Mycobacterium tuberculosis-dependent monocyte expression quantitative trait loci, cytokine production, and TB pathogenesis.

Introduction: The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. Methods: We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. Results: cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in uninfected condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. Discussion: These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.

Genetic Variants in Carbohydrate Digestive Enzyme and Transport Genes Associated with Risk of Irritable Bowel Syndrome.

Irritable Bowel Syndrome (IBS) is characterized by abdominal pain and alterations in bowel pattern, such as constipation (IBS-C), diarrhea (IBS-D), or mixed (IBS-M). Since malabsorption of ingested carbohydrates (CHO) can cause abdominal symptoms that closely mimic those of IBS, identifying genetic mutations in CHO digestive enzymes associated with IBS symptoms is critical to ascertain IBS pathophysiology. Through candidate gene association studies, we identify several common variants in TREH, SI, SLC5A1 and SLC2A5 that are associated with IBS symptoms. By investigating rare recessive Mendelian or oligogenic inheritance patterns, we identify case-exclusive rare deleterious variation in known disease genes (SI, LCT, ALDOB, and SLC5A1) as well as candidate disease genes (MGAM and SLC5A2), providing potential evidence of monogenic or oligogenic inheritance in a subset of IBS cases. Finally, our data highlight that moderate to severe IBS-associated gastrointestinal symptoms are often observed in IBS cases carrying one or more of deleterious rare variants.

Mycobacterium tuberculosis -induced monocyte transcriptional responses associated with resistance to tuberculin skin test/interferon-γ release assay conversion in people with HIV.

OBJECTIVE: To determine whether Mycobacterium tuberculosis (Mtb)-induced monocyte transcriptional responses differ in people with HIV (PWH) who do (RSTR) or do not (LTBI) resist tuberculin skin test/interferon-γ (IFN-γ) release assay (TST/IGRA) conversion after exposure. DESIGN: We compared ex-vivo Mtb-induced monocyte transcriptional responses in a Ugandan tuberculosis (TB) household contact study of RSTR and LTBI individuals among PWH. METHODS: Monocytes were isolated from peripheral blood mononuclear cells from 19 household contacts of pulmonary TB patients, and their transcriptional profiles were measured with RNA-Seq after a 6 h infection with Mtb (H37Rv) or media. Differentially expressed genes (DEGs) were identified by a linear mixed effects model and pathways by gene set enrichment analysis that compared RSTR and LTBI phenotypes with and without Mtb stimulation. RESULTS: Among PWH, we identified 8341 DEGs that were dependent on Mtb stimulation [false discovery rate (FDR) <0.01]. Of these, 350 were not significant (FDR >0.2) in individuals without HIV. Additionally, we found 26 genes that were differentially expressed between RSTR and LTBI monocytes in PWH, including 20 which were Mtb-dependent (FDR <0.2). In unstimulated monocytes, several gene sets [TGF-ß signaling, TNF-α signaling via NF-κB, NOTCH signaling, coagulation, and epithelial mesenchymal transition (EMT)] were enriched in RSTR relative to LTBI monocytes (FDR <0.1). These patterns were not observed in individuals without HIV. CONCLUSION: RSTR monocytes in PWH show different gene expressions in response to Mtb infection when compared with those with LTBI and RSTR without HIV. These differential expression patterns are enriched in inflammatory pathways.

Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis.

The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in media condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.

Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation.

BACKGROUND: Tuberculosis (TB) remains a major public health problem globally, even compared to COVID-19. Genome-wide studies have failed to discover genes that explain a large proportion of genetic risk for adult pulmonary TB, and even fewer have examined genetic factors underlying TB severity, an intermediate trait impacting disease experience, quality of life, and risk of mortality. No prior severity analyses used a genome-wide approach. METHODS AND FINDINGS: As part of our ongoing household contact study in Kampala, Uganda, we conducted a genome-wide association study (GWAS) of TB severity measured by TBScore, in two independent cohorts of culture-confirmed adult TB cases (n = 149 and n = 179). We identified 3 SNPs (P<1.0 x 10-7) including one on chromosome 5, rs1848553, that was GWAS significant (meta-analysis p = 2.97x10-8). All three SNPs are in introns of RGS7BP and have effect sizes corresponding to clinically meaningful reductions in disease severity. RGS7BP is highly expressed in blood vessels and plays a role in infectious disease pathogenesis. Other genes with suggestive associations defined gene sets involved in platelet homeostasis and transport of organic anions. To explore functional implications of the TB severity-associated variants, we conducted eQTL analyses using expression data from Mtb-stimulated monocyte-derived macrophages. A single variant (rs2976562) associated with monocyte SLA expression (p = 0.03) and subsequent analyses indicated that SLA downregulation following MTB stimulation associated with increased TB severity. Src Like Adaptor (SLAP-1), encoded by SLA, is highly expressed in immune cells and negatively regulates T cell receptor signaling, providing a potential mechanistic link to TB severity. CONCLUSIONS: These analyses reveal new insights into the genetics of TB severity with regulation of platelet homeostasis and vascular biology being central to consequences for active TB patients. This analysis also reveals genes that regulate inflammation can lead to differences in severity. Our findings provide an important step in improving TB patient outcomes.

