Tracking cell-type-specific temporal dynamics in human and mouse brains.

Progenitor cells are critical in preserving organismal homeostasis, yet their diversity and dynamics in the aged brain remain underexplored. We introduced TrackerSci, a single-cell genomic method that combines newborn cell labeling and combinatorial indexing to characterize the transcriptome and chromatin landscape of proliferating progenitor cells in vivo. Using TrackerSci, we investigated the dynamics of newborn cells in mouse brains across various ages and in a mouse model of Alzheimer's disease. Our dataset revealed diverse progenitor cell types in the brain and their epigenetic signatures. We further quantified aging-associated shifts in cell-type-specific proliferation and differentiation and deciphered the associated molecular programs. Extending our study to the progenitor cells in the aged human brain, we identified conserved genetic signatures across species and pinpointed region-specific cellular dynamics, such as the reduced oligodendrogenesis in the cerebellum. We anticipate that TrackerSci will be broadly applicable to unveil cell-type-specific temporal dynamics in diverse systems.

Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain.

Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq)1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.

Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Infernape uncovers cell type-specific and spatially resolved alternative polyadenylation in the brain.

Differential polyadenylation sites (PAs) critically regulate gene expression, but their cell type-specific usage and spatial distribution in the brain have not been systematically characterized. Here, we present Infernape, which infers and quantifies PA usage from single-cell and spatial transcriptomic data and show its application in the mouse brain. Infernape uncovers alternative intronic PAs and 3'-UTR lengthening during cortical neurogenesis. Progenitor-neuron comparisons in the excitatory and inhibitory neuron lineages show overlapping PA changes in embryonic brains, suggesting that the neural proliferation-differentiation axis plays a prominent role. In the adult mouse brain, we uncover cell type-specific PAs and visualize such events using spatial transcriptomic data. Over two dozen neurodevelopmental disorder-associated genes such as Csnk2a1 and Mecp2 show differential PAs during brain development. This study presents Infernape to identify PAs from scRNA-seq and spatial data, and highlights the role of alternative PAs in neuronal gene regulation.

Deep spatial profiling of Venezuelan equine encephalitis virus reveals increased genetic diversity amidst neuroinflammation and cell death during brain infection.

Venezuelan equine encephalitis virus (VEEV) causes a febrile illness that can progress to neurological disease with the possibility of death in human cases. The evaluation and optimization of therapeutics that target brain infections demands knowledge of the host's response to VEEV, the dynamics of infection, and the potential for within-host evolution of the virus. We hypothesized that selective pressures during infection of the brain may differ temporally and spatially and so we investigated the dynamics of the host response, viral transcript levels, and genetic variation of VEEV TC-83 in eight areas of the brain in mice over 7 days post-infection (dpi). Viral replication increased throughout the brain until 5-6 dpi and decreased thereafter with neurons as the main site of viral replication. Low levels of genetic diversity were noted on 1 dpi and were followed by an expansion in the genetic diversity of VEEV and nonsynonymous (Ns) mutations that peaked by 5 dpi. The pro-inflammatory response and the influx of immune cells mirrored the levels of virus and correlated with substantial damage to neurons by 5 dpi and increased activation of microglial cells and astrocytes. The prevalence and dynamics of Ns mutations suggest that the VEEV is under selection within the brain and that progressive neuroinflammation may play a role in acting as a selective pressure. IMPORTANCE Treatment of encephalitis in humans caused by Venezuelan equine encephalitis virus (VEEV) from natural or aerosol exposure is not available, and hence, there is a great interest to address this gap. In contrast to natural infections, therapeutic treatment of infections from aerosol exposure will require fast-acting drugs that rapidly penetrate the blood-brain barrier, engage sites of infection in the brain and mitigate the emergence of drug resistance. Therefore, it is important to understand not only VEEV pathogenesis, but the trafficking of the viral population within the brain, the potential for within-host evolution of the virus, and how VEEV might evolve resistance.

The salience of structural barriers and behavioral health problems to ART adherence in people receiving HIV primary care in South Africa.

