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Background: The aging Mexican American (MA) population is the fastest growing ethnic minority group in the US. MAs have a unique metabolic-related risk for Alzheimer’s disease (AD) and mild cognitive impairment (MCI), compared to non-Hispanic whites (NHW). This risk for cognitive impairment (CI) is multifactorial involving genetics, environmental, and lifestyle factors. Changes in environment and lifestyle can alter patterns and even possibly reverse derangement of DNA methylation (a form of epigenetic regulation). Objective: We sought to identify ethnicity-specific DNA methylation profiles that may be associated with CI in MAs and NHWs. Methods: DNA obtained from peripheral blood of 551 participants from the Texas Alzheimer’s Research and Care Consortium was typed on the Illumina Infinium® MethylationEPIC chip array, which assesses over 850K CpG genomic sites. Within each ethnic group (N = 299 MAs, N = 252 NHWs), participants were stratified by cognitive status (control versus CI). Beta values, representing relative degree of methylation, were normalized using the Beta MIxture Quantile dilation method and assessed for differential methylation using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. Results: Two differentially methylated sites were significant: cg13135255 (MAs) and cg27002303 (NHWs) based on an FDR p

Youth living with perinatally acquired HIV (YLPHIV) have been found to have a range of mental disorders. Some adult HIV studies have linked mental health to adverse metabolic outcomes due to dysregulation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, but this association has not previously been explored in YLPHIV.We investigated the association of mental health measures with metabolic outcomes in YLPHIV and HIV-uninfected youth (HIV-U) and linear regression was used to assess the adjusted associations.Overall, 203 YLPHIV (median age = 10.7years; 52% female; mean duration on ART 8 years, 12% CD4 count 50 copies/mL) and 44 HIV-U (median age = 10.3 years; 55% female) were enrolled. YLPHIV had higher median total cholesterol (4.2 vs 3.9 mmol/L, p = 0.049) and triglyceride (0.9 vs 0.7 mmol/L, p < 0.001) compared to HIV-U. We found higher percentage of poor functional competence (40% vs 25%, p = 0.02) and self-concept (23% vs 9%, p = 0.03) and higher depression (6% vs 2%, p < 0.01), anger (6% vs 2%, p = 0.04) and disruptive behaviour (4% vs 0%, p < 0.01) in YLPHIV as compared to HIV-U. Among YLPHIV, higher scores of anger were associated with higher total cholesterol and higher low-density lipoprotein (s = 0.010, p = 0.041 and s = 0.012, p = 0.048 respectively) and disruptive behaviour with higher low-density lipoprotein (s = 0.010, p = 0.043) after adjusting for age, sex and BMIZ.This is the one of first study to investigate the association of mental health with metabolic outcomes among YLPHIV. The association of increased anger and disruptive behaviour with increased lipid concentration is a novel finding. Further longitudinal studies are needed to evaluate the causal relationships between mental health and metabolic outcomes.

Introduction: The placenta, a metabolically active tissue, forms a critical interface between the developing fetus and mother. Stressors such as oxidative stress contribute to placental inflammation, cell death, and release of proinflammatory factors into the maternal circulation. Extracellular mitochondrial DNA (mtDNA) is a proinflammatory factor that can be found in blood circulation in response to cellular stress. Circulating cell-free mtDNA increases during healthy pregnancy and is dysregulated in pregnancies with preeclampsia. Mechanisms underlying the release of mtDNA into circulation from the placenta remain unclear. The objective of this study is to elucidate the relationship between oxidative stress, cell death, and the release of mtDNA from the placenta. We hypothesized that human placental cells exposed to oxidative stressors release mtDNA into the extracellular space via cell death-dependent mechanisms. Methods: BeWo cells (ATCC® CCL-98), a model of placental trophoblast, were treated with the oxidative stressors, rotenone (0.8, 5, 10, 25, 50 μM) or antimycin A (10, 50, 100, 320 μM) and their respective vehicles for 4 hours. Supernatants were collected and the following experiments were performed: absolute real-time qPCR quantification with TaqMan™ probes and chemistry to quantify intracellular and extracellular mtDNA (amplification target: MT-ND5gene) and nuclear DNA (nDNA), assays to measure reactive oxygen species, flow cytometry to assess cell death mechanisms. Results: Exposure of placental cells to antimycin A induced the release of mtDNA (p NIH R01 HL146562, AHA 22PRE-900431, AHA 22POST-903250, NIH T32 AG 020494 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and

Purpose of the review By reviewing the most recent common mental health disorders (CMHD) studies in people living with HIV (PLWH) (2018-2020), this review discusses the prevalence of CMHD, factors associated with CMHD in PLWH, mental health in PLWH from vulnerable groups, the impact of CMHD on HIV disease progression and adherence to antiretroviral therapy and the efficacy of different treatment approaches. Recent findings After screening for eligibility 142 studies were included in the final systematic review. Only 27% of studies were conducted in Sub-Saharan Africa, which carries the highest burn of HIV disease globally. Despite the well-established increased risk of CMHD in PLWH, the current prevalence remains high, with studies reporting 28%-62% of PLWH having mental health symptoms. Conclusion Despite the significant challenges that CMHDs present to successful HIV treatment, there are many mental health treatments and interventions which can improve outcomes in PLWH and opportunities to task-shift and integrate mental health care with HIV care. Supplementary Information The online version contains supplementary material available at 10.1007/s11904-021-00583-w.

