Child maltreatment and resilience in adulthood: a protocol for a systematic review and meta-analysis.

Background: Although child maltreatment (CM) has been linked to health problems and poor psychosocial functioning, not all individuals exposed to CM develop or experience negative consequences later in life. This suggests that some individuals show resilience after being exposed to CM. However, conclusions have been limited by inconsistent findings across different CM subtypes and resilience domains.Objective: To develop a protocol for conducting a systematic review and meta-analysis to quantify associations between CM (overall and its subtypes) and resilience (global and its multiple domains) in adulthood, and to examine moderators and mediators of these associations.Method: PubMed, PsycINFO, Embase, Scopus, and Web of Science will be searched to identify relevant studies on the association between CM (exposure) and resilience (outcome) in adults (≥ 18 years). Data will be screened and extracted by at least two independent reviewers. The methodological quality of the included studies will be independently assessed with a modified version of the Newcastle-Ottawa Scale (NOS). If deemed viable, a meta-analysis will be conducted using a random effects model. Heterogeneity of evidence will be estimated with the I2 statistic, and publication bias will be assessed. The effects of potential moderators (e.g. timing and severity of CM, age, sex, family cohesion, socio-economic status, country/region) will be analysed using meta-regression and subgroup analyses, and meta-analytical structural equation modelling will be employed to synthesise indirect mediation effects. Candidate moderators and mediators (e.g. genetic factors, brain functioning, attachment style, personality traits, physical activity, and social support) will be also examined qualitatively.Conclusions: This protocol will facilitate a systematic review and meta-analysis that has the potential to enhance our knowledge about the association between CM exposure in early life and resilience in adulthood. Understanding associations and underlying mechanisms between CM and resilience is potentially important in informing prevention and interventions to sustain health and improve outcomes among adults with a history of CM.PROSPERO registration: CRD42023394120.

In this study protocol, we propose to quantitatively summarise the existing literature on the relationship between child maltreatment and resilience with regard to mental health consequences and psychosocial functioning later in life.This preregistered systematic review and meta-analysis will establish the procedures to investigate associations between an overall classification of child maltreatment and its different associated subtypes, and a global/trait classification of resilience and its different domains in adults.This protocol will further determine the analytical approach to explore and summarise effect moderators and mediators of the association between child maltreatment and resilience in adulthood.The resulting synthesis, that will be based on this protocol, could enhance our understanding of the strength of the association between child maltreatment and resilience and inform prevention strategies and clinical interventions to improve health and psychosocial functioning in adult survivors.

Advances in the molecular neurobiology of posttraumatic stress disorder from global contexts: A systematic review of longitudinal studies.

Trauma exposure is prevalent globally and is a defining event for the development of posttraumatic stress disorder (PTSD), characterised by intrusive thoughts, avoidance behaviours, hypervigilance and negative alterations in cognition and mood. Exposure to trauma elicits a range of physiological responses which can interact with environmental factors to confer relative risk or resilience for PTSD. This systematic review summarises the findings of longitudinal studies examining biological correlates predictive of PTSD symptomology. Databases (Pubmed, Scopus and Web of Science) were systematically searched using relevant keywords for studies published between 1 January 2021 and 31 December 2022. English language studies were included if they were original research manuscripts or meta-analyses of cohort investigations that assessed longitudinal relationships between one or more molecular-level measures and either PTSD status or symptoms. Eighteen of the 1,042 records identified were included. Studies primarily included military veterans/personnel, individuals admitted to hospitals after acute traumatic injury, and women exposed to interpersonal violence or rape. Genomic, inflammation and endocrine measures were the most commonly assessed molecular markers and highlighted processes related to inflammation, stress responding, and learning and memory. Quality assessments were done using the Systematic Appraisal of Quality in Observational Research, and the majority of studies were rated as being of high quality, with the remainder of moderate quality. Studies were predominantly conducted in upper-income countries. Those performed in low- and middle-income countries were not broadly representative in terms of demographic, trauma type and geographic profiles, with three out of the four studies conducted assessing only female participants, rape exposure and South Africa, respectively. They also did not generate multimodal data or use machine learning or multilevel modelling, potentially reflecting greater resource limitations in LMICs. Research examining molecular contributions to PTSD does not adequately reflect the global burden of the disorder.

