The Nitric Oxide-Cyclic GMP Pathway Regulates FoxO and Alters Dopaminergic Neuron Survival in Drosophila

Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a Drosophila model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines Drosophila genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and Drosophila orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A Drosophila FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD

Are socioeconomic conditions associated with asthma prevalence, severity, and treatment access? A cross-sectional study of children living in low-income South African communities

South Africa has the highest prevalence of child- hood asthma in sub-Saharan Africa and the fourth highest asthma mortality rate among young people worldwide. While poverty and social deprivation are pervasive, asthma studies in the region have largely focused on biomedical factors or urban-rural differences. This study sought to identify broader socioeconomic risk factors for childhood asthma prevalence, severity, and treatment access in South Africa and possible mediating pathways

Are socioeconomic conditions associated with asthma prevalence, severity, and treatment access? A cross-sectional study of children living in low-income South African communities

South Africa has the highest prevalence of child- hood asthma in sub-Saharan Africa and the fourth highest asthma mortality rate among young people worldwide. While poverty and social deprivation are pervasive, asthma studies in the region have largely focused on biomedical factors or urban-rural differences. This study sought to identify broader socioeconomic risk factors for childhood asthma prevalence, severity, and treatment access in South Africa and possible mediating pathways

Socioeconomic factors associated with asthma prevalence and severity among children living in low-income South African communities.

Background Rates of asthma, poverty and social deprivation are high among young people in South Africa (SA), yet asthma interventions largely remain focused on biomedical factors. Objective To investigate associations between socioeconomic factors and childhood asthma. Methods We recruited 6 002 children aged 10 - 17 years from six low-income urban and rural sites in three SA provinces. Self-report questionnaires measured health status, sociodemographics and socioeconomic factors. Logistic regression and mediation analyses were used to test models of risk factors for asthma prevalence and severity (frequency of attacks). Results Child anxiety (odds ratio (OR) 1.08; 95% confidence interval (CI) 1.04 - 1.12) and community violence (OR 1.14; 95% CI 1.00 - 1.30) were associated with increased odds of having asthma. Children doing more outdoor housework (OR 0.83; 95% CI 0.71 - 0.98) and living in greater poverty (OR 0.93; 95% CI 0.88 - 0.99) had lower odds of having asthma. Severe asthma was predicted by child depression (OR 1.14; 95% CI 1.03 - 1.26) and greater household poverty (OR 1.14; 95% CI 1.01 - 1.28). Most socioeconomic factors operated in ‘risk pathways’, wherein structural factors (e.g. urban living) were associated with individual factors (e.g. fewer outdoor tasks), which predicted greater odds of having asthma or severe exacerbations. Conclusions This study suggests the need to consider the context of childhood asthma in SA for improved prevention and treatment. A multidisciplinary approach may be more effective than a biomedical model, given the plausible effects of psychosocial stress and poverty on asthma outcomes.</p

Combination social protection for reducing HIV-risk behavior amongst adolescents in South Africa

Background: Social protection (i.e. cash transfers, free schools, parental support) has potential for adolescent HIV-prevention. We aimed to identify which social protection interventions are most effective and whether combined social protection has greater effects in South Africa. Methods: In this prospective longitudinal study, we interviewed 3516 adolescents aged 10-18 between 2009 and 2012. We sampled all homes with a resident adolescent in randomly-selected census areas in four urban and rural sites in two South African provinces. We measured household receipt of fourteen social protection interventions and incidence of HIV-risk behaviors. Using gender-disaggregated multivariate logistic regression and marginal-effects analyses, we assessed respective contributions of interventions and potential combination effects. Results: Child-focused grants, free schooling, school feeding, teacher support, and parental monitoring were independently associated with reduced HIV-risk behavior incidence (OR 0.10-0.69). Strong effects of combination social protection were shown, with cumulative reductions in HIV-risk behaviors. For example, girls’ predicted past-year incidence of economically-driven sex dropped from 11% with no interventions, to 2% amongst those with a child grant, free school and good parental monitoring. Similarly, girls’ incidence of unprotected/casual sex or multiple-partners dropped from 15% with no interventions to 10% with either parental monitoring or school feeding, and to 7% with both interventions. Conclusion: In real-world, high-epidemic conditions, ‘combination social protection’ shows strong HIV-prevention effects for adolescents and may maximize prevention efforts

Beyond clinical trials: Cross-sectional associations of combination antiretroviral therapy with reports of multiple symptoms and non-adherence among adolescents in South Africa

