Layered vulnerability and researchers’ responsibilities: learning from research involving Kenyan adolescents living with perinatal HIV infection

Background: Carefully planned research is critical to developing policies and interventions that counter physical, psychological and social challenges faced by young people living with HIV/AIDS, without increasing burdens. Such studies, however, must navigate a ‘vulnerability paradox’, since including potentially vulnerable groups also risks unintentionally worsening their situation. Through embedded social science research, linked to a cohort study involving Adolescents Living with HIV/AIDS (ALH) in Kenya, we develop an account of researchers’ responsibilities towards young people, incorporating concepts of vulnerability, resilience, and agency as ‘interacting layers’. Methods: Using a qualitative, iterative approach across three linked data collection phases including interviews, group discussions, observations and a participatory workshop, we explored stakeholders’ perspectives on vulner- ability and resilience of young people living with HIV/AIDS, in relation to home and community, school, health care and health research participation. A total of 62 policy, provider, research, and community-based stakeholders were involved, including 27 ALH participating in a longitudinal cohort study. Data analysis drew on a Framework Analysis approach; ethical analysis adapts Luna’s layered account of vulnerability. Results: ALH experienced forms of vulnerability and resilience in their daily lives in which socioeconomic context, institutional policies, organisational systems and interpersonal relations were key, interrelated influences. Anticipated and experienced forms of stigma and discrimination in schools, health clinics and communities were linked to actions undermining ART adherence, worsening physical and mental health, and poor educational outcomes, indicating cascading forms of vulnerability, resulting in worsened vulnerabilities. Positive inputs within and across sectors could build resilience, improve outcomes, and support positive research experiences. Conclusions: The most serious forms of vulnerability faced by ALH in the cohort study were related to structural, inter-sectoral influences, unrelated to study participation and underscored by constraints to their agency. Vulnerabili- ties, including cascading forms, were potentially responsive to policy-based and interpersonal actions. Stakeholder engagement supported cohort design and implementation, building privacy, stakeholder understanding, interper- sonal relations and ancillary care policies. Structural forms of vulnerability underscore researchers’ responsibilitie

Data on trajectories of measures of cardiovascular health in the Avon Longitudinal Study of Parents and Children (ALSPAC)

Cardiometabolic disease risk begins in early life and tracks through the life course. As described in "Sex-specific trajectories of measures of cardiovascular health during childhood and adolescence: a prospective cohort study" (O'Keeffe et al., 2018), we modelled sex-specific change in 11 key measures of cardiovascular health from birth/early childhood to age 18 years in a British birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). In this article, we describe the data used in these analyses. Risk factors measured included BMI, fat and lean mass, blood pressure and blood-based biomarkers. Data are from several sources including cord blood at birth, clinic assessments, routine health records, questionnaires and nuclear magnetic resonance spectroscopy. Outcomes were measured over varying time spans from birth or mid-childhood to age 18 and with different numbers of repeated measures per outcome. Analyses were performed using fractional polynomial and linear spline multilevel models. Further information can be found in O'Keeffe et al. (2018)

Sex-specific trajectories of measures of cardiovascular health during childhood and adolescence:A prospective cohort study