A systematic review of the association between health literacy and pain self-management.

OBJECTIVE: To synthesize the impact of health literacy on pain self-management contexts, processes, and outcomes. METHODS: This systematic review employed a narrative synthesis. We used databases, including PubMed and PsycINFO, and handsearching of the reference lists to identify articles published before December 2020. Pain self-management variables were chosen based on the Individual and Family Self-Management Theory. Quality was assessed using the National Institute of Health quality assessment tool for observational and cross-sectional studies. RESULTS: Twenty studies that included 6173 participants were used. Most studies measured functional domains of the health literacy concept. Twelve studies reported small to large associations between health literacy and pain knowledge, medication regimen adherence, or pain. Thirteen studies considered health literacy clinical risks in tailoring education, while seven viewed it as personal assets developed via education. CONCLUSIONS: Limited information on the contribution of health literacy to pain self-management context factors and processes exists. Current evidence was limited by a lack of temporality, theoretical basis, and a priori sample estimation. PRACTICE IMPLICATIONS: Using brief functional literacy scales in the clinical environment can be more practical. Identifying patients' literacy levels helps clinicians personalize education, which then promotes patients' knowledge of pain, medication regimen adherence, and pain control.

Prevalence of Pre-Existing Hearing Loss Among Patients With Drug-Resistant Tuberculosis in South Africa.

Purpose Hearing loss, resulting from aminoglycoside ototoxicity, is common among patients with drug-resistant tuberculosis (DR-TB). Those with pre-existing hearing loss are at particular risk of clinically important hearing loss with aminoglycoside-containing treatment than those with normal hearing at baseline. This study aimed to identify factors associated with pre-existing hearing loss among patients being treated for DR-TB in South Africa. Method Cross-sectional analysis nested within a cluster-randomized trial data across 10 South African TB hospitals. Patients ≥ 13 years old received clinical and audiological evaluations before DR-TB treatment initiation. Results Of 936 patients, average age was 35 years. One hundred forty-two (15%) reported pre-existing auditory symptoms. Of 482 patients tested by audiometry, 290 (60%) had pre-existing hearing loss. The prevalence of pre-existing hearing loss was highest among patients ≥ 50 years (adjusted prevalence ratio [aPrR] for symptoms 5.53, 95% confidence interval (CI) [3.63, 8.42]; aPrR for audiometric hearing loss 1.63, 95% CI [1.31, 2.03] compared to age 13-18 years) and among those with a prior history of second-line TB treatment (aPrR for symptoms 1.73, 95% CI [1.66, 1.80]; PrR for audiometric hearing loss 1.33, 95% CI [1.03, 1.73]). Having HIV with cluster of differentiation 4 cell count < 200 cells/mm3 and malnutrition were risk factors but did not reach statistical significance in adjusted analyses. Conclusion Pre-existing hearing loss is common among patients presenting for DR-TB treatment in South Africa, and those older than the age of 50 years or who had prior second-line TB treatment history were at highest risk.

Aminoglycoside-induced Hearing Loss Among Patients Being Treated for Drug-resistant Tuberculosis in South Africa: A Prediction Model.

BACKGROUND: Individuals treated for drug-resistant tuberculosis (DR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss, yet there is no practical method to identify those at higher risk. We sought to develop a clinical prediction model of AG-induced hearing loss among patients initiating DR-TB treatment in South Africa. METHODS: Using nested, prospective data from a cohort of 379 South African adults being treated for confirmed DR-TB with AG-based regimens we developed the prediction model using multiple logistic regression. Predictors were collected from clinical, audiological, and laboratory evaluations conducted at the initiation of DR-TB treatment. The outcome of AG-induced hearing loss was identified from audiometric and clinical evaluation by a worsened hearing threshold compared with baseline during the 6-month intensive phase. RESULTS: Sixty-three percent of participants (n = 238) developed any level of hearing loss. The model predicting hearing loss at frequencies from 250 to 8000 Hz included weekly AG dose, human immunodeficiency virus status with CD4 count, age, serum albumin, body mass index, and pre-existing hearing loss. This model demonstrated reasonable discrimination (area under the receiver operating characteristic curve [AUC] = 0.71) and calibration (χ2[8] = 6.10, P = .636). Using a cutoff of 80% predicted probability of hearing loss, the positive predictive value of this model was 83% and negative predictive value was 40%. Model discrimination was similar for ultrahigh-frequency hearing loss (frequencies >9000 Hz; AUC = 0.81) but weaker for clinically determined hearing loss (AUC = 0.60). CONCLUSIONS: This model may identify patients with DR-TB who are at highest risk of developing AG-induced ototoxicity and may help prioritize patients for AG-sparing regimens in clinical settings where access is limited.