Multilevel factors (individual and structural) influence adherence to antiretroviral therapy, particularly in high HIV prevalence areas such as South Africa. The present study examined the relative importance of structural barriers to HIV care and behavioral health factors, depression and alcohol use, in Khayelitsha, Cape Town, South Africa. People receiving HIV care in six primary care clinics in Khayelitsha (N = 194) completed the Center for Epidemiologic Studies Depression Scale, the Alcohol Use Disorders Identification Test, the Structural Barriers to Medication Taking questionnaire, and a qualitative rating of past-two-week adherence. Correlations were employed to examine associations among these variables, and hierarchical regression analysis was used to examine the unique effects of structural barriers over and above depression and alcohol use as predictors of adherence. Participants were primarily Black South African (99%) women (83%), and 41 years old on average. All four variables were significantly correlated. The hierarchical regression analysis showed that among behavioral health predictors, alcohol use alone significantly predicted ART adherence (b = -.032, p = .002). When structural barriers was added to the model, it was the only significant unique predictor of ART adherence (b = -1.58, p < .001). Findings highlight the need to consider structural vulnerabilities in HIV care in South Africa when developing behavioral health interventions.

A network analysis of positive psychosocial factors and indication of suboptimal HIV care outcomes among Black women living with HIV.

Black women living with HIV (BWLWH) face barriers that impact health outcomes. However, positive psychosocial indicators may influence HIV care outcomes. Among this cross-sectional study of 119 BWLWH, a network analysis was utilized to examine relationships between positive psychosocial factors and HIV-related health outcomes. A preliminary polychoric analysis was conducted to examine correlations between the variables, and the network analyzed connections between resilience, self-efficacy, self-esteem, perceived social support, religious coping, post-traumatic growth, and an indicator variable for suboptimal HIV care outcomes (low medication adherence, detectable viral load, and missed HIV-related health visits) and determined the centrality measures within the network. Seven significant associations were found among the factors: self-efficacy and self-esteem, post-traumatic growth and resilience, post-traumatic growth and self-efficacy, post-traumatic growth and religious coping, perceived social support and resilience, self-esteem and resilience, self-esteem and perceived social support (bootstrapped 95% CI did not contain zero). Self-efficacy was the strongest indicator associated with the other factors. Although not statistically significant, the indicator for suboptimal HIV care outcomes was negatively associated with perceived social support and religious coping. Future interventions incorporating self-efficacy may be beneficial to the overall well-being of Black women.

Intersecting Relationships of Psychosocial and Structural Syndemic Problems Among People with HIV in South Africa: Using Network Analysis to Identify Influential Problems.

In South Africa, little is known about interrelationships between syndemic problems among people with HIV (PWH). A better understanding of syndemic problems may yield important information regarding factors amenable to mitigation. We surveyed 194 PWH in Khayelitsha, outside of Cape Town, South Africa. We used network analysis to examine the frequency of 10 syndemic problems and their interrelationships. Syndemic problems among PWH in South Africa were common; 159 (82.8%) participants reported at least 2 co-occurring syndemic problems and 90 (46.9%) endorsed 4 or more. Network analysis revealed seven statistically significant associations. The most central problems were depression, substance use, and food insecurity. Three clusters of syndemics were identified: mood and violence; structural factors; and behavioral factors. Depression, substance use, and food insecurity commonly co-occur among PWH in sub-Saharan Africa and interfere with HIV outcomes. Network analysis can identify intervention targets to potentially improve HIV treatment outcomes.

RESUMEN: En Sudáfrica, poco se sabe sobre interrelaciones entre problemas sindémicos entre personas con VIH (PCV). Un major entendimiento de los problemas sindémicos puede arrojar información importante sobre los factores susceptibles de mitigación. Utilizamos el análisis de redes para examinar la frecuencia de 10 problemas sindémicos y sus interrelaciones. Problemas sindémicos entre PCV en Sudáfrica eran communes; 159 (82.8%) participantes presentaron al menos 2 problemas sindémicos concurrentes y 90 (46.9%) presentaron 4 o más. El análisis de red reveló siete asociaciones estadísticamente significativas. Los problemas más centrales fueron la depresión, el uso de sustancias y la inseguridad alimentaria. Se indetificaron tres grupos de sindemias: estado de ánimo y violencia; factores estructurales; y factores de comportamiento. La depresión, el uso de sustancias y la inseguridad alimentaria comúnmente ocurren simultáneamente entre las PCV en el África subsahariana e interfieren con los resultados del VIH. El análisis de redes puede identificar objetivos de intervención para potencialmente mejorar los resultados del tratamiento del VIH.