Background: Age-related comorbidity is common and significantly increases the burden for the healthcare of the elderly. Alzheimer’s disease (AD) and hypertension are the two most prevalent age-related conditions and are highly comorbid. While hypertension is a risk factor for vascular dementia (VD), hypertension with AD (ADHyp+) is often characterized as probable vascular dementia. In the absence of imaging and other diagnostic tests, differentiating the two pathological states is difficult. Objective: Our goals are to (1) identify differences in CSF-based vascular dementia profiles, if any, between individuals who have AD only (ADHyp-), and individuals with ADHyp+ using CSF levels of amyloid β, tau and p-tau, and (2) compare genome-wide DNA profiles of ADHyp- and ADHyp+ with an unaffected control population. Method: Genotype and clinical data were used to compare healthy controls to AD Hyp- vs. AD Hyp+. We compared the CSF biomarkers followed by evaluating genome wide profiles in three groups, and mapped SNPs to genes based on position and lowest p-value. The significant genes were examined for co-expression and known disease networks. Results: We found no differences between Aβ, tau and p-tau levels between ADHyp- and ADHyp+. We found TOMM40 to be associated with ADHyp- as expected but not with ADHyp+. Interestingly, SLC9A3R2 polymorphism was associated with ADHyp+, and significant gene expression changes were observed for neighboring genes. Conclusion: Through this exploratory study using a novel cohort stratification design, we highlight the genetic differences in clinically similar phenotypes, indicating the utility of genetic profiling in aiding differential diagnosis of ADHyp+ and VD.

The relationship between cognitive performance, macro and microstructural brain anatomy and accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock in healthy adolescents has not been studied. Healthy adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort Study were studied cross sectionally. The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 44 adolescents aged 9 to 12 years old. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration residual (AAR) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent neurocognitive testing, T1 structural magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI). Correlation tests were run between the two epigenetic aging measures and 10 cognitive functioning domains, to assess for differences in cognitive performance as epigenetic aging increases. In order to investigate the associations of epigenetic age acceleration on brain structure, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, and cortical surface area, as well as DTI measures of white matter microstructural integrity. In addition to negatively affecting two cognitive domains, visual memory (p = .026) and visual spatial acuity (p = .02), epigenetic age acceleration was associated with alterations of brain volumes, cortical thickness, cortical surface areas and abnormalities in neuronal microstructure in a range of regions. Stress was a significant predictor (p = .029) of AAR. Understanding the drivers of epigenetic age acceleration in adolescents could lead to valuable insights into the development of neurocognitive impairment in adolescents.

To investigate the association between neurocognitive impairment, neuroimaging, and systemic inflammation in perinatally infected adolescents living with HIV (PHIV) on antiretroviral therapy (ART). Systemic inflammation may be one mechanism driving neurocognitive impairment despite ART, but this has not been investigated in adolescence when the brain is undergoing rapid development.Cape Town, South Africa.Baseline data were drawn from the Cape Town Adolescent Antiretroviral Cohort. PHIV on ART6 months completed a comprehensive neurocognitive test battery. Diffusion tensor imaging and structural brain magnetic resonance imaging was done to determine whole brain fractional anisotropy, mean diffusion (MD), grey and white matter volumes, and cortical thickness. We examined how neurocognitive and neurostructural measures were associated with a concurrently measured marker of systemic inflammation, high-sensitive C-reactive protein (hs-CRP).One hundred sixty-eight PHIV ages 9-12 years (mean CD4 980 cells/µL; 85.3% viral load50 copies/mL) and 43 controls were included in the analysis. PHIV had similar hs-CRP (P = 0.17) to controls, after participants with hs-CRP10 were excluded from the analysis. Forty-eight percent of the PHIV in this analysis have a neurocognitive disorder. Whole brain grey (P = 0.049) and white matter volumes (P = 0.044) were lowest in PHIV with a major neurocognitive disorder. Higher MD, was found in PHIV with a major neurocognitive disorder (P = 0.002). Among PHIV with a neurocognitive disorder, hs-CRP negatively correlated with general intelligence, visual spatial acuity, and executive function (all P =0.05). Whole brain MD correlated with higher hs-CRP values (P =0.01) in PHIV.A marker of systemic inflammation was associated with both neurocognitive impairment and MD increases in PHIV.

We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01years) of the participants was higher than their mean chronological age (10.77years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+ .

