Structural Determinants of Health and Markers of Immune Activation and Systemic Inflammation in Sexual Minority Men With and Without HIV.

Among sexual minority men (SMM), HIV and use of stimulants such as methamphetamine are linked with immune activation and systemic inflammation. Throughout the COVID-19 pandemic, SMM encountered financial challenges and structural obstacles that might have uniquely contributed to immune dysregulation and systemic inflammation, beyond the impacts of HIV and stimulant use. Between August 2020 and February 2022, 72 SMM with and without HIV residing in South Florida enrolled in a COVID-19 prospective cohort study. Multiple linear regression analyses examined unemployment, homelessness, and history of arrest as structural correlates of soluble markers of immune activation (i.e., sCD14 and sCD163) and inflammation (i.e., sTNF-α receptors I and II) at baseline after adjusting for HIV status, stimulant use, and recent SARS-CoV-2 infection. Enrolled participants were predominantly Latino (59%), gay-identified (85%), and with a mean age of 38 (SD, 12) years with approximately one-third (38%) of participants living with HIV. After adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use, unemployment independently predicted higher levels of sCD163 (ß = 0.24, p = 0.04) and sTNF-α receptor I (ß = 0.26, p = 0.02). Homelessness (ß = 0.25, p = 0.02) and history of arrest (ß = 0.24, p = 0.04) independently predicted higher levels of sCD14 after adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use. Independent associations exist between structural barriers and immune activation and systemic inflammation in SMM with and without HIV. Future longitudinal research should further elucidate complex bio-behavioral mechanisms linking structural factors with immune activation and inflammation.

Loneliness, Methamphetamine Use, and Cardiovascular Risk Factors Among Sexual Minority Men in the COVID-19 Era.

BACKGROUND: Important gaps exist in our understanding of loneliness and biobehavioral outcomes among sexual minority men (SMM), such as faster HIV disease progression. At the same time, SMM who use methamphetamine are approximately one-third more likely than non-users to develop cardiovascular disease. This study examined associations of loneliness, stimulant use, and cardiovascular risk in SMM with and without HIV. METHOD: Participants were enrolled from August 2020 to February 2022 in a 6-month prospective cohort study. The study leveraged self-report baseline data from 103 SMM, with a subset of 56 SMM that provided a blood sample to measure markers of cardiovascular risk. RESULTS: Loneliness showed negative bivariate associations with total cholesterol and LDL cholesterol in the cardiometabolic subsample (n = 56). SMM with methamphetamine use (t(101) = 2.03, p < .05; d = .42) and those that screened positive for a stimulant use disorder (t(101) = 2.07, p < .05; d = .46) had significantly higher mean loneliness scores. In linear regression analyses, negative associations of loneliness with LDL and total cholesterol were observed only among SMM who used methamphetamine. CONCLUSION: We observed lower cholesterol in SMM reporting loneliness and methamphetamine use. Thus, in addition to the observed associations of loneliness with cholesterol, there are important medical consequences of methamphetamine use including cardiovascular risk, higher HIV acquisition risk and progression, as well as stimulant overdose death. This cross-sectional study underscores the need for clinical research to develop and test interventions targeting loneliness among SMM with stimulant use disorders.

Overamped: Stimulant Use and HIV Pathogenesis.

PURPOSE OF REVIEW: In the era of HIV treatment as prevention (TasP), more clarity is needed regarding whether people with HIV who use stimulants (i.e., methamphetamine, powder cocaine, and crack cocaine) display elevated HIV viral load and greater immune dysregulation. RECENT FINDINGS: Although rates of viral suppression have improved in the TasP era, stimulant use was independently associated with elevated viral load in 23 of 28 studies included in our review. In the 12 studies examining other HIV disease markers, there was preliminary evidence for stimulant-associated alterations in gut-immune dysfunction and cellular immunity despite effective HIV treatment. Studies generally focused on documenting the direct associations of stimulant use with biomarkers of HIV pathogenesis without placing these in the context of social determinants of health. Stimulant use is a key barrier to optimizing the effectiveness of TasP. Elucidating the microbiome-gut-brain axis pathways whereby stimulants alter neuroimmune functioning could identify viable targets for pharmacotherapies for stimulant use disorders. Examining interpersonal, neighborhood, and structural determinants that could modify the associations of stimulant use with biomarkers of HIV pathogenesis is critical to guiding the development of comprehensive, multi-level interventions.

Classification of gastrointestinal symptom patterns in young adults.