Cognitive Performance, as well as Depression, Alcohol Use, and Gender, predict Anti-Retroviral Therapy Adherence in a South African Cohort of People with HIV and Comorbid Major Depressive Disorder.

Depression and cognitive impairment, which commonly coexist in people with HIV (PWH), have been identified as potential barriers to optimal antiretroviral therapy (ART) adherence. We investigated associations between cognitive performance, depression (as well as other sociodemographic, psychosocial and psychiatric variables) and ART adherence in a South African cohort of PWH with comorbid major depressive disorder (MDD). Cognitive performance and ART adherence were assessed at two time points 8 months apart (Nbaseline = 105, Nfollow-up = 81). Adherence was indicated by self-report, objective measures (Wisepill usage and plasma tenofovir-diphosphate levels), and HIV viral suppression. Mixed-effects regression models examined associations across both time points. Univariate models detected no significant associations between cognitive performance (globally and within-domain) and ART adherence. Multivariate modelling showed increased depression severity (ß = - 0.54, p < 0.001) and problematic alcohol use (ß = 0.73, p = 0.015) were associated with worse adherence as measured subjectively. Being female (OR 0.27, p = 0.048) and having better global cognitive performance (OR 1.83, p = 0.043) were associated with better adherence as indicated by viral suppression. This study identifies poor global cognitive performance, as well as depression and problematic alcohol use, as potential barriers to optimal ART adherence in PWH and comorbid MDD. Hence, clinicians could consider assessing for cognitive deficits, depression, and problematic alcohol use, and should endeavour to provide the appropriate support so as to improve adherence.

Cognitive performance in a South African cohort of people with HIV and comorbid major depressive disorder.

Cognitive performance in people with HIV (PWH) may be affected by brain injury attributable to the infection itself, by other medical and psychiatric comorbidities (including major depressive disorder; MDD), and by psychosocial factors (e.g., education, food insecurity). We investigated effects of these variables on cognitive performance in a South African cohort of PWH with comorbid MDD and incomplete adherence to antiretroviral therapy (ART). We also examined (a) associations of depression severity with cognitive performance, and (b) whether improvement in depression led to improved cognitive performance. Participants (N = 105) completed baseline neuropsychological, psychiatric, and sociodemographic assessments. Subsequently, 33 were assigned to a cognitive-behavioural therapy for ART adherence and depression (CBT-AD) and 72 to standard-of-care treatment. Eight months post-baseline, 81 (nCBT-AD = 29) repeated the assessments. We investigated (a) baseline associations between sociodemographic, medical, and psychiatric variables and cognitive performance, (b) whether, from baseline to follow-up, depression and cognitive performance improved significantly more in CBT-AD participants, and (c) associations between post-intervention improvements in depression and cognitive performance. At baseline, less education (ß = 0.62) and greater food insecurity (ß = -0.20) predicted poorer overall cognitive performance; more severe depression predicted impairment in the attention/working memory domain only (ß = -0.25). From baseline to follow-up, depression decreased significantly more in CBT-AD participants (p = .017). Improvement over time in depression and cognitive performance was not significantly associated except in the attention/working memory domain (p = .026). Overall, factors associated with cognitive performance were unrelated to brain injury. We conclude that clinicians examining PWH presenting with cognitive difficulties must assess depression, and that researchers investigating cognitive impairment in PWH must collect information on psychosocial factors.

The Relationship Between Harmful Alcohol Use and Antiretroviral Non-adherence in People Accessing HIV Treatment in Cape Town, South Africa: An Event-Level Analysis.