Religious institutions have been responsive to the needs of Black men and other marginalized populations. Religious service attendance is a common practice that has been associated with stress management and extended longevity. The objective of this study was to examine the relationship between religious service attendance and all-cause mortality among Black men 50 years of age and older. Data for this study were from NHANES III (1988–1994). The analytic sample (n = 839) was restricted to participants at least 50 years of age at the time of interview who self-identified as Black and male. Mortality was the primary outcome for this study and the NHANES III Linked Mortality File was used to estimate race-specific, non-injury-related death rates using a probabilistic matching algorithm, linked to the National Death Index through December 31, 2015, providing up to 27 years follow-up. The primary independent variable was religious service attendance, a categorical variable indicating that participants attended religious services at least weekly, three or fewer times per month, or not at all. The mean age of participants was 63.6±0.3 years and 36.4% of sample members reported that they attended religious services one or more times per week, exceeding those attending three or fewer times per month (31.7%), or not at all (31.9%). Cox proportional hazard logistic regression models were estimated to determine the association between religious service attendance and mortality. Participants with the most frequent religious service attendance had a 47% reduction of all-cause mortality risk compared their peer who did not attend religious services at all (HR 0.53, CI 0.35–0.79) in the fully adjusted model including socioeconomic status, non-cardiovascular medical conditions, health behaviors, social support and allostatic load. Our findings underscore the potential salience of religiosity and spirituality for health in Black men, an understudied group where elevated risk factors are often present.

Alcohol use, presents unique challenges for HIV-1 treatment in adolescents with perinatally acquired infection. The effects of alcohol on host–virus interaction in the brain and the immune system remains understudied in this population. Adolescents with perinatally acquired HIV infection (PHIV) well established on ART, from the Cape Town Adolescent Antiretroviral Cohort who self-reported alcohol use (PHIV + alcohol) (n = 26) were compared to age matched 26 PHIV (PHIV-alcohol) and 26 healthy controls (HC) who reported no use of alcohol. Participants completed clinical investigations including highly-sensitive CRP (hs-CRP), a comprehensive neurocognitive test battery and mental health measures. In addition, we investigated the relationship between alcohol use in PHIV and diffusion tensor imaging (DTI) and structural brain magnetic resonance imaging (MRI) to determine fractional anisotropy (FA), mean diffusivity (MD), grey and white matter volumes and cortical thickness. PHIV (mean age 12,5 years; mean age of ART initiation 3.15 years) reported an occasional weekend drinking pattern of alcohol use. hs-CRP was significantly different between groups, with PHIV + alcohol higher than PHIV-alcohol and HC. General intelligence, attention, working memory, processing speed and executive function were more impaired in the PHIV + alcohol than PHIV alone, with HC having the highest scores. In addition, self-concept was significantly lower in PHIV + alcohol. The Child Behavior Checklist (CBCL) Externalizing behaviour, internalising behaviour and CBCL Total problems were significantly higher in PHIV + alcohol. FA of the superior corona radiata, superior fronto-occipital fasciculus and corpus callosum was significantly lower in PHIV + alcohol compared to PHIV-alcohol and MD of the corona radiata was significantly increased in PHIV + alcohol. The cortical thickness of the lateral orbitofrontal, middle frontal and precentral gyri were significantly lower in PHIV + alcohol compared to PHIV-alcohol and HC. In conclusion PHIV associated impairments in systemic inflammation, cognitive function, mental health and changes in brain structure may be exacerbated by alcohol use, even if only occasional use. However, the study is cross-sectional, which is not able to distinguish between cause and effect.

Context Perinatal HIV infection has adverse cognitive consequences into adolescence. However, there are no screening tools that assess risk for HIV-associated neurocognitive disorders in adolescent populations. Such screening tools are needed urgently for clinical care in resource-poor settings with a high prevalence of HIV. Objective To investigate the performance of the International HIV Dementia Scale (IHDS) as a screening tool for HIV-associated neurocognitive disorders in perinatally adolescents. Design The current study is a quantitative, quasiexperimental design. Methods Perinatally HIV-infected adolescents aged 9-12 years were recruited from community health clinics into the Cape Town Adolescent Antiretroviral Cohort; matched HIV-negative controls from the same communities were enrolled. Each participant completed the IHDS and a comprehensive neuropsychological battery. The adult version of the IHDS was performed, except for two minor modifications. We evaluated the diagnostic validity of this modified instrument, the youth-IHDS (y-IHDS), using a four-step process that included sensitivity and specificity calculations, and generating receiver operating characteristic curves. Validity was measured against the youth HIV-associated diagnostic criteria. Results At a cut-off score of 10 or less, the y-IHDS demonstrated good sensitivity (94%) but poor specificity (24%) for detecting all forms of neurocognitive disorders, with an acceptable area under the curve value of 0.695. Conclusion The y-IHDS requires minimal resources and is based on a screening tool for adult HIV-associated cognitive disorders that is already widely used globally. Hence, this brief, cost-efficient, and valid screening tool may be a useful addition for clinicians working in resource-poor contexts in which adolescent HIV is highly prevalent.