A network analysis investigating the associations between posttraumatic stress symptoms, markers of inflammation and metabolic syndrome.

Chronic systemic inflammation has been implicated in trauma exposure, independent of a psychiatric diagnosis, and in posttraumatic stress disorder (PTSD) and its highly comorbid conditions, such as metabolic syndrome (MetS). The present study used network analysis to examine the interacting associations between pro-inflammatory cytokines, posttraumatic stress (PTS) symptoms and symptom clusters, and individual components of MetS, in a cohort of 312 participants (n = 139 PTSD cases, n = 173 trauma-exposed controls). Pro-inflammatory cytokines were measured in serum samples using immunoturbidimetric and multiplex assays. Three network models were assessed, and the decision on which model to use was guided by network stability estimates and denseness. Weak negative associations were observed between interleukin one beta (IL-1ß) and detachment (D6) and irritability (E1); tumour necrosis factor alpha (TNFα) and hypervigilance (E3); and C-reactive protein (CRP) and emotional cue reactivity (B4), which could be due to high cortisol levels present in a female-majority cohort. Network models also identified positive associations between CRP and waist circumference, blood pressure, and high-density lipoprotein cholesterol (HDL-C). The strongest association was observed between CRP and waist circumference, providing evidence that central obesity is an important inflammatory component of MetS. Some networks displayed high instability, which could be due to the small pool of participants with viable cytokine data. Overall, this study provides evidence for associations between inflammation, PTS symptoms and components of MetS. Future longitudinal studies measuring pro-inflammatory cytokines in the immediate aftermath of trauma are required to gain better insight into the role of inflammation in trauma-exposure and PTSD.

Identifying genetic loci that are associated with changes in gene expression in PTSD in a South African cohort.

The molecular mechanisms underlying posttraumatic stress disorder (PTSD) are yet to be fully elucidated, especially in underrepresented population groups. Expression quantitative trait loci (eQTLs) are DNA sequence variants that influence gene expression, in a local (cis-) or distal (trans-) manner, and subsequently impact cellular, tissue, and system physiology. This study aims to identify genetic loci associated with gene expression changes in a South African PTSD cohort. Genome-wide genotype and RNA-sequencing data were obtained from 32 trauma-exposed controls and 35 PTSD cases of mixed-ancestry, as part of the SHARED ROOTS project. The first approach utilised 108 937 single-nucleotide polymorphisms (SNPs) (MAF > 10%) and 11 312 genes with Matrix eQTL to map potential eQTLs, while controlling for covariates as appropriate. The second analysis was focused on 5638 SNPs related to a previously calculated PTSD polygenic risk score for this cohort. SNP-gene pairs were considered eQTLs if they surpassed Bonferroni correction and had a false discovery rate <0.05. We did not identify eQTLs that significantly influenced gene expression in a PTSD-dependent manner. However, several known cis-eQTLs, independent of PTSD diagnosis, were observed. rs8521 (C > T) was associated with TAGLN and SIDT2 expression, and rs11085906 (C > T) was associated with ZNF333 expression. This exploratory study provides insight into the molecular mechanisms associated with PTSD in a non-European, admixed sample population. This study was limited by the cross-sectional design and insufficient statistical power. Overall, this study should encourage further multi-omics approaches towards investigating PTSD in diverse populations.

FKBP5 intron 7 methylation is associated with higher anxiety proneness and smaller right thalamus volume in adolescents.