Management of the Patient With HIV/Hepatitis C Drug Interactions: A Guide for Nurses and Nurse Practitioners.

Approximately one third of patients coinfected with HIV and hepatitis C virus (HCV) who initiate direct-acting antivirals (DAAs) for HCV treatment may have to switch antiretroviral therapy (ART) because of drug interactions. ART switches can negatively affect quality of life, increase HIV symptom burden, and delay HCV therapy. Approaches to identify ART/DAA drug interactions that minimize the impact of switching ART are urgently needed. Nurses can lead the way in addressing this new and major need. We provide a guide for registered nurses and nurse practitioners who care for patients coinfected with HIV and HCV to identify HIV/HCV drug interactions and manage ART/DAA coadministration when needed.

Adverse outcome pathway for aminoglycoside ototoxicity in drug-resistant tuberculosis treatment.

Individuals treated for multidrug-resistant tuberculosis (MDR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss. However, AG ototoxicity has never been conceptually integrated or causally linked to MDR-TB patients' pre-treatment health condition. We sought to develop a framework that examines the relationships between pre-treatment conditions and AG-induced hearing loss among MDR-TB-infected individuals in sub-Saharan Africa. The adverse outcome pathway (AOP) approach was used to develop a framework linking key events (KEs) within a biological pathway that results in adverse outcomes (AO), which are associated with chemical perturbation of a molecular initiating event (MIE). This AOP describes pathways initiating from AG accumulation in hair cells, sound transducers of the inner ear immediately after AG administration. After administration, the drug catalyzes cellular oxidative stress due to overproduction of reactive oxygen species. Since oxidative stress inhibits mitochondrial protein synthesis, hair cells undergo apoptotic cell death, resulting in irreversible hearing loss (AO). We identified the following pre-treatment conditions that worsen the causal linkage between MIE and AO: HIV, malnutrition, aging, noise, smoking, and alcohol use. The KEs are: (1) nephrotoxicity, pre-existing hearing loss, and hypoalbuminemia that catalyzes AG accumulation; (2) immunodeficiency and antioxidant deficiency that trigger oxidative stress pathways; and (3) co-administration of mitochondrial toxic drugs that hinder mitochondrial protein synthesis, causing apoptosis. This AOP clearly warrants the development of personalized interventions for patients undergoing MDR-TB treatment. Such interventions (i.e., choosing less ototoxic drugs, scheduling frequent monitoring, modifying nutritional status, avoiding poly-pharmacy) will be required to limit the burden of AG ototoxicity.

Strategies to Promote African-American Church Leadership Engagement in HIV Testing and Linkage to Care.

A vital piece in implementing and sustaining HIV testing and linkage-to-care within Black churches is the support of the pastors and church leadership. In order to promote church-based HIV testing and linkage-to-care, we explored pastor and church leaders' (1) HIV-related knowledge, (2) their perception of congregant and community engagement in HIV-related risks, and (3) the potential role of the church in HIV testing and linkage-to-care. We conducted focus groups with 57 church leaders and 8 interviews with pastors across 6 churches in Baltimore, MD, USA. Conventional content analysis was used to analyze the qualitative data. The leadership demonstrated different levels of knowledge of the need for confidentiality, and the HIV testing process and reported that low levels of HIV knowledge among their congregants was related to low perceived risk of contracting HIV. Pastors and church leaders indicated that community members engaged in sexual risk and drug use but denied that any of their congregants engaged in such behaviors. Finally, pastors and church leaders have stated that churches were best suited as HIV service centers. These findings can be used to develop culturally appropriate interventions for pastors and church leaders to be better equipped and willing to incorporate HIV testing and linkage-to-care in their churches.

eHealth Literacy in People Living with HIV: Systematic Review.