BACKGROUND AND AIMS: Sex differences in measures of cardiovascular health in adults are well documented. However, the sex-specific aetiology of cardiovascular health across childhood and adolescence is poorly understood. METHODS: We examined sex differences in trajectories of 11 measures of cardiovascular health from birth to 18 years, in a contemporary birth cohort study in England (N participants per outcomes: 662-13,985, N repeated measures per outcome: 1,831-112,768). Outcomes were measured over varying time spans from birth or mid-childhood to age 18 and with different numbers of repeated measures per outcome. Analyses were performed using fractional polynomial and linear spline multilevel models. RESULTS: Females had higher mean BMI, height-adjusted fat mass, pulse rate, insulin, triglycerides, and non-high-density lipoprotein cholesterol (HDL-c) and lower mean height-adjusted lean mass from birth or from mid-childhood to age 18. For example, mean non-HDL-c was 0.07 mmol/l (95% confidence interval (CI), 0.04, 0.10) higher in females compared with males at birth. By age 18, this difference persisted and widened to 0.19 mmol/l (95% CI, 0.16, 0.23) higher non-HDL-c in females compared with males. Females had lower levels of glucose from mid-childhood and developed lower systolic blood pressure and higher HDL-c from mid-adolescence onward. For example, females had 0.08 mmol/l (95% CI, 0.05, 0.10) lower mean glucose compared with males at age seven which widened to a difference of 0.22 mmol/l (95% CI, 0.25, 0.19) at age 18. CONCLUSIONS: Sex differences in measures of cardiovascular health are apparent from birth or mid-childhood and change during early life. These differences may have implications for sex-specific disease risk in future adult populations

Nine challenges for deterministic epidemic models

Deterministic models have a long history of being applied to the study of infectious disease epidemiology. We highlight and discuss nine challenges in this area. The first two concern the endemic equilibrium and its stability. We indicate the need for models that describe multi-strain infections, infections with time-varying infectivity, and those where superinfection is possible. We then consider the need for advances in spatial epidemic models, and draw attention to the lack of models that explore the relationship between communicable and non-communicable diseases. The final two challenges concern the uses and limitations of deterministic models as approximations to stochastic systems

A descriptive model of patient readiness, motivators, and hepatitis C treatment uptake among Australian prisoners

Background: Hepatitis C virus infection (HCV) has a significant global health burden with an estimated 2%–3% of the world's population infected, and more than 350,000 dying annually from HCV-related conditions including liver failure and liver cancer. Prisons potentially offer a relatively stable environment in which to commence treatment as they usually provide good access to health care providers, and are organised around routine and structure. Uptake of treatment of HCV, however, remains low in the community and in prisons. In this study, we explored factors affecting treatment uptake inside prisons and hypothesised that prisoners have unique issues influencing HCV treatment uptake as a consequence of their incarceration which are not experienced in other populations. Method and Findings: We undertook a qualitative study exploring prisoners' accounts of why they refused, deferred, delayed or discontinued HCV treatment in prison. Between 2010 and 2013, 116 Australian inmates were interviewed from prisons in New South Wales, Queensland, and Western Australia. Prisoners experienced many factors similar to those which influence treatment uptake of those living with HCV infection in the community. Incarceration, however, provides different circumstances of how these factors are experienced which need to be better understood if the number of prisoners receiving treatment is to be increased. We developed a descriptive model of patient readiness and motivators for HCV treatment inside prisons and discussed how we can improve treatment uptake among prisoners.Conclusion: This study identified a broad and unique range of challenges to treatment of HCV in prison. Some of these are likely to be diminished by improving treatment options and improved models of health care delivery. Other barriers relate to inmate understanding of their illness and stigmatisation by other inmates and custodial staff and generally appear less amenable to change although there is potential for peer-based education to address lack of knowledge and stigma

Playing Position is Associated with Injury Incidence Rate in Male Academy Soccer Players

Context: It is unclear whether playing position influences injury in male academy soccer players (ASP). Objective: To determine if playing position is associated with injury in ASP. Design: Descriptive Epidemiology Study. Setting: English, Spanish, Uruguayan and Brazilian soccer academies. Participants: 369 ASP from Under 14 (U14) to U23 age groups, classified as ‘post-peak height velocity' using maturity offset, and grouped as goalkeepers (GK), lateral defenders (LD), central defenders (CD), lateral midfielders (LM), central midfielders (CM) and forwards (FWD). Additional analysis compared central (CENT) with lateral/forward (LAT/FWD) positions. Main Outcome Measures: Injuries were recorded prospectively over one season. Injury prevalence proportion (IPP), days missed and injury incidence rate (IIR, injuries per 1000 training/match hours, n=116) were analysed according to playing position. Results: No association with playing position was observed for any injury type/location regarding IPP (P≥0.089) or days missed (P≥0.235). The IIR was higher in CD than LD for general (9.30 vs. 4.18 injuries/1000h, P=0.009), soft-tissue (5.14 vs. 1.95 injuries/1000h, P=0.026) and ligament/tendon injuries (2.69 vs. 0.56 injuries/1000h, P=0.040). Regarding CENT vs. LAT/FWD, there were no associations with IPP (P≥0.051) or days missed (P≥0.083), but general IIR was greater in CENT than LAT/FWD (8.67 vs. 6.12 injuries/1000h, P=0.047). Conclusions: ASP playing position was not associated with IPP or days missed but the higher general, soft-tissue and ligament/tendon IIR in CD suggests this position warrants specific attention regarding injury prevention strategies. These novel findings highlight the importance of including training/match exposure when investigating the influence of playing position on injury in ASP