Harmful alcohol consumption can significantly compromise adherence to antiretroviral therapy (ART). Prior research has identified aggregate relationships between alcohol use and ART non-adherence, largely relying on concurrent assessment of these domains. There is relatively limited evidence on more nuanced day-level associations between alcohol use and ART non-adherence, despite potentially important clinical implications. We recruited adults with HIV treatment adherence challenges and harmful alcohol use (n = 53) from HIV care in South Africa. We examined relationships between alcohol use and same and next day ART adherence, accounting for the role of weekends/holidays and participant demographics, including gender. Results demonstrated that ART adherence was significantly worse on weekend/holiday days. Next day adherence was significantly worse in the context of weekend alcohol use and among men. These results suggest the importance of tailoring intervention strategies to support ART adherence during weekend drinking and for men engaged in heavy episodic drinking.

Formative acceptance of ingestible biosensors to measure adherence to TB medications.

BACKGROUND: Tuberculosis (TB) represents a significant public health threat in India. Adherence to antitubercular therapy (ATT) is the key to reducing the burden of this infectious disease. Suboptimal adherence to ATT and lack of demonstrated feasibility of current strategies for monitoring ATT adherence highlights the need for alternative adherence monitoring systems. METHODS: A quantitative survey was conducted to assess the acceptance of and willingness to use a digital pill system (DPS) as a tool for monitoring ATT adherence among stakeholders directly involved in the management of patients with TB in India. Participants reviewed a video explaining the DPS and completed a survey, which covered sociodemographics, degree of involvement with TB patients, initial impressions of the DPS, and perceived challenges for deploying the technology in India. Participants were also asked to interpret mock DPS adherence data. RESULTS: The mean age was 34.3 (SD = 7.3), and participants (N = 50) were predominantly male (70%). The sample comprised internists (52%) and pulmonologists (30%), with a median of 4 years' experience (IQR 3, 6) in the management of TB patients. No participants had previously used a DPS, but some reported prior awareness of the technology (22%). Most reported that they would recommend use of a DPS to patients on ATT (76%), and that they would use a DPS in both the intensive and continuation phases of TB management (64%). The majority viewed the DPS (82%) as a useful alternative to directly observed therapy-short course (DOTS), particularly given the ongoing COVID-19 pandemic. Participants reported that a DPS would be most effective in patients at risk of nonadherence (64%), as well as those with past nonadherence (64%). Perceived barriers to DPS implementation included lack of patient willingness (92%), cost (86%), and infrastructure constraints (66%). The majority of participants were able to accurately interpret patterns of adherence (80%), suboptimal adherence (90%), and frank nonadherence (82%) when provided with mock DPS data. CONCLUSIONS: DPS are viewed as an acceptable, feasible, and useful technology for monitoring ATT adherence by stakeholders directly involved in TB management. Future investigations should explore patient acceptance of DPS and pilot demonstration of the system in the TB context.

Emergence and Magnitude of ML336 Resistance in Venezuelan Equine Encephalitis Virus Depend on the Microenvironment.

Venezuelan equine encephalitis virus (VEEV) is a New World Alphavirus that can cause neurological disease and death in humans and equines following transmission from infected mosquitoes. Despite the continued epidemic threat of VEEV, and its potential use as a bioterrorism agent, there are no FDA-approved antivirals or vaccines for treatment or prevention. Previously, we reported the discovery of a small molecule, ML336, with potent antiviral activity against VEEV. To further explore the population-level resistance profiles of ML336, we developed a whole-genome next-generation sequencing (NGS) approach to examine single nucleotide polymorphisms (SNPs) from virus passaged in dose escalation studies in a nonhuman primate kidney epithelial and a human astrocyte cell line, Vero 76 and SVGA, respectively. We passaged VEEV TC-83 in these two cell lines over seven concentrations of ML336, starting at 50 nM. NGS revealed several prominent mutations in the nonstructural protein (nsP) 3 and nsP4 genes that emerged consistently in these two distinct in vitro environments-notably, a mutation at Q210 in nsP4. Several of these mutations were stable following passaging in the absence of ML336 in Vero 76 cells. Network analyses showed that the trajectory of resistance differed between Vero and SVGA. Moreover, the penetration of SNPs was lower in SVGA. In conclusion, we show that the microenvironment influenced the SNP profile of VEEV TC-83. Understanding the dynamics of resistance in VEEV against newly developed antiviral compounds will guide the design of optimal drug candidates and dosing regimens for minimizing the emergence of resistant viruses.IMPORTANCE RNA viruses, including Venezuelan equine encephalitis virus (VEEV), have high mutation rates that allow for rapid adaptation to selective pressures in their environment. Antiviral compounds exert one such pressure on virus populations during infections. Next-generation sequencing allows for examination of viruses at the population level, which enables tracking of low levels of single-nucleotide polymorphisms in the population over time. Therefore, the timing and extent of the emergence of resistance to antivirals can be tracked and assessed. We show here that in VEEV, the trajectory and penetration of antiviral resistance reflected the microenvironment in which the virus population replicates. In summary, we show the diversity of VEEV within a single population under antiviral pressure and two distinct cell types, and we show that population dynamics in these viruses can be examined to better understand how they evolve over time.