Background.Studies investigating symptoms associated with combination antiretroviral therapy (cART) use among adolescents in resource-limited settings are rare beyond clinical trials. Identifying adolescents at risk of non-adherence is imperative for HIV/AIDS programming and controlling the epidemic in this key population. Objective. To examine which cART regimens were associated with reports of multiple symptoms and past-week non-adherence in a large community-traced sample of HIV-positive adolescents in South Africa (SA). Methods. A total of 1 175 HIV-positive ART-experienced adolescents aged 10 - 19 years attending 53 health facilities in the Eastern Cape Province, SA, were interviewed in 2014 - 2015. Ninety percent (n=1 059) were included in the study. Adolescents who reported no medication use and those with unclear or missing data were excluded from further analysis, resulting in a sample for analysis of n=501. Outcomes were reports of multiple symptoms (three or more symptoms in the past 6 months) and past-week ART non-adherence (&lt;95% correct doses in the past week). Multivariable logistic regression analyses controlled for sociodemographic and HIV-related covariates in Stata 13/IC. Results. Of the adolescents included, 54.3% were female. The median age was 14 (interquartile range 12 - 16) years, and 66.5% were vertically infected. The prevalence of multiple symptoms was 59.7% (95% confidence interval (CI) 55.3 - 63.9). Independent of covariates, stavudine (d4T)-containing cART regimens and the fixed-dose combination of tenofovir (TDF) + emtricitabine (FTC) + efavirenz (EFV) were associated with more reports of multiple symptoms (adjusted odds ratio (aOR) 3.38; 95% CI 1.19 - 9.60 and aOR 2.67; 95% CI 1.21 - 5.88, respectively). Lopinavir/ritonavir (LPV/r)-containing regimens were associated with fewer reports of multiple symptoms (aOR 0.47; 95% CI 0.21 - 1.04). For EFV-based regimens, adolescents on d4T + lamivudine (3TC) + EFV were more likely to report multiple symptoms than those on TDF + FTC + EFV or those on abacavir (ABC) + 3TC + EFV (aOR 3.26; 95% CI 1.01 - 10.52, aOR 2.86; 95% CI 1.35 - 6.05 and aOR 1.08; 95% CI 0.64 - 1.82, respectively). However, only TDF + FTC + EFV cART was associated with lower levels of non-adherence among participants (aOR 0.44; 95% CI 0.21 - 0.93). Conclusions. Rates of multiple symptoms among HIV-positive ART-experienced adolescents were high. d4T-containing regimens and TDF + FTC + EFV were associated with more reports of multiple symptoms, whereas LPV/r-containing regimens were associated with fewer reports. However, adolescents on TDF + FTC + EFV were the most adherent subgroup. These findings support the World Health Organization-recommended discontinuation of d4T use, but also underscore the dilemma faced by clinicians when choosing between low-toxicity regimens and those that promote ART adherence, particularly among HIV-positive adolescents.</p

Response strategies for promoting gender equality in public health emergencies: a rapid scoping review

Objectives The COVID-19 pandemic threatens to widen existing gender inequities worldwide. A growing body of literature assesses the harmful consequences of public health emergencies (PHEs) for women and girls; however, evidence of what works to alleviate such impacts is limited. To inform viable mitigation strategies, we reviewed the evidence on gender-based interventions implemented in PHEs, including disease outbreaks and natural disasters. Methods We conducted a rapid scoping review to identify eligible studies by systematically searching the databases MEDLINE, Global Health and Web of Science with the latest search update on 28 May 2021. We used the Sustainable Development Goals as a guiding framework to identify eligible outcomes of gender (in)equality. Results Out of 13 920 records, 16 studies met our eligibility criteria. These included experimental (3), cohort (2), case–control (3) and cross-sectional (9) studies conducted in the context of natural disasters (earthquakes, droughts and storms) or epidemics (Zika, Ebola and COVID-19). Six studies were implemented in Asia, seven in North/Central America and three in Africa. Interventions included economic empowerment programmes (5); health promotion, largely focused on reproductive health (10); and a postearthquake resettlement programme (1). Included studies assessed gender-based outcomes in the domains of sexual and reproductive health, equal opportunities, access to economic resources, violence and health. There was a dearth of evidence for other outcome domains relevant to gender equity such as harmful practices, sanitation and hygiene practices, workplace discrimination and unpaid work. Economic empowerment interventions showed promise in promoting women’s and girls’ economic and educational opportunities as well as their sexual and reproductive health during PHEs. However, some programme beneficiaries may be at risk of experiencing unintended harms such as an increase in domestic violence. Focused reproductive health promotion may also be an effective strategy for supporting women’s sexual and reproductive health, although additional experimental evidence is needed. Conclusions This study identified critical evidence gaps to guide future research on approaches to alleviating gender inequities during PHEs. We further highlight that interventions to promote gender equity in PHEs should take into account possible harmful side effects such as increased gender-based violence. Review registration DOI 10.17605/OSF.IO/8HKFD