The effect of chronic HIV-infection on psychological adjustment, including the impact of HIV-related stigma in perinatally HIV-infected (PHIV+) youth across Africa is largely unknown. This study examined psychological adjustment and HIV-related stigma using the Strengths and Difficulties Questionnaire (SDQ) and a 10-item stigma questionnaire in a cohort of PHIV+ youth in Cape Town, South Africa. The relationships between SDQ scores, elevated viral load, and suboptimal antiretroviral therapy (ART) adherence were also explored. Among 473 PHIV+ youth (aged 9–14 years, on ART > 6 months at enrollment), higher perceived HIV-related stigma was associated with higher scores across all adolescent and caregiver-reported SDQ difficulty subscales. Higher socioeconomic status (SES) was associated with lower scores on adolescent self- and caregiver-reported hyperactivity subscales. Higher adolescent-reported prosocial scores were associated with lower odds of self-reported suboptimal ART adherence, and higher caregiver-reported conduct scores were associated with higher odds of elevated viral load. No associations were observed between perceived HIV-related stigma and treatment outcomes. These findings highlight the potentially detrimental impact of perceived stigma on psychological adjustment in PHIV+ youth. The use of psychosocial metrics and interventions aimed at reducing illness related stigma in PHIV+ youth is also considered.

The high variability characteristic of short tandem repeat (STR) markers is harnessed for human identification in forensic genetic analyses. Despite the power and reliability of current typing techniques, sequence-level information both within and around STRs are masked in the length-based profiles generated. Forensic STR typing using next generation sequencing (NGS) has therefore gained attention as an alternative to traditional capillary electrophoresis (CE) approaches. In this proof-of-principle study, we evaluate the forensic applicability of the newest and smallest NGS platform available – the Oxford Nanopore Technologies (ONT) MinION device. Although nanopore sequencing on the handheld MinION offers numerous advantages, including on-site sample processing, the relatively high error rate and lack of forensic-specific analysis software has prevented accurate profiling across STR panels in previous studies. Here we present STRspy, a streamlined method capable of producing length- and sequence-based STR allele designations from noisy, long-read data. To demonstrate the capabilities of STRspy, seven reference samples (female: n = 2; male: n = 5) were amplified at 15 and 30 PCR cycles using the Promega PowerSeq 46GY System and sequenced on the ONT MinION device in triplicate. Basecalled reads were processed with STRspy using a custom database containing alleles reported in the STRSeq BioProject NIST 1036 dataset. Resultant STR allele designations and flanking region single nucleotide polymorphism (SNP) calls were compared to the manufacturer-validated genotypes for each sample. STRspy generated robust and reliable genotypes across all autosomal STR loci amplified with 30 PCR cycles, achieving 100% concordance based on both length and sequence. Furthermore, we were able to identify flanking region SNPs with >90% accuracy. These results demonstrate that nanopore sequencing platforms are capable of revealing additional variation in and around STR loci depending on read coverage. As the first long-read platform-specific method to successfully profile the entire panel of autosomal STRs amplified by a commercially available multiplex, STRspy significantly increases the feasibility of nanopore sequencing in forensic applications.

The high variability characteristic of short tandem repeat (STR) markers is harnessed for human identification in forensic genetic analyses. Despite the power and reliability of current typing techniques, sequence-level information both within and around STRs are masked in the length-based profiles generated. Forensic STR typing using next generation sequencing (NGS) has therefore gained attention as an alternative to traditional capillary electrophoresis (CE) approaches. In this proof-of-principle study, we evaluate the forensic applicability of the newest and smallest NGS platform available – the Oxford Nanopore Technologies (ONT) MinION device. Although nanopore sequencing on the handheld MinION offers numerous advantages, including low startup cost and on-site sample processing, the relatively high error rate and lack of forensic-specific analysis software has prevented accurate profiling across STR panels in previous studies. Here we present STRspy, a streamlined method capable of producing length- and sequence-based STR allele designations from noisy, error-prone third generation sequencing reads. To assess the capabilities of STRspy, seven reference samples (female: n = 2; male: n = 5) were amplified at 15 and 30 PCR cycles using the Promega PowerSeq 46GY System and sequenced on the ONT MinION device in triplicate. Basecalled reads were then processed with STRspy using a custom database containing alleles reported in the STRSeq BioProject NIST 1036 dataset. Resultant STR allele designations and flanking region single nucleotide polymorphism (SNP) calls were compared to the manufacturer-validated genotypes for each sample. STRspy generated robust and reliable genotypes across all autosomal STR loci amplified with 30 PCR cycles, achieving 100% concordance based on both length and sequence. Furthermore, we were able to identify flanking region SNPs in the 15-cycle dataset with > 90% accuracy. These results demonstrate that when analyzed with STRspy ONT reads can reveal additional variation in and around STR loci depending on read coverage. As the first and only third generation sequencing platform-specific method to successfully profile the entire panel of autosomal STRs amplified by a commercially available multiplex, STRspy significantly increases the feasibility of nanopore sequencing in forensic applications.