Nation, state and identity in international sport

The question of eligibility for international sporting representation (ISR) has become increasingly contentious. In this paper we argue that the current ISR regulations are outdated and problematic. Sporting governing bodies ought to ignore citizenship as a criterion for ISR, and instead ISR should be based on a normative account of national belonging which would operate primarily on grounds of early socialisation and longterm residency. This approach would avoid many of the pragmatic and moral pathologies of ISR, and would utilise sports potential in promoting a liberal and progressive understanding of national ties

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

A HIV-1 Tat mutant protein disrupts HIV-1 Rev function by targeting the DEAD-box RNA helicase DDX1

BACKGROUND: Previously we described a transdominant negative mutant of the HIV-1 Tat protein, termed Nullbasic, that downregulated the steady state levels of unspliced and singly spliced viral mRNA, an activity caused by inhibition of HIV-1 Rev activity. Nullbasic also altered the subcellular localizations of Rev and other cellular proteins, including CRM1, B23 and C23 in a Rev-dependent manner, suggesting that Nullbasic may disrupt Rev function and trafficking by intervening with an unidentified component of the Rev nucleocytoplasmic transport complex. RESULTS: To seek a possible mechanism that could explain how Nullbasic inhibits Rev activity, we used a proteomics approach to identify host cellular proteins that interact with Nullbasic. Forty-six Nullbasic-binding proteins were identified by mass spectrometry including the DEAD-box RNA helicase, DDX1. To determine the effect of DDX1 on Nullbasic-mediated Rev activity, we performed cell-based immunoprecipitation assays, Rev reporter assays and bio-layer interferometry (BLI) assays. Interaction between DDX1 and Nullbasic was observed by co-immunoprecipitation of Nullbasic with endogenous DDX1 from cell lysates. BLI assays showed a direct interaction between Nullbasic and DDX1. Nullbasic affected DDX1 subcellular distribution in a Rev-independent manner. Interestingly overexpression of DDX1 in cells not only restored Rev-dependent mRNA export and gene expression in a Rev reporter assay but also partly reversed Nullbasic-induced Rev subcellular mislocalization. Moreover, HIV-1 wild type Tat co-immunoprecipitated with DDX1 and overexpression of Tat could rescue the unspliced viral mRNA levels inhibited by Nullbasic in HIV-1 expressing cells. CONCLUSIONS: Nullbasic was used to further define the complex mechanisms involved in the Rev-dependent nuclear export of the 9 kb and 4 kb viral RNAs. All together, these data indicate that DDX1 can be sequestered by Nullbasic leading to destabilization of the Rev nucleocytoplasmic transport complex and decreased levels of Rev-dependent viral transcripts. The outcomes support a role for DDX1 in maintenance of a Rev nuclear complex that transports viral RRE-containing mRNA to the cytoplasm. To our knowledge Nullbasic is the first anti-HIV protein that specifically targets the cellular protein DDX1 to block Rev’s activity. Furthermore, our research raises the possibility that wild type Tat may play a previously unrecognized but very important role in Rev function. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12977-014-0121-9) contains supplementary material, which is available to authorized users