Dysregulation of stress response systems may mediate the detrimental effects of childhood trauma (CT) on mental health. FKBP5 regulates glucocorticoid receptor sensitivity and exerts pleiotropic effects on intracellular signaling, neurobiology and behavior. We investigated whether CT, alone and in combination with rs1360780 genotype, is associated with altered FKBP5 methylation and whether CT-associated methylation profiles are associated with anxiety proneness (AP) and structural brain volumes. Ninety-four adolescents completed the Childhood Trauma Questionnaire, and a composite AP score was generated from the Childhood Anxiety Sensitivity Index and the State-Trait Anxiety Inventory-Trait measure. Mean methylation values for 12 regulatory regions and 25 individual CpG sites were determined using high-accuracy measurement via targeted bisulfite sequencing. FKBP5 rs1360780 genotype and structural MRI data were available for a subset of participants (n = 71 and n = 75, respectively). Regression models revealed an inverse association between methylation of three intron 7 CpG sites (35558438, 35558566 and 35558710) and right thalamus volume. CpG35558438 methylation was positively associated with AP scores. Our data indicate that an intron 7 methylation profile, consistent with lower FKBP5 expression and elevated high sensitivity glucocorticoid receptor levels, is associated with higher AP and smaller right thalamus volume. Research into the mechanisms underlying the intron 7 methylation-thalamus volume relationship, and whether it confers increased risk for long-term psychopathology by altering the regulatory threshold of stress responding, is required.

Childhood trauma and genetic variation in the DAT 40-bp VNTR contribute to HIV-associated neurocognitive disorders.

HIV/AIDS is a major public health burden in South Africa, currently affecting an estimated 13.5% of the population. Despite improved access to antiretroviral therapies, HIV-associated neurocognitive disorders (HAND), characterised by a spectrum of neurocognitive impairment, emotional disturbances and motor abnormalities, continue to persist. Gene-environment interactions contribute to HAND pathophysiology and previous research has identified childhood trauma as an environmental risk factor. Dopaminergic signalling in the prefrontal cortex plays a key role in cognitive function. Thus, variants in genes encoding the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT), which are responsible for dopamine transport and metabolism, could represent genetic risk factors for HAND. This study investigated whether the DAT variable number of tandem repeats (VNTR) and COMT Val158Met (rs4680) polymorphisms are associated with longitudinal change in cognitive function in the context of childhood trauma and HIV. Participants (n = 49 HIV-negative and n = 64 HIV-positive women) completed the Childhood Trauma Questionnaire - Short Form (CTQ-SF) and provided blood for genetic analyses. Global cognitive scores were generated from baseline and one-year follow-up assessments. Following polymerase chain reaction, genotypes were determined using gel electrophoresis and confirmed by Sanger sequencing. Baseline global cognitive scores, genotype, HIV status and CTQ-SF scores were regressed on one-year global cognitive scores in regression models. Analysis of variance was used to examine the effect of including predictor variable interactions on model fit. HIV seropositivity was associated with poorer cognitive performance at one-year follow-up (p = 2.46 ×10-4). The combination of HIV and DAT 10-repeat homozygosity (DAT 10/10) was associated with reduced global cognitive scores in longitudinal models (p = 0.010). Including the interaction between DAT 10/10, childhood trauma, and HIV explained significantly more of the variance in longitudinal cognitive scores (p = 0.008). There were no significant associations with the COMT genotype. Our research indicates that childhood trauma and genetic variation in DAT contribute toward the aetiology of HAND. Future studies in larger cohorts are warranted to verify these results.

Childhood trauma, the stress response and metabolic syndrome: A focus on DNA methylation.

Childhood trauma (CT) is well established as a potent risk factor for the development of mental disorders. However, the potential of adverse early experiences to exert chronic and profound effects on physical health, including aberrant metabolic phenotypes, has only been more recently explored. Among these consequences is metabolic syndrome (MetS), which is characterised by at least three of five related cardiometabolic traits: hypertension, insulin resistance/hyperglycaemia, raised triglycerides, low high-density lipoprotein and central obesity. The deleterious effects of CT on health outcomes may be partially attributable to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates the response to stress, and the consequent fostering of a pro-inflammatory environment. Epigenetic tags, such as DNA methylation, which are sensitive to environmental influences provide a means whereby the effects of CT can be biologically embedded and persist into adulthood to affect health and well-being. The methylome regulates the transcription of genes involved in the stress response, metabolism and inflammation. This narrative review examines the evidence for DNA methylation in CT and MetS in order to identify shared neuroendocrine and immune correlates that may mediate the increased risk of MetS following CT exposure. Our review specifically highlights differential methylation of FKBP5, the gene that encodes FK506-binding protein 51 and has pleiotropic effects on stress responding, inflammation and energy metabolism, as a central candidate to understand the molecular aetiology underlying CT-associated MetS risk.