This study aimed to assess the association of childhood trauma, stressful life events and HIV stigma with mental health in South African adolescents from the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Childhood Trauma Questionnaire, Life Events Questionnaire and the HIV Stigma Scale for South African Adolescents Living with HIV was used to assess childhood trauma, stressful life events and stigma in adolescents living with perinatally acquired HIV and healthy controls enrolled in the CTAAC. These measures were associated with mental health outcomes including the Beck-Youth Inventories, Child Behaviour Checklist, Columbian Impairment Scale, Childrens Motivation Scale, Conners Scale for Attention Deficit Hyperactivity Disorder using Pearson correlations and self-reported alcohol use, using Spearman-rank correlation. 63.7% of adolescents reported at least one childhood trauma on the CTQ. Significant associations were reported between CTQ measures and Beck-Youth Inventories. Emotional abuse was associated with anxiety, anger, depression and disruptive behaviour. Emotional neglect was associated with poor self-concept and disruptive behaviour. LEQ total score was significantly associated with Beck-Youth Inventories including anxiety, depression, anger and disruptive behaviour scales. HIV stigma was significantly associated with Beck-Youth Inventories including depression, anger and disruptive behaviour. Childhood trauma, stressful life events and HIV stigma in South African adolescents are associated with anxiety, depression, anger, disruptive-behaviour and poor self-concept. This study highlights the importance of enquiring about exposure to a variety of traumas, particularly those commonly experienced by South African adolescents. In addition, it is important to understand the impact of trauma exposure on each individuals mental health and functioning.

Background The COVID-19 pandemic has caused unprecedented global demand for personal protective equipment (PPE). A paucity of data on PPE burn rate (PPE consumption over time) in pandemic situations exacerbated these issues as there was little historic research to indicate volumes of PPE required to care for surges in infective patients and thus plan procurement requirements. Methods To better understand PPE requirements for care of suspected or confirmed COVID-19 patients in our Australian quaternary referral hospital, the number of staff-to-patient interactions in a 24-h period for three patient groups (ward-based COVID suspect, ward-based COVID confirmed, intensive care COVID confirmed) was audited prospectively from 1st to 30th April 2020. Results The average number of staff-to-patient interactions in a 24-h period was: 13.1 ± 5.0 (mean ± SD) for stable ward-managed COVID-19 suspect patients; 11.9 ± 3.8 for stable ward-managed confirmed COVID-19 patients; and 30.0 ± 5.3 for stable, mechanically ventilated, ICU-managed COVID-19 patients. This data can be used in PPE demand simulation modelling for COVID-19 and potentially other respiratory illnesses. Conclusion Data on the average number of staff-to-patient interactions needed for the care of COVID-19 patients is presented. This data can be used for PPE demand simulation modelling.

HIV-associated functional impairment may cause cognitive impairment secondary to the viral infection, hence, associations between cognitive impairment and functional impairment in youth living with HIV are important to assess. We sought to determine whether cognitive impairment is associated with functional impairment and if it carries higher risk for also having functional impairment. We collected parent-rated information regarding youth functional impairment on four different measures and administered a cognitive battery to youth to determine cognitive impairment, 203 HIV-infected youth and 44 HIV-uninfected controls. Degree of cognitive impairment correlated strongly with decreased function: CBCL

Cell-free circulating mitochondrial DNA (CFCmtDNA) is a damage-associated molecular pattern (DAMP) that can activate Toll-like receptor 9 (TLR-9). The main objectives of this case-control study were 1) to determine absolute concentrations and immunostimulatory capacity of CFCmtDNA, in membrane-bound and -unbound states, in cases with preeclampsia and healthy controls and 2) to implement a bootstrapped penalized regression analysis to establish the contribution of CFCmtDNA to preeclampsia diagnosis and its interaction with commonly collected patient characteristics. To determine the contribution of membrane-bound and -unbound CFCmtDNA in preeclampsia, DNA from plasma samples was exctracted with lysis buffer (membrane-unbound) and without lysis buffer (membrane-bound). CFCmtDNA, quantified using absolute PCR quantification protocol, was reduced in preeclampsia compared to healthy controls (P≤0.02). While the pattern of reduced CFCmtDNA in preeclampsia was similar between methods of DNA extraction, DNA isolation with membrane lysis buffer resulted in 1,000-fold higher CFCmtDNA quantification in the preeclampsia group (P=0.0014) and 430-fold higher CFCmtDNA quantification in the control group (PTLR-9. Penalized regression analysis showed that women with preeclampsia are strongly likely to have high concentrations of nDNA and DNase I along with a prior history of preeclampsia. Low concentrations of CFCmtDNA and mode of delivery were also associated with preeclampsia. In conclusion, our data demonstrate increases in the immunostimulatory potential of CFCmtDNA and upregulation of DNA degradation mechanisms in women with preeclampsia at the third trimester.