BACKGROUND: The purpose of this study was to identify common gastrointestinal (GI) symptom groups using the Patient-Reported Outcomes Measurement Information System - GI symptom scales (PROMIS-GI) within a large sample of young adults. An attempt was made to relate the emergent groups to the Rome IV disorders of gut-brain interaction symptom domains. The PROMIS-GI is a freely available, adaptable, normatively referenced symptom measurement system that is applicable to many health assessment situations. METHODS: Participants were 956 introductory psychology students between the ages of 18 and 25 who completed the PROMIS-GI as part of ongoing research monitoring physical and psychological health of students at a major southeastern university. GI symptom groups were determined using a latent class analysis (LCA) approach. These GI symptom groups were then compared on key psychosocial factors including self-reported mood, anxiety, and health related quality of life (HRQoL) using MANOVA. RESULTS: Three groups were identified based on GI symptom elevations: Normal (n = 649), Mild (n = 257), and Moderate (n = 50). Self-reported anxiety, depression, and bodily pain levels were significantly higher in the Mild and Moderate GI symptom groups, and they indicated significantly lower work functioning, and general health ratings compared to participants in the normal group. CONCLUSIONS: Approximately a third of young adults surveyed were experiencing at least one GI symptom of a severity greater than normative levels. Both the Mild and Moderate GI groups demonstrated a similar configuration of symptoms with significantly the higher levels of pain, gas/bloating, and nausea/vomiting compared to the Normal group. The configuration of symptoms did not map discretely onto the Rome IV diagnostic categories for Bowel Disorders, such as IBS with predominant Diarrhea or Functional Constipation as might be expected. Rather, the emergent groups suggest that Bowel Disorders occur on a continuum of severity across multiple symptom areas. Mild to moderate GI symptoms appear to emerge at much earlier ages and are more frequent than previously documented. It is recommended that health service providers evaluate individual patterns of "GI health" when young adults present with anxiety and depression, and conversely, they should assess anxiety and depression when they present with GI complaints.

The Impact of a Gluten-Free Diet on Celiac Disease: A Comprehensive Evaluation of Two Cases Using NIH Patient Reported Outcome Measures (PROMIS, NTCB, and Neuro-QoL).

The aim of this study is to demonstrate the effectiveness of the gluten-free diet (GFD) for celiac disease (CD) in a multidisciplinary outpatient Gastroenterology clinic with two adult cases using the innovative, paradigm-shifting measurement systems: The NIH Patient reported outcome measures (PROs). CD results in gastrointestinal (GI) dysfunction, but is also associated with other inflammatory responses, psychosocial impairment, and cognitive deficits such as "brain fog." Adherence to the GFD for 6 months was associated with improvement in specific GI symptoms in one case (PROMIS-GI; Case 2) and improvement in cognitive functioning (NIH Toolbox Cognitive Battery) and psychosocial functioning (Neuro-QOL) in both cases. Notably, improvement in cognitive flexibility occurred in both younger and an older adult patient. This suggests that cognitive decline and the psychosocial deficits associated with CD are reversible with GFD. The NIH PROs were found to be effective, sensitive to change, and minimally disruptive to clinic operations.

Characterization of Coding/Noncoding Variants for SHROOM3 in Patients with CKD.

Background Interpreting genetic variants is one of the greatest challenges impeding analysis of rapidly increasing volumes of genomic data from patients. For example, SHROOM3 is an associated risk gene for CKD, yet causative mechanism(s) of SHROOM3 allele(s) are unknown.Methods We used our analytic pipeline that integrates genetic, computational, biochemical, CRISPR/Cas9 editing, molecular, and physiologic data to characterize coding and noncoding variants to study the human SHROOM3 risk locus for CKD.Results We identified a novel SHROOM3 transcriptional start site, which results in a shorter isoform lacking the PDZ domain and is regulated by a common noncoding sequence variant associated with CKD (rs17319721, allele frequency: 0.35). This variant disrupted allele binding to the transcription factor TCF7L2 in podocyte cell nuclear extracts and altered transcription levels of SHROOM3 in cultured cells, potentially through the loss of repressive looping between rs17319721 and the novel start site. Although common variant mechanisms are of high utility, sequencing is beginning to identify rare variants involved in disease; therefore, we used our biophysical tools to analyze an average of 112,849 individual human genome sequences for rare SHROOM3 missense variants, revealing 35 high-effect variants. The high-effect alleles include a coding variant (P1244L) previously associated with CKD (P=0.01, odds ratio=7.95; 95% CI, 1.53 to 41.46) that we find to be present in East Asian individuals at an allele frequency of 0.0027. We determined that P1244L attenuates the interaction of SHROOM3 with 14-3-3, suggesting alterations to the Hippo pathway, a known mediator of CKD.Conclusions These data demonstrate multiple new SHROOM3-dependent genetic/molecular mechanisms that likely affect CKD.