Associations between telomere length and symptoms of posttraumatic stress disorder and appetitive aggression in trauma-exposed men.

Exposure to community violence is common in South Africa and negatively impacts on biopsychosocial health. Posttraumatic stress disorder (PTSD) is characterised by symptoms of intrusion, avoidance, hypervigilance and negative alterations in cognition and mood, and can develop consequent to trauma exposure. Individuals who repeatedly experience and witness violence may also come to view it as appealing and rewarding. This appetitive aggression (AA) increases the likelihood of perpetrating violence. Telomeres are repetitive nucleotide sequences that protect the ends of chromosomes. Telomere length (TL) attrition is a stress-sensitive marker of biological aging that has been associated with a range of psychiatric disorders. This study investigated the cross-sectional relationship between TL and symptoms of PTSD and AA in South African men residing in areas with high community violence. PTSD and AA symptom severity was assessed in 290 men using the Posttraumatic Stress Disorder Symptom Scale - Interview (PSS-I) and Appetitive Aggression Scale (AAS), respectively. Quantitative polymerase chain reaction was performed on DNA extracted from saliva and used to calculate relative TL (rTL). Regression models were used to assess the relationships between rTL and PSS-I and AAS scores. Network analyses using EBIC glasso methods were performed using rTL and items from each of the AAS and PSS-I measures. Both PSS-I (p = 0.023) and AAS (p = 0.016) scores were positively associated with rTL. Network analyses indicated that rTL was weakly related to two PSS-I and five AAS items but performed poorly on indicators of centrality and was not strongly associated with measure items either directly or indirectly. The positive association between rTL and measures of AA and PTSD may be due to the induction of protective homeostatic mechanisms, which reduce TL attrition, following early life trauma exposure.

Association of Stress, Glucocorticoid Receptor, and FK506 Binding Protein Gene Polymorphisms With Internalizing Disorders Among HIV-Infected Children and Adolescents From Kampala and Masaka Districts-Uganda.

Children and adolescents living with human immunodeficiency virus (CA-HIV) suffer a considerable burden of internalizing disorders (IDs; depressive and anxiety disorders). Environmental and genetic factors have been reported to influence the vulnerability to IDs in western settings; however, their role among African populations remains inadequately explored. We investigated the individual and interactive effects of stress and single-nucleotide polymorphisms within the FK506 binding protein 5 (rs1360780) and glucocorticoid receptor (rs10482605) genes on ID status in a cohort of CA-HIV in Uganda. We genotyped rs10482605 (309 cases and 315 controls) and rs1360780 (350 cases and 335 controls) among CA-HIV with and without IDs using Kompetitive Allele-Specific PCR. Socio-demographic variables, as well as allele and genotype distributions, were compared between cases and controls using chi-square tests. Genotypes were assessed for Hardy-Weinberg equilibrium. Composite indices of recent and chronic stress classes were also generated. A hierarchical cluster analysis was used to generate cutoff points within each of the indices of recent and chronic stress. Logistic regression was used to assess the association between IDs and each of recent stress, chronic stress, and the investigated genotypes. The interaction effect of chronic/recent stress on the association between each of the polymorphisms and IDs was determined using a likelihood ratio test. We observed no significant association between IDs and rs1360780 and rs10482605 polymorphisms within the FKBP5 and glucocorticoid receptor genes, respectively (P > 0.050). Severe recent stress increased the vulnerability to IDs among CA-HIV (P = 0.001). We did not observe any gene-environment effect on vulnerability to IDs in this population. These findings support the currently held opinion that polymorphisms at single genetic loci only contribute a very small effect to the genetic vulnerability to IDs.

Longitudinal telomere length profile does not reflect HIV and childhood trauma impacts on cognitive function in South African women.

