SUMMARY Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.

Difficulty obtaining reliable transportation to clinic is frequently cited as a barrier to HIV care in sub-Saharan Africa (SSA). Numerous studies have sought to characterize the impact of geographic and transportation-related barriers on HIV outcomes in SSA, but to date there has been no systematic attempt to summarize these findings. In this systematic review, we summarized this body of literature. We searched for studies conducted in SSA examining the following outcomes in the HIV