Could we have predicted that the second deadliest pandemic encountered since the influenza pandemic of 1918 would result in the highest mortality and adverse health outcomes among minority and underserved populations in the United States? Given the abundant evidence documenting the disproportionately high burden of preventable disease, disability, and injury among these underserved groups, our answer should echo a resounding ‘yes’.

Objective Childhood adversity (e.g., abuse/neglect) negatively affects neurocognitive functioning among people living with HIV (PLWH). However, less is known about this relationship among youth with perinatally-acquired HIV (PHIV) in low-and-middle-income countries, such as South Africa, many whom experience tremendous adversity in addition to living with a chronic, highly stigmatized disease. This study examined associations between adversity and neurocognitive functioning among South African adolescents (14–17 years) with PHIV. Method 72 adolescents with PHIV (Mage = 15.63 years; 52.8% female) recruited from HIV clinics in Cape Town, South Africa completed the Adverse Childhood Experiences (ACE) scale and a tablet-based neurocognitive assessment. Controlling for age and sex, multiple regressions tested associations between ACE scores and processing speed, working memory, and executive functioning tests. T-tests assessed differences between participants exposed to high (≥2 ACEs) versus low (0–1 ACEs) adversity. Results Adjusting for covariates, ACE scores predicted performance on tests of processing speed (Trail Making 1: B = 5.87, p = 0.001; Visual Discrimination 1: B = -1.01, p = 0.02; Visual Discrimination 2: B = -1.55, p = 0.002; Number Speed; B = 2.15, p = 0.02) and executive functioning (Inhibition errors: B = 1.27, p = 0.03), explaining 10–19% of variance in test scores. Significant differences between the high and low adversity groups on processing speed and executive functioning tests represented medium-to-large effects (d range = 0.51–1.11; Table 1). Conclusions Childhood adversity predicts poorer neurocognitive functioning among youth with PHIV, specifically worse processing speed and executive functions – known drivers of functional outcomes among PLWH. Elucidating mechanisms by which adversity impacts neurocognitive functioning is critical to identify therapeutic targets and inform interventions to support neurocognitive health in PLWH across the lifespan.

Adjudicating business and commercial disputes often requires judges to interpret complex and intersecting specialized bodies of law. In the United States, for example, such disputes often involve intersecting provisions of the Uniform Commercial Code (“UCC”) and the Bankruptcy Code. Given human limitations, courts sometimes err in deciding these disputes. This essay presents conspicuous examples of these errors, focusing on the UCC and the Bankruptcy Code. The essay also cautions parties to be aware of this heightened potential for judicial error and suggests a possible remedy: to further develop specialized business courts, which should be able to adjudicate these types of disputes much better than general jurisdiction courts.

Larvae of marine organisms play an important role in the dynamics of populations, are generally sensitive to environmental stressors, and vary dramatically among species in life history traits. We examined the effects of suspended sediments from terrestrial runoff on larval development, survival, and settlement of New Zealand sea urchins Evechinus chloroticus and abalone Haliotis iris. Larval urchins and abalone were reared under 5 suspended sediment regimes (variable concentrations and timing of exposure, benchmarked against nearby field conditions), and in the absence of sediments. Stage specific per capita mortality rates of urchin larvae increased with concentrations of suspended sediments, and generally, these rates (and the sensitivity of urchin larvae to sediments) decreased with age. Mortality rates of abalone similarly increased in response to sediment concentrations, although older larvae continued to incur high losses when exposed to sediments. Mortality rates of both abalone and urchins increased in response to acute exposure to sediments early in development. For urchins, this effect was immediate and coincident only with exposure to sediments, whereas elevated mortality rates persisted well after the removal of sediments for abalone. Cumulative survival to competency was similar among species and generally decreased with exposure time and/or concentration of sediments. Urchins were twice as likely to settle and metamorphose as abalone but patterns were not related to larval sediment regime for either species. The strong species specific responses to suspended sediments we observe may greatly alter patterns of larval connectivity in marine meta-communities. © Inter-Research 2006.

Coronavirus disease 2019 (COVID-19) accounts for over 180,000 deaths in the USA. Although COVID-19 affects all racial ethnicities, non-Hispanic Blacks have the highest mortality rates. Evidence continues to emerge, linking the disproportion of contagion and mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a result of adverse social determinants of health. Yet, genetic predisposition may also play a credible role in disease transmission. SARS-CoV-2 enters cells by interaction between SARS-CoV-2 spike protein and the receptor molecule angiotensin converting enzyme 2 (ACE2) expressed on the surface of the target cells, such that polymorphisms and the expression level of ACE2 influence infectivity and consequent pathogenesis of SARS-CoV-2. Genetic polymorphisms in other multiple genes, such as acetylcholinesterase (AChE) and interleukin-6, are also closely associated with underlying diseases, such as hypertension and type 2 diabetes mellitus, which substantially raise SARS-CoV-2 mortality. However, it is unknown how these genetic polymorphisms contribute to the disparate mortality rates, with or without underlying diseases. Of particular interest is the potential that genetic polymorphisms in these genes may be influencing the disparity of COVID-19 mortality rates in Black communities. Here, we review the evidence that biological predisposition for high-risk comorbid conditions may be relevant to our ability to fully understand and therefore address health disparities of COVID-19 deaths in Blacks. Electronic supplementary material The online version of this article (10.1007/s40615-020-00871-y) contains supplementary material, which is available to authorized users.