HIV-associated neurocognitive disorders (HAND) present a challenge in South Africa where the burden of HIV infection is the highest. Identification of biological correlates of HAND is required to improve diagnosis and inform interventions. Telomeres maintain genomic integrity and their shortening is a marker of biological aging sensitive to environmental influences. This study examined relative telomere length (rTL) as a predictor of cognitive function in the context of HIV and childhood trauma (CT), a risk factor for HAND. Two hundred and eighty-six women completed a neurocognitive assessment battery and the Childhood Trauma Questionnaire-Short Form (CTQ). Quantitative polymerase chain reaction for amplification of telomeric repeats and the reference gene human beta-globin was used to calculate rTL. Neurocognitive and rTL assessments were repeated at 1 year in 110 participants. Cross-sectional and longitudinal data were assessed using linear and mixed models, respectively. Participants with HIV (n = 135 in cross-sectional and n = 62 in longitudinal study groups) reported more severe CT and had shorter baseline rTL compared to seronegative controls. Participants without HIV had a greater 1-year decline in rTL. Global cognitive and attention/working memory scores declined in participants with HIV. Our data indicate that baseline rTL in the context of CT and HIV did not predict decline in cognitive scores. HIV-associated pathophysiological processes driving cognitive decline may also engage mechanisms that protect against telomere shortening. The results highlight the importance of examining biological correlates in longitudinal studies.

The 5-HTTLPR-rs25531 S-A-S-A Haplotype and Chronic Stress Moderate the Association Between Acute Stress and Internalizing Mental Disorders Among HIV+ Children and Adolescents in Uganda.

Background: Internalizing mental disorders (IMDs) among HIV-positive (HIV+) children and adolescents are associated with poor disease outcomes, such as faster HIV disease progression. Although it has been suggested that the development of IMDs is moderated by interaction of stressful life events and vulnerability factors, the underlying etiology is largely unknown. Serotonin transporter gene [solute carrier family 6 member A4 (SLC6A4)] and human tryptophan hydroxylase 2 gene (TPH2) polymorphisms have been implicated in the development of IMDs. This study investigated the association between acute stress and IMDs, and moderation by chronic stress and genetic variants in SLC6A4 and TPH2. Hypothesis: Acute stress acts through genetic and environmental vulnerability factors to increase the risk of developing IMDs. Methods: Polymorphisms in SLC6A4 (5-HTTLPR, rs25531, 5-HTTLPR-rs25531, and STin2 VNTR) and TPH2 (rs1843809, rs1386494, rs4570625, and rs34517220) were genotyped in 368 HIV+ children and adolescents (aged 5-17 years) with any internalizing mental disorder (depression, anxiety disorders, or posttraumatic stress disorder), and 368 age- and sex-matched controls, who were also HIV+. Chronic and acute stress categories were derived by hierarchical cluster analysis. Logistic regression analysis was used to assess the independent moderating effect of chronic stress and each selected polymorphism on the association between acute stress and IMDs. Results: We observed a statistically significant association between severe acute stress and IMDs (p = 0.001). Children and adolescents who experienced severe acute stress were twice as likely to develop IMDs, compared to children and adolescents who experienced mild acute stress (p = 0.001). Chronic stress interacted with severe acute stress to increase the risk of IMDs (p = 0.033). Acute stress was found to interact with 5-HTTLPR-rs25531 S-A-S-A haplotype to increase the risk for IMDs among Ugandan HIV+ children and adolescents (p = 0.049). We found no evidence for a combined interaction of acute stress, chronic stress, and 5-HTTLPR-rs25531 on IMDs. Conclusion: The odds of having an internalizing mental disorder (IMD) were higher among HIV+ children and adolescents who experienced severe acute stress compared to HIV+ children and adolescents who experienced mild acute stress. Chronic stress and 5-HTTLPR-rs25531 independently moderated the association between acute stress and IMDs.

TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda.

BACKGROUND: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years). RESULTS: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months. CONCLUSIONS: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.

Genetic variation in neuropeptide Y interacts with childhood trauma to influence anxiety sensitivity.