How effective is help on the doorstep? A longitudinal study of the impact of community-based organisation support on child behaviour and mental health

Community-based responses have a lengthy history. The ravages of HIV on family functioning has included a widespread community response. Although much funding has been invested in front line community-based organisations (CBO), there was no equal investment in evaluations. This study was set up to compare children aged 9–13 years old, randomly sampled from two South African provinces, who had not received CBO support over time (YC) with a group of similarly aged children who were CBO attenders (CCC). YC baseline refusal rate was 2.5% and retention rate was 97%. CCC baseline refusal rate was 0.7% and retention rate was 86.5%. 1848 children were included—446 CBO attenders compared to 1402 9–13 year olds drawn from a random sample of high-HIV prevalence areas. Data were gathered at baseline and 12–15 months follow-up. Standardised measures recorded demographics, violence and abuse, mental health, social and educational factors. Multivariate regression analyses revealed that children attending CBOs had lower odds of experiencing weekly domestic conflict between adults in their home (OR 0.17; 95% CI 0.09, 0.32), domestic violence (OR 0.22; 95% CI 0.08, 0.62), or abuse (OR 0.11; 95% CI 0.05, 0.25) at follow-up compared to participants without CBO contact. CBO attenders had lower odds of suicidal ideation (OR 0.41; 95% CI 0.18, 0.91), fewer depressive symptoms (B = -0.40; 95% CI -0.62, -0.17), less perceived stigma (B = -0.37; 95% CI -0.57, -0.18), fewer peer problems (B = -1.08; 95% CI -1.29, -0.86) and fewer conduct problems (B = -0.77; 95% CI -0.95, -0.60) at follow-up. In addition, CBO contact was associated with more prosocial behaviours at follow-up (B = 1.40; 95% CI 1.13, 1.67). No associations were observed between CBO contact and parental praise or post-traumatic symptoms. These results suggest that CBO exposure is associated with behavioural and mental health benefits for children over time. More severe psychopathology was not affected by attendance and may need more specialised input

Community-based organisations for vulnerable children in South Africa: Reach, psychosocial correlates, and potential mechanisms

Community-based organizations (CBOs) have the potential to provide high quality services for orphaned and vulnerable children in resource-limited settings. However, evidence is lacking as to whether CBOs are reaching those who are most vulnerable, whether attending these organizations is associated with greater psychosocial wellbeing, and how they might work. This study addressed these three questions using cross-sectional data from 1848 South African children aged 9–13. Data were obtained from the Young Carers and Child Community Care studies, which both investigated child wellbeing in South Africa using standardized self-report measures. Children from the Child Community Care study were all CBO attenders, whereas children from Young Carers were not receiving any CBO services, thereby serving as a comparison group. Multivariable regression analyses were used to test whether children attending CBOs were more deprived on socio-demographic variables (e.g., housing), and whether CBO attendance was in turn associated with better psychosocial outcomes (e.g., child depression). Mediation analysis was conducted to test whether more positive home environments mediated the association between CBO attendance and significantly higher psychological wellbeing. Overall, children attending CBOs did show greater vulnerability on most socio-demographic variables. For example, compared to children not attending any CBO, CBO-attending children tended to live in more crowded households (OR 1.22) and have been exposed to more community violence (OR 2.06). Despite their heightened vulnerability, however, children attending CBOs tended to perform better on psychosocial measures: for instance, showing fewer depressive symptoms (B = − 0.33) and lower odds of experiencing physical (OR 0.07) or emotional abuse (OR 0.22). Indirect effects of CBO attendance on significantly better child psychological wellbeing (lower depressive symptoms) was observed via lower rates of child abuse (B = − 0.07) and domestic conflict/violence (B = − 0.03) and higher rates of parental praise (B = − 0.03). Null associations were observed between CBO attendance and severe psychopathology (e.g., suicidality). These cross-sectional results provide promising evidence regarding the potential success of CBO reach and impact but also highlight areas for improvement