Improving Detection of Depression in People Living with HIV: Psychometric Properties of the South African Depression Scale (SADS).

Most measures developed in high income countries to screen for major depressive disorder (MDD) among people living with HIV (PWH) demonstrate suboptimal psychometric properties when utilized in non-western, resource limited settings due to their high false positive rates. For standardized MDD screening to be implementable in local settings, a measure is needed that reduces diagnostic burden by being highly sensitive while limiting false positives. This study sought to evaluate the ability of the locally developed South African Depression Scale (SADS) to screen for MDD in PWH in Cape Town. The SADS was administered along with the SCID-5-RV as gold standard to 236 PWH. It demonstrated good discriminating ability in detecting MDD with an area under the curve of 0.85. A cut-off of 27 yielded 78.2% sensitivity and 54.4% PPV. Given its robust psychometric properties, routine use of the SADS in community clinics to screen at-risk PWH, combined with evidence-based depression treatment, could improve the health outcomes and well-being of PWH in South Africa.ResumenLa mayoría de las medidas desarrolladas en países de ingresos altos para detectar el trastorno depresivo mayor (TDM) entre las personas que viven con el VIH (PVV) demuestran propiedades psicométricas subóptimas cuando se utilizan en entornos no occidentales de recursos limitados debido a sus altas tasas de falsos positivos. Para que la detección de TDM estandarizada sea implementable en entornos locales, se necesita una medida que reduzca la carga diagnóstica al ser altamente sensible mientras limita los falsos positivos. Este estudio trató de evaluar la capacidad de la Escala de Depresión Sudafricana (SADS, por sus siglas en inglés) desarrollada localmente para detectar TDM en PVV en Ciudad del Cabo. El SADS se administró junto con el SCID-5-RV como el test de referencia a 236 PWH. Demostró una buena capacidad discriminatoria en la detección de TDM con un área bajo la curva de 0,85. Un corte de 27 produjo un 78,2% de sensibilidad y un 54,4% de VPP. Dadas sus sólidas propiedades psicométricas, el uso rutinario del SADS en clínicas comunitarias para detectar las PVV en riesgo, combinado con un tratamiento de depresión basado en la evidencia, podría mejorar los resultados de salud y el bienestar de las PVV en Sudáfrica.

Improving the measurement of food insecurity among people with HIV in South Africa: a psychometric examination.