BACKGROUND AND OBJECTIVES: Anxiety sensitivity (AS) refers to a fear of the negative implications of anxiety, and arises due to gene-environment interactions. We investigated whether genetic variation in two neuropeptides implicated in the stress response, neuropeptide Y (NPY) and pituitary adenylate cyclase-activating polypeptide receptor 1, interacted with childhood trauma (CT) to influence AS. DESIGN AND METHODS: This cross-sectional study examined the CT x genetic variant effects on AS in 951 adolescents who self-identified as Xhosa or South African Colored (SAC) ethnicity. RESULTS: In Xhosa females, the NPY rs5573 A allele and rs3037354 deletion variant were associated with increased (p = 0.035) and decreased (p = 0.034) AS, respectively. The interaction of CT and the NPY rs5574 A allele increased AS in SAC female participants (p = 0.043). The rs3037354 deletion variant protected against AS with increased CT in SAC male participants (p = 0.011). CONCLUSIONS: The NPY rs5574 A allele and rs3037354 deletion variant interact with CT to act as risk and protective factors, respectively, for AS in an ethnicity- and sex- differentiated manner. Our results reaffirm the role of NPY and gene-environment interactions in anxiety-related behaviors and reinforce the need for psychiatric genetics studies in diverse populations.

DNA methylation and psychotherapy response in trauma-exposed men with appetitive aggression.

Exposure to violence can lead to appetitive aggression (AA), the positive feeling and fascination associated with violence, and posttraumatic stress disorder (PTSD), characterised by hyperarousal, reexperience and feelings of ongoing threat. Psychotherapeutic interventions may act via DNA methylation, an environmentally sensitive epigenetic mechanism that can influence gene expression. We investigated epigenetic signatures of psychotherapy for PTSD and AA symptoms in South African men with chronic trauma exposure. Participants were assigned to one of three groups: narrative exposure therapy for forensic offender rehabilitation (FORNET), cognitive behavioural therapy or waiting list control (n = 9-10/group). Participants provided saliva and completed the Appetitive Aggression Scale and PTSD Symptom Severity Index at baseline, 8-month and 16-month follow-up. The relationship, over time, between methylation in 22 gene promoter region sites, symptom scores, and treatment was assessed using linear mixed models. Compared to baseline, PTSD and AA symptom severity were significantly reduced at 8 and 16 months, respectively, in the FORNET group. Increased methylation of genes implicated in dopaminergic neurotransmission (NR4A2) and synaptic plasticity (AUTS2) was associated with reduced PTSD symptom severity in participants receiving FORNET. Analyses across participants revealed a proportional relationship between AA and methylation of TFAM, a gene involved in mitochondrial biosynthesis.

Childhood emotional neglect and oxytocin receptor variants: Association with limbic brain volumes.

Objectives: Childhood emotional neglect (EN) is a predictor for the development of affective disorders. Oxytocin (OXT) may mediate the interplay between EN and changes in stress biological systems, brain development, and mental health outcomes. We investigated, in a cross-sectional study, the associations between EN, (epi)genetic variation in the OXT receptor (OXTR) gene, and amygdalar and hippocampal volumes, two brain regions implicated in emotional processing.Methods: We recruited 63 Caucasian South African adults (35 women) with and without social anxiety disorder. Childhood EN was assessed using the Childhood Trauma Questionnaire. rs53576 and rs2254298 genotypes, as well as methylation status, was determined using DNA purified from whole blood. Bilateral amygdalar and hippocampal volumes were determined by structural magnetic resonance imaging. The relationships between these variables were investigated using linear regression.Results: The interaction of the rs2254298 A risk allele and EN was nominally associated with reduced left hippocampal volume. The rs2254298 A risk allele was independently associated with reduced bilateral amygdalar volumes. We found no association between EN, OXTR methylation and amygdalar or hippocampal volumes. The rs53576 GG risk genotype was, however, associated with decreased OXTR methylation.Conclusions: The rs2254298 A allele may increase susceptibility to the structural brain effects of EN.

Women and substance use disorders in low- and middle-income countries: A call for advancing research equity in prevention and treatment.