BACKGROUND: In the era of eHealth, eHealth literacy is emerging as a key concept to promote self-management of chronic conditions such as HIV. However, there is a paucity of research focused on eHealth literacy for people living with HIV (PLWH) as a means of improving their adherence to HIV care and health outcome. OBJECTIVE: The objective of this study was to critically appraise the types, scope, and nature of studies addressing eHealth literacy as a study variable in PLWH. METHODS: This systematic review used comprehensive database searches, such as PubMed, EMBASE, CINAHL, Web of Science, and Cochrane, to identify quantitative studies targeting PLWH published in English before May 2017 with eHealth literacy as a study variable. RESULTS: We identified 56 unique records, and 7 papers met the eligibility criteria. The types of study designs varied (descriptive, n=3; quasi-experimental, n=3; and experimental, n=1) and often involved community-based settings (n=5), with sample sizes ranging from 18 to 895. In regards to instruments used, 3 studies measured eHealth literacy with validated instruments such as the eHealth Literacy Scale (eHEALS); 2 studies used full or short versions of Test of Functional Health Literacy in Adults, whereas the remaining 2 studies used study-developed questions. The majority of studies included in the review reported high eHealth literacy among the samples. The associations between eHealth literacy and health outcomes in PLWH were not consistent. In the areas of HIV transmission risk, retention in care, treatment adherence, and virological suppression, the role of eHealth literacy is still not fully understood. Furthermore, the implications for future research are discussed. CONCLUSIONS: Understanding the role of eHealth literacy is an essential step to encourage PLWH to be actively engaged in their health care. Avenues to pursue in the role of eHealth literacy and PLWH should consider the development and use of standardized eHealth literacy definitions and measures.

Effectiveness of macronutrient supplementation on nutritional status and HIV/AIDS progression: A systematic review and meta-analysis.

BACKGROUND & AIMS: Malnutrition is common in Sub-Saharan Africa, weakening the immune function of persons living with HIV infection (PLWH). Being malnourished at the initiation of antiretroviral therapy (ART) leads to higher risk of early mortality and reduced quality of life. Thus, introduction of protein-energy-fortified macronutrient supplements at ART initiation may improve HIV treatment outcomes. This review aimed to evaluate the effectiveness of macronutrient interventions. METHODS: This systematic review and meta-analysis included 15 studies conducted from 2000 to 2015 among Sub-Saharan African adults. RESULTS: Six randomized controlled trials and 4 retrospective cohort studies provided data eligible for a meta-analysis. Supplementation significantly increased the overall standardized mean difference (SMD) between baseline and follow-up data in weight (SMD = 0.382, p < .001), BMI (SMD = 0.799, p < .001); fat-free mass (SMD = 0.154, p = .009); and CD4 count (SMD = 0.428, p < .001). CONCLUSION: Protein-energy-fortified macronutrient supplementation at ART initiation may positively influence nutritional status and immunologic response in PLWH in Sub-Saharan Africa.

African American Church Engagement in the HIV Care Continuum.

Providing comprehensive services across the HIV care continuum through African American churches may improve HIV treatment outcomes for African Americans. We explored the feasibility of a church-led HIV care program in six churches in Baltimore, Maryland. Church leaders (n = 57) participated in focus groups and eight pastors participated in interviews. Data were analyzed by qualitative hybrid thematic analysis. Findings revealed eight themes: four themes were related to linkage to care: being unaware of community resources, concerns about HIV-associated regulations, ongoing personalized contact with HIV-infected persons, and desire for integration of spiritual education; four themes were related to HIV care and support services, including existing church infrastructure, provision of HIV support groups, using the church as an HIV care resource hub, and prevention education for uninfected people. These findings can support initiatives and efforts to promote delivery of HIV services along the HIV care continuum through African American churches.

HIV Testing, Stigma, and Risk: A Comparison of Church Leaders and Their Congregants.

The involvement of African American churches in HIV testing and prevention is a viable community-based strategy in efforts to reduce rates of HIV among African Americans; however, church members' beliefs and attitudes are often barriers to successful implementation. This study aimed to compare church leaders and congregants regarding HIV testing behaviors, HIV-related stigma, HIV knowledge, and perceived risk. This comparative, cross-sectional study used self-reporting questionnaires across six churches in Baltimore, Maryland. Of the 173 participants (68 leaders, 105 congregants), leaders and congregants had equally high levels of HIV knowledge and equally low levels of HIV stigma, but leaders had higher homosexuality stigma than congregants t(169) = 1.773, p = .039. Congregants had higher perceived HIV risk t(170) = 3.814, p < .001, and were more likely to be tested annually for HIV than leaders, c2(1) = 8.940, p = .002. Given the higher rates of stigma, lower perceived risk and lower likelihood to be tested, interventions should focus on changing the beliefs and behaviors of church leadership to promote implementation of HIV efforts.