The purpose of this study was to assess the effectiveness of regulations and behavioral interventions on head impacts and concussions in youth, high-school, and collegiate football, using a systematic search strategy to identify relevant literature. Six databases were searched using key search terms related to three categories: football, head-injuries, and interventions. Studies that met inclusion criteria were included in the study and underwent data extraction. Twenty articles met inclusion criteria and were included in the final systematized review. Of the 20 included studies, 8 studies evaluated interventions in high-school football, 5 studies evaluated interventions in collegiate football, 6 studies evaluated interventions in youth football, and 1 study evaluated interventions in both, high-school and collegiate football. The four categories of interventions and regulations included rule changes, training, education/instruction/coaching tactical changes, and tackle football alternatives. Studies evaluating the effectiveness of interventions and regulations on reducing head impact exposures or head injuries have shown mixed results. Some regulations may be more effective than others, but methodological design and risk of bias pose limitations to generalize effects.

Ancestry informative single nucleotide polymorphisms (SNPs) can identify biogeographic ancestry (BGA); however, population substructure and relatively recent admixture can make differentiation difficult in heterogeneous Hispanic populations. Utilizing unrelated individuals from the Genomic Origins and Admixture in Latinos dataset (GOAL, n = 160), we designed an 80 SNP panel (Setser80) that accurately depicts BGA through STRUCTURE and PCA. We compared our Setser80 to the Seldin and Kidd panels via resampling simulations, which models data based on allele frequencies. We incorporated Admixed American 1000 Genomes populations (1000 G, n = 347), into a combined populations dataset to determine robustness. Using multinomial logistic regression (MLR), we compared the 3 panels on the combined dataset and found overall MLR classification accuracies: 93.2% Setser80, 87.9% Seldin panel, 71.4% Kidd panel. Naïve Bayesian classification had similar results on the combined dataset: 91.5% Setser80, 84.7% Seldin panel, 71.1% Kidd panel. Although Peru and Mexico were absent from panel design, we achieved high classification accuracy on the combined populations for Peru (MLR = 100%, naïve Bayes = 98%), and Mexico (MLR = 90%, naïve Bayes = 83.4%) as evidence of the portability of the Setser80. Our results indicate the Setser80 SNP panel can reliably classify BGA for individuals of presumed Hispanic origin.

Rapid maturation of major white matter pathways occurs in the first 2 years of life, indicating a critical neuronal developmental period. The impact of initiating antiretroviral therapy (ART) in children perinatally infected with HIV-1, after the age of 2 years on neurocognitive functioning and white matter development in adolescence has not been studied. Forty-six adolescents who initiated ART during the first 2 years of life ( 2 years) and 79 adolescents who initiated ART after 2 years of age ( 2 years), with perinatally acquired HIV were enrolled in the Cape Town Adolescent Antiretroviral Cohort. Adolescents completed a comprehensive neurocognitive battery testing a number of cognitive domains. Diffusion tensor imaging (DTI) was done to determine fractional anisotropy (FA), mean diffusivity (MD), axial diffusion (AD), and radial diffusion (RD) in a region of interest analysis. Neurocognitive performance was similar between adolescents who initiated ART 2 years or 2 years. There was a trend towards attention (p = .07) and working memory (p = .05) being poorer in the group who initiated ART 2 years. FA was lower in the 2-year group in the superior corona radiata (p = .03), and the external capsule (p = .04). MD was higher in the 2-year group in the cerebral peduncle (p = .02), the superior corona radiata (p = .01), and the superior fronto-occipital fasciculus (p = .03). RD was higher in the 2-year group in the superior corona radiata (p = .02), the cerebral peduncle (p = .01), and the superior fronto-occipital fasciculus (p = .01). However, the higher AD in the 2-year group in the superior corona radiata was not in the expected direction (p = .01). Initiation of ART after the neuronal development period of the second postnatal year is associated with white matter alterations on neuroimaging.

Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and SNP-derived transcriptomic profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2 , and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which ( ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.

Background Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. Methods We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369). Results In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury. Conclusions We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual’s susceptibility to developing radiotoxicity.

