COVID‐19 severity but it is all indirect. Community‐based placebo‐controlled trials of vitamin D supplementation may be difficult. Further evidence could come from study of COVID‐19 outcomes in large cohorts with information on prescribing data for vitamin D supplementation or assay of serum unbound 25(OH) vitamin D levels. Meanwhile, vitamin D supplementation should be strongly advised for people likely to be deficient

Genetic testing in dementia — utility and clinical strategies

Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information

The Enteropathogenic E. coli (EPEC) Tir Effector Inhibits NF-κB Activity by Targeting TNFα Receptor-Associated Factors

Enteropathogenic Escherichia coli (EPEC) disease depends on the transfer of effector proteins into epithelia lining the human small intestine. EPEC E2348/69 has at least 20 effector genes of which six are located with the effector-delivery system genes on the Locus of Enterocyte Effacement (LEE) Pathogenicity Island. Our previous work implied that non-LEE-encoded (Nle) effectors possess functions that inhibit epithelial anti-microbial and inflammation-inducing responses by blocking NF-κB transcription factor activity. Indeed, screens by us and others have identified novel inhibitory mechanisms for NleC and NleH, with key co-operative functions for NleB1 and NleE1. Here, we demonstrate that the LEE-encoded Translocated-intimin receptor (Tir) effector has a potent and specific ability to inhibit NF-κB activation. Indeed, biochemical, imaging and immunoprecipitation studies reveal a novel inhibitory mechanism whereby Tir interaction with cytoplasm-located TNFα receptor-associated factor (TRAF) adaptor proteins induces their proteasomal-independent degradation. Infection studies support this Tir-TRAF relationship but reveal that Tir, like NleC and NleH, has a non-essential contribution in EPEC's NF-κB inhibitory capacity linked to Tir's activity being suppressed by undefined EPEC factors. Infections in a disease-relevant intestinal model confirm key NF-κB inhibitory roles for the NleB1/NleE1 effectors, with other studies providing insights on host targets. The work not only reveals a second Intimin-independent property for Tir and a novel EPEC effector-mediated NF-κB inhibitory mechanism but also lends itself to speculations on the evolution of EPEC's capacity to inhibit NF-κB function

Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series

Background - The causes of phenotypic heterogeneity in familial Alzheimer’s disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer’s disease (ADAD). Methods - We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. Findings - Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1’s first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1 mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs. Interpretation - ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. Funding - Medical Research Council and National Institute for Health Research

A cross-national study on the antecedents of work–life balance from the fit and balance perspective

Drawing on the perceived work–family fit and balance perspective, this study investigates demands and resources as antecedents of work–life balance (WLB) across four countries (New Zealand, France, Italy and Spain), so as to provide empirical cross-national evidence. Using structural equation modelling analysis on a sample of 870 full time employees, we found that work demands, hours worked and family demands were negatively related to WLB, while job autonomy and supervisor support were positively related to WLB. We also found evidence that resources (job autonomy and supervisor support) moderated the relationships between demands and work–life balance, with high resources consistently buffering any detrimental influence of demands on WLB. Furthermore, our study identified additional predictors of WLB that were unique to some national contexts. For example, in France and Italy, overtime hours worked were negatively associated with WLB, while parental status was positively associated with WLB. Overall, the implications for theory and practice are discussed.Peer ReviewedPostprint (author's final draft

Intrapreneurial self-capital training: a case study of an Italian university student

This chapter presents a case study which describes the application of the Intrapreneurial Self-Capital Training with a final-year postgraduate female biology student, Erica. The chapter presents an overview of theory that is relevant to the world of work and the conceptual dimensions of intrapreneurial self capital (ISC). Training for ISC aims to assist young people to identify their personal strengths in terms of intrapreneurship and career adaptability. A qualitative instrument, the Life Adaptability Qualitative Assessment (LAQuA) was administered before and after the training to detect meaningful changes in the participant’s narratives about career adaptability and enhanced reflexivity. The LAQuA coding system revealed enhancements to the participant’s awareness about her personal intrapreneurial resources and career adaptability. The relevance of ISC to employability and career services in education contexts is discussed along with recommendations for research into ISC training

The assertive cardiac care trial: A randomised controlled trial of a coproduced assertive cardiac care intervention to reduce absolute cardiovascular disease risk in people with severe mental illness in the primary care setting

BACKGROUND: Cardiovascular disease (CVD) accounts for 40% of the excess mortality identified in people with severe mental illness (SMI). Modifiable CVD risk factors are higher and can be exacerbated by the cardiometabolic impact of psychotropic medications. People with SMI frequently attend primary care presenting a valuable opportunity for early identification, prevention and management of cardiovascular health. The ACCT Healthy Hearts Study will test a coproduced, nurse-led intervention delivered with general practitioners to reduce absolute CVD risk (ACVDR) at 12 months compared with an active control group. METHODS/DESIGN: ACCT is a two group (intervention/active control) individually randomised (1:1) controlled trial (RCT). Assessments will be completed baseline (pre-randomisation), 6 months, and 12 months. The primary outcome is 5-year ACVDR measured at 12 months. Secondary outcomes include 6-month ACVDR; and blood pressure, lipids, HbA1c, BMI, quality of life, physical activity, motivation to change health behaviour, medication adherence, alcohol use and hospitalisation at 6 and 12 months. Linear mixed-effects regression will estimate mean difference between groups for primary and secondary continuous outcomes. Economic cost-consequences analysis will be conducted using quality of life and health resource use information and routinely collected government health service use and medication data. A parallel process evaluation will investigate implementation of the intervention, uptake and outcomes. DISCUSSION: ACCT will deliver a coproduced and person-centred, guideline level cardiovascular primary care intervention to a high need population with SMI. If successful, the intervention could lead to the reduction of the mortality gap and increase opportunities for meaningful social and economic participation. Trial registration ANZCTR Trial number: ACTRN12619001112156