OBJECTIVE: Food insecurity is a structural barrier to HIV care in peri-urban areas in South Africa (SA), where approximately 80 % of households are moderately or severely food insecure. For people with HIV (PWH), food insecurity is associated with poor antiretroviral therapy adherence and survival rates. Yet, measurement of food insecurity among PWH remains a challenge. DESIGN: The current study examines the factor structure of the nine-item Household Food Insecurity Access Scale (HFIAS, isiXhosa-translated) among PWH in SA using a restrictive bifactor model. SETTING: Primary care clinics in Khayelitsha, a peri-urban settlement in Cape Town, SA. PARTICIPANTS: Participants (n 440) were PWH who received HIV care in Khayelitsha screening for a clinical trial. Most were categorised as severely (n 250, 56·82 %) or moderately (n 107, 24·32 %) food insecure in the past 30 d. RESULTS: Revised parallel analysis suggested a three-factor structure, which was inadmissible. A two-factor structure was examined but did not adequately fit the data. A two-factor restrictive bifactor model was examined, such that all items loaded on a general factor (food insecurity) and all but two items loaded on one of two specific additional factors, which adequately fit the data (comparative fit index = 0·995, standardised root mean square residual = 0·019). The two specific factors identified were: anxiety/insufficient quality and no food intake. Reliability was adequate (ω = 0·82). CONCLUSIONS: Results supported the use of a total score, and identified two specific factors of the HFIAS, which may be utilised in future research and intervention development. These findings help identify aspects of food insecurity that may drive relationships between the construct and important HIV-related variables.

Tobacco Use and Health-Related Quality of Life Among Individuals with Depression Who Are Receiving Treatment for HIV in Cape Town, South Africa.

BACKGROUND: Tobacco use is the leading cause of preventable death worldwide, and prevalence rates are high among people living with HIV (PLWH), particularly in men. Depression is also common among PLWH, especially among smokers, who may use tobacco to manage mood. Although HIV and depression have been linked to functional impairment and poor health-related quality of life (HRQOL), little research has examined the degree to which smoking impacts these relationships in low- and middle-income countries with high HIV burden. METHOD: Participants (N = 289) were people living with HIV (PLWH) who were being assessed for inclusion in a study targeting depression as a barrier to HIV medication adherence. Linear regression models measured the effect of gender on tobacco use (assessed by the WHO-ASSIST) and on each of the five HRQOL functional impairment domains (assessed by the SF-21). Separate multivariable regression models examined the relationships between habitual tobacco use, defined as daily, almost daily, or weekly use, and the HRQOL domains. RESULTS: The prevalence of habitual tobacco use was 23.9% (48.1% among men, 15.5% among women). Habitual tobacco use was associated with decreased cognitive functioning for the whole sample (B = - 8.99, p < 0.05) and with lower levels of pain-related impairment for men (B = 18.1, p < 0.05). Although men reported more tobacco use (B = 8.50, p < 0.001), they reported less pain-related limitations than women (B = 8.70, p < 0.05). CONCLUSIONS: In our sample, men reported higher rates of habitual tobacco use than women. Smoking was associated with cognitive impairment and with less pain-related impairment among men. Future smoking cessation treatments tailored to PLWH who have symptoms of depression may benefit from strategies that consider pain management as a pathway to habitual smoking and recognize that motivations for use may differ by gender.

Heterotrimeric Gα12/13 proteins in kidney injury and disease.

Gα12 and Gα13 are ubiquitous members of the heterotrimeric guanine nucleotide-binding protein (G protein) family that play central and integrative roles in the regulation of signal transduction cascades within various cell types in the kidney. Gα12/Gα13 proteins enable the kidney to adapt to an ever-changing environment by transducing stimuli from cell surface receptors and accessory proteins to effector systems. Therefore, perturbations in Gα12/Gα13 levels or their activity can contribute to the pathogenesis of various renal diseases, including renal cancer. This review will highlight and discuss the complex and expanding roles of Gα12/Gα13 proteins on distinct renal pathologies, with emphasis on more recently reported findings. Deciphering how the different Gα12/Gα13 interaction networks participate in the onset and development of renal diseases may lead to the discovery of new therapeutic strategies.

Examining a Syndemics Network Among Young Latino Men Who Have Sex with Men.