Endothelin-1 (ET-1) is a vasoactive peptide that is elevated in aqueous humor as well as circulation of primary open angle glaucoma (POAG) patients. ET-1 has been shown to promote degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs), however, the precise mechanisms are still largely unknown. In this study, RNA-seq analysis was used to assess changes in ET-1 mediated gene expression in primary RGCs, which revealed that 23 out of 156 differentially expressed genes (DEGs) had known or predicted mitochondrial function, of which oxidative phosphorylation emerged as the top-most enriched pathway. ET-1 treatment significantly decreased protein expression of key mitochondrial genes including cytochrome C oxidase copper chaperone (COX17) and ATP Synthase, H+ transporting, Mitochondrial Fo Complex (ATP5H) in primary RGCs and in vivo following intravitreal ET-1 injection in rats. A Seahorse ATP rate assay revealed a significant decrease in the rate of mitochondrial ATP production following ET-1 treatment. IOP elevation in Brown Norway rats showed a trend towards decreased expression of ATP5H. Our results demonstrate that ET-1 produced a decrease in expression of vital components of mitochondrial electron transport chain, which compromise bioenergetics and suggest a mechanism by which ET-1 promotes neurodegeneration of RGCs in glaucoma.

Integrating pregnancy and HIV prevention services would make reproductive health care settings an optimal venue for the promotion and delivery of preexposure prophylaxis (PrEP) to cisgender women. However, these settings have been slow to adopt PrEP. Planned parenthood clinicians and leaders possess critical insight that can help accelerate PrEP implementation in reproductive health care settings and elements of the Consolidated Framework for Implementation Research (i.e., relative priority of the intervention to staff, implementation climate, available resources to implement the intervention, and staff access to knowledge and information about the intervention) can shed light on elements of Planned Parenthood’s inner setting that can facilitate PrEP implementation. In this study, individual 60-min interviews were conducted with clinical care team members (n = 10), leadership team members (n = 6), and center managers (n = 2) to explore their perspectives on PrEP implementation and associated training needs. Transcripts were transcribed verbatim and thematically analyzed. Despite having variable PrEP knowledge, participants (100% women, 61% non-Hispanic White) expressed positive attitudes toward implementing PrEP. Barriers and facilitators toward providing PrEP were reported at the structural, provider, and patient levels. Participants desired PrEP training that incorporated culturally competent patient-provider communication. Although participants identified ways that Planned Parenthood uniquely enabled PrEP implementation, barriers must be overcome to optimize promotion and delivery of PrEP to cisgender women.

Type 2 diabetes is a significant risk factor for developing Alzheimer's disease later in life, and particular populations have a disproportionate risk because of the high prevalence of type 2 diabetes. There are many overlapping pathologies, and teasing out the primary root cause, if one indeed exists, is very difficult. Here, we review (1) the key facets of mitochondrial biology that are relevant to the two conditions, and (2) the role that mitochondrial dysfunction plays in the shared pathophysiology. We posit that mitochondrial dysfunction lies at the root of the affected processes rather than alongside them as a co-pathology.

OBJECTIVE: Recent studies demonstrate that infection with the Human Immunodeficiency Virus-1 (HIV) is associated with accelerated aging effects in adults according to a highly accurate epigenetic biomarker of aging known as epigenetic clock. However, it not yet known whether epigenetic age acceleration occurs as early as adolescence in perinatally HIV-infected (PHIV+) youth. DESIGN: Observational study of PHIV and HIV-uninfected adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC) Study. METHODS: The Illumina EPIC array was used to generate blood DNA methylation data from 204 PHIV and 44 age-matched, uninfected (HIV-) adolescents aged 9 to 12 years old. The epigenetic clock software and method was used to estimate two measures of epigenetic age acceleration. Each participant completed a comprehensive neuropsychological test battery upon enrolment to CTAAC. RESULTS: HIV is associated with biologically older blood in PHIV+ adolescents according to both measures of epigenetic age acceleration. One of the measures, extrinsic epigenetic age acceleration, is negatively correlated with measures of cognitive functioning (executive functioning, working memory, processing speed). CONCLUSIONS: Overall, our results indicate that epigenetic age acceleration in blood can be observed in PHIV+ adolescents and that these epigenetic changes accompany poorer cognitive functioning.

MDM2 is a key negative regulator of the p53 tumor suppressor. Direct binding of MDM2 to p53 represses the protein's transcriptional activity and induces its polyubiquitination, targeting it for degradation by the proteasome. Consequently, small molecule inhibitors that antagonize MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming to reactivate p53 function in TP53 wild-type tumors. Here, we describe the design, synthesis, and biological evaluation of a trans-cyclooctene tagged derivative of RG7388, RG7388-TCO, which showed high cellular potency and specificity for MDM2. The in-cell reaction of RG7388-TCO with a tetrazine-tagged BODIPY dye enabled fluorescence imaging of endogenous MDM2 in SJSA-1 and T778 tumor cells. RG7388-TCO was also used to pull down MDM2 by reaction with tetrazine-tagged agarose beads in SJSA-1 lysates. The data presented show that RG733-TCO enables precise imaging of MDM2 in cells and can permit a relative assessment of target engagement and MDM2-p53 antagonism in vitro.