Single Quantum Dot Tracking Illuminates Neuroscience at the Nanoscale.

The use of nanometer-sized semiconductor crystals, known as quantum dots, allows us to directly observe individual biomolecular transactions through a fluorescence microscope. Here, we review the evolution of single quantum dot tracking over the past two decades, highlight key biophysical discoveries facilitated by quantum dots, briefly discuss biochemical and optical implementation strategies for a single quantum dot tracking experiment, and report recent accomplishments of our group at the interface of molecular neuroscience and nanoscience.

Three dimensional modeling of biologically relevant fluid shear stress in human renal tubule cells mimics in vivo transcriptional profiles.

The kidney proximal tubule is the primary site for solute reabsorption, secretion and where kidney diseases can originate, including drug-induced toxicity. Two-dimensional cell culture systems of the human proximal tubule cells (hPTCs) are often used to study these processes. However, these systems fail to model the interplay between filtrate flow, fluid shear stress (FSS), and functionality essential for understanding renal diseases and drug toxicity. The impact of FSS exposure on gene expression and effects of FSS at differing rates on gene expression in hPTCs has not been thoroughly investigated. Here, we performed RNA-sequencing of human RPTEC/TERT1 cells in a microfluidic chip-based 3D model to determine transcriptomic changes. We measured transcriptional changes following treatment of cells in this device at three different fluidic shear stress. We observed that FSS changes the expression of PTC-specific genes and impacted genes previously associated with renal diseases in genome-wide association studies (GWAS). At a physiological FSS level, we observed cell morphology, enhanced polarization, presence of cilia, and transport functions using albumin reabsorption via endocytosis and efflux transport. Here, we present a dynamic view of hPTCs response to FSS with increasing fluidic shear stress conditions and provide insight into hPTCs cellular function under biologically relevant conditions.

Gastrointestinal health: An investigation of mediating effects on mood and quality of life.

High prevalence rates for depression, anxiety, and gastrointestinal (GI) symptoms are found in emerging adults. However, the consequences of mood, anxiety, and GI health on health-related quality of life (HRQOL) are not well established. The biopsychosocial model and the gut-brain axis (GBA) explains the interactions of these psychological phenomenon on social and biological functioning. Following this theoretical framework, it was hypothesized that pathways between depression, anxiety, and HRQOL would be mediated by GI health. Data was cross-sectional. Undergraduates in psychology courses (N = 956) were recruited for course credit as part of ongoing research monitoring physical and psychological health of students at a major southeastern university. Participants were between 18 and 25 years old and measures were administered online. Pathways between depression, anxiety, and HRQOL were investigated using SEM analysis. The SEM was tested and specified for mediating effects. A well-fitting latent variable of GI health was created from the PROMIS-GI® scales, advancing its utility. The mediation model demonstrated anxiety and depression have significant consequences for HRQOL in emerging adults. Direct pathways from GAD7 and PHQ9 scores were found between Physical and Mental HRQOL. Notably, the path from anxiety to Physical HRQOL was fully mediated by GI health. The direct path from depressive symptoms to Physical and Mental HRQOL was partially mediated by GI health, and anxiety to Mental HRQOL was partially mediated by GI health. Findings were consistent with the biopsychosocial model and GBA. The mediation model tested here has treatment and conceptual implications. Individuals presenting with anxiety or depression should be assessed for GI symptoms and conversely, those presenting with GI complaints should be evaluated for anxiety and depression. Research is needed to develop a scoring approach to combine the PROMIS-GI® scales, so the latent construct of GI health may be used in related applications.

Optimizing Community and Hospital Services Using the Cancer Support Source Program.

BACKGROUND: The Cancer Support Community developed the Cancer Support Source (CSS) to assess the needs of cancer patients with distress. Each item on this self-administered questionnaire represents an area of concern which the patient rates and indicates their need for action with a "staff person," but no details about the category of staff is given. OBJECTIVE: To examine the factor structure of the CSS and to increase its utility to triage patients for referral to services based on a needs assessment. METHODS: Data from 690 patients who completed the CSS over a 1-year period were analyzed. In study 1, an exploratory principal component analysis was conducted. In study 2, the fit of this proposed model was evaluated with confirmatory factor analysis (CFA). RESULTS: Three factors were retained in the final CFA: emotional distress, physical health concerns, and resource needs. This model demonstrated adequate fit, Root Mean Square Error of Approximation (RMSEA)= 0.056, Comparitive Fit Index (CFI) = .907, Standardized Root Mean Square Residual (SRMR) = 0.050. CONCLUSIONS: Three factors are proposed as CSS subscales to guide referral and coordinate services: Emotional Distress/Patient and Family Counselor, Physical Health Concerns/Medical Care Provider, and Resource Needs/Case Management-Clinical Social Worker. The clinical utility of these referral subscales should be established with additional research.