BACKGROUND: Although studies consistently find that syndemic indicators are additively associated with increased HIV/STI risk behavior (e.g., condomless anal sex; CAS) among men who have sex with men (MSM), information is lacking about how syndemic indicators are associated with each other. Young Latino MSM are one of the most at-risk groups for acquiring HIV in the U.S. Understanding the associations of syndemic indicators with each other and with CAS may improve understanding of how to enhance sexual and behavioral health in this population. METHOD: Network analysis using the graphical LASSO (glasso) algorithm was employed to explore associations between CAS and syndemic indicators among 139 young Latino MSM. Structural and psychosocial syndemic indicators were assessed via self-report. CAS was defined as the number of partners in the past 3 months with whom one engaged in CAS. RESULTS: Results of the network analysis suggested the variables with the highest centrality were unstable housing, prison history, childhood sexual abuse, and CAS. Specific significant associations included links between CAS and alcohol use (b = 0.40), childhood sexual abuse and unstable housing (b = - 0.75), alcohol use and childhood sexual abuse (b = 0.40), and substance use and intimate partner violence (b = 0.43). CONCLUSION: This pattern of interconnectedness demonstrates the potential for network analysis to examine nuanced interrelationships of syndemic indicators. The specific associations in this sample raise the question whether a primary focus of interventions should address the more central syndemic indicators for this population, such as alcohol use and unstable housing, and whether this would, via downstream effects, affect other aspects of behavioral health in this population.

Pathways to Health: an Examination of HIV-Related Stigma, Life Stressors, Depression, and Substance Use.

BACKGROUND: Despite antiretroviral treatment (ART) being an efficacious treatment for HIV, essentially making it a chronic non-terminal illness, two related and frequent concerns for many people living with HIV/AIDS (PLWHA) continue to be HIV-related stigma and life stress. These two variables are frequently associated with depression, substance use, and poorer functional health. Studies to date have not fully examined the degree to which these constructs may be associated within one model, which could reveal a more nuanced understanding of how HIV-related stigma and life stress affect functional health in PLWHA. METHODS: The current study employed hybrid structural equation modeling to examine the interconnectedness and potential indirect relationships of HIV-related stigma and life stress to worse health through substance use and depression, controlling for ART adherence and age. Participants were 240 HIV-infected individuals who completed a biopsychosocial assessment battery upon screening for an RCT on treating depression in those infected with HIV. RESULTS: Both HIV-related stigma and stressful life events were directly related to depression, and depression was directly related to health. There were significant indirect effects from stigma and stress to health via depression. There were no significant effects involving substance use. CONCLUSION: It is important to continue to develop ways to address stigma, stressful life events, and their effects on distress in those living with HIV. Expanding our knowledge of disease progression risk factors beyond ART adherence is important to be able to design adjuvant interventions, particularly because treatment means that people living with HIV have markedly improved life expectancy and that successful treatment means that HIV is not transmittable to others.

Openness to adopting evidence-based practice in public substance use treatment in South Africa using task shifting: Caseload size matters.

BACKGROUND: In response to the lack of coverage for substance use treatment in the Western Cape province of South Africa, the local government expanded funding for evidence-based practices (EBPs) for treating substance use. Yet, little is known about provider and staff attitudes towards adopting EBPs in this setting, which is particularly relevant in this context where task shifting clinical care increases demands on paraprofessional providers. This study aimed to (1) assess attitudes towards adopting EBPs among a range of staff working in substance use treatment in Cape Town using a task shifting model; and (2) evaluate factors associated with openness towards adopting EBPs in this setting. METHODS: Staff (n = 87) were recruited from 11 substance use treatment clinics. Demographics and job-related characteristics were assessed. Staff perceptions of organizational factors were assessed using the TCU Organizational Readiness for Change (ORC) scale. The dependent variable, attitudes towards adopting EBPs, was assessed using the Evidence-Based Practice Attitude Scale (EBPAS). RESULTS: This study is one of the first to administer the EBPAS in South Africa and found good internal consistency (total score: α = .82). In a multivariable model adjusting for site and factors associated with EBPAS total score at the bivariate level, only smaller caseload size was associated with greater openness to adopting EBPs (B = 1.61, SE = .73; t = 2.21; p<.05). CONCLUSIONS: As pressure to scale up implementation of EBPs in South African substance use treatment services intensifies, additional efforts are needed to understand barriers to adopt EBPs in this setting. Supporting staff adoption of EBPs in resource-limited settings may require additional resources to limit staff caseloads in the context of task shifting.