Although the prevalence of substance use disorders (SUDs) is higher among men, women with SUDs in low- and middle-income countries (LMICs) face unique challenges. Poverty and adversity, inequality of women, and disparities in access to treatment and prevention services exacerbate biological, psychological and social correlates of substance use disorders for women living in low-resource settings. Increasing the inclusion of women in research has long been a goal, though even high income countries struggle to achieve parity. In LMICs, women with SUDs are often neglected from global research due to underreporting and the disproportionate focus of global substance use research on men. We will discuss risk factors for SUDs that are particularly relevant for women residing in LMICs in order to gain insight into neglected areas of research and opportunities for prevention and treatment.

The effect of childhood trauma, ApoE genotype and HIV-1 viral protein R variants on change in cognitive performance.

OBJECTIVE: Gene-environment interactions contribute to the development of HIV-associated neurocognitive disorders. We examined whether childhood trauma, apolipoprotein E isoforms and viral protein R (Vpr) variants were associated with change in cognitive performance. Seventy-three seropositive women completed neuropsychological assessments at baseline and 1-year follow-up. We conducted genetic analyses using DNA obtained from blood and calculated risk scores based on Vpr amino acid 37, 41 and 55 variants that were previously associated with cognitive performance. RESULTS: Global cognitive scores declined significantly over the 1-year study period (p = 0.029). A reduction in global cognitive scores was associated with childhood trauma experience (p = 0.039).

Internalizing Mental Disorders and Accelerated Cellular Aging Among Perinatally HIV-Infected Youth in Uganda.

Introduction: Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated. Objective: We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY). Methods: IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe). t-tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex. Results: We observed longer rTL among cases of IMDs compared with controls (p < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (p < 0.001). The same statistical difference was observed when cases and controls were individually analyzed (p < 0.001). We found no significant difference in rTL between cases and controls at 12 months (p = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. Conclusion: rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings.

Targeting redox regulation to treat substance use disorder using N­acetylcysteine

Substance use disorder (SUD) is a chronic relapsing disorder characterized by transitioning from acute drug reward to compulsive drug use. Despite the heavy personal and societal burden of SUDs, current treatments are limited and unsatisfactory. For this reason, a deeper understanding of the mechanisms underlying addiction is required. Altered redox status, primarily due to drug-induced increases in dopamine metabolism, is a unifying feature of abused substances. In recent years, knowledge of the effects of oxidative stress in the nervous system has evolved from strictly neurotoxic to include a more nuanced role in redox-sensitive signaling. More specifically, S-glutathionylation, a redox-sensitive post-translational modification, has been suggested to influence the response to drugs of abuse. In this review we will examine the evidence for redox-mediating drugs as therapeutic tools focusing on N-acetylcysteine as a treatment for cocaine addiction. We will conclude by suggesting future research directions that may further advance this field.

Childhood trauma interacts with ApoE to influence neurocognitive function in women living with HIV.

HIV-associated neurocognitive disorder (HAND) describes a spectrum of behavioural, motor and cognitive disturbances that can occur secondary to HIV infection. Less severe forms of the disorder persist despite advances in antiretroviral medication efficacy and availability. Childhood trauma (CT) may predispose individuals to developing HAND. As genetic variation in human apolipoprotein E (ApoE) has been implicated in cognitive decline and may mediate the development of long-term health outcomes following CT, we investigated the influence of ApoE and CT on cognitive function in the context of HIV. One hundred twenty-eight HIV-positive Xhosa women completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF) as well as the HIV Neurobehavioural Research Center neurocognitive test battery. rs7412 and rs429358 were genotyped using KASP assays, and this data was used to determine the ApoE isoform. Baseline differences in demographic and clinical variables according to CT exposure were calculated. Analysis of covariance was used to assess the contributions of CT and ApoE variants, as well as their interaction, to cognitive function. Eighty-eight participants reported experiencing CT. The rs7412 C allele protected against the harmful effect of CT on motor scores using an additive model. The interaction of ApoE ε4 and CT was associated with worse attention/working memory scores. ApoE ε4, alone and in combination with CT, is associated with poorer cognitive function. Further research into this gene-environment interaction may assist in identifying at-risk individuals for targeted interventions.