Examining the Role of Anxiety and Depression in Dietary Choices among College Students.

This study examines the role of anxiety and depression symptoms in predicting dietary choices in emerging adults while accounting for sex differences in these relationships. Participants were 225 English speaking undergraduates enrolled in a university in southeastern United States. Participants were recruited through an online research recruitment application utilized by the university. Participants volunteered for a two-phased anonymous survey monitoring the effects of eating habits and gastrointestinal health in young adults. As part of this effort, participants completed self-reporting measures related to anxiety and depression, as well as an automated, self-administered 24-h diet recall. Multigroup path analysis was used to test primary hypotheses. Overall, a decrease in total caloric intake and an increase in sugar consumption were found as self-reported symptoms of anxiety and depression increased. In addition, there were sex differences in the relationship between depression and food choices. Men consumed more saturated fat as well as less fruits and vegetables as self-reported symptoms of depression increased. Results suggest symptoms of depression are a greater risk factor for poor nutrition in male college students than females. The findings provide another justification to screen for psychological distress in student health services given the implications on behavioral lifestyle and health.

Developmental consequences of fetal exposure to drugs: what we know and what we still must learn.

Most drugs of abuse easily cross the placenta and can affect fetal brain development. In utero exposures to drugs thus can have long-lasting implications for brain structure and function. These effects on the developing nervous system, before homeostatic regulatory mechanisms are properly calibrated, often differ from their effects on mature systems. In this review, we describe current knowledge on how alcohol, nicotine, cocaine, amphetamine, Ecstasy, and opiates (among other drugs) produce alterations in neurodevelopmental trajectory. We focus both on animal models and available clinical and imaging data from cross-sectional and longitudinal human studies. Early studies of fetal exposures focused on classic teratological methods that are insufficient for revealing more subtle effects that are nevertheless very behaviorally relevant. Modern mechanistic approaches have informed us greatly as to how to potentially ameliorate the induced deficits in brain formation and function, but conclude that better delineation of sensitive periods, dose-response relationships, and long-term longitudinal studies assessing future risk of offspring to exhibit learning disabilities, mental health disorders, and limited neural adaptations are crucial to limit the societal impact of these exposures.

A flow cytometry-based dopamine transporter binding assay using antagonist-conjugated quantum dots.

Here we present the development and validation of a flow cytometry-based dopamine transporter (DAT) binding assay that uses antagonist-conjugated quantum dots (QDs). We anticipate that our QD-based assay is of immediate value to the high throughput screening of novel DAT modulators.

Activation of the Oryza sativa non-symbiotic haemoglobin-2 promoter by the cytokinin-regulated transcription factor, ARR1.

Using in silico methods, several putative phytohormone-responsive cis-elements in the Oryza sativa non-symbiotic haemoglobin (NSHB) 1-4 and Arabidopsis thaliana NSHB1-2 promoters have been identified. An OsNSHB2 promoter::GUS reporter gene fusion shows tissue-specific expression in A. thaliana. GUS expression was observed in roots, the vasculature of young leaves, in flowers, and in the pedicel/stem junction. In transient assays, activity of the OsNSHB2 promoter was significantly up-regulated in the presence of the cytokinin, 6-benzylaminopurine (BA). Deletion analyses indicated that the full-length promoter was required for maximal trans-activation in the presence of cytokinin. Mutation of the single cytokinin-regulated ARR1-binding element abolished promoter activation in response to cytokinin. Constitutive expression of ARR1 under the control of the 35S cauliflower mosaic virus promoter enhanced wild-type OsNSHB2 promoter activity, but had no effect on the activity of the mutated promoter in the absence of cytokinin. However, overexpression of ARR1 in the presence of cytokinin resulted in super-activation of the wild-type promoter. The mutated promoter was only moderately activated in the presence of cytokinin and ARR1, indicating that the OsNSHB2 promoter can be regulated by the ARR1 protein, but requires other cytokinin-induced factors for optimal activation. This is the first report that identifies a trans-acting factor involved in the activation of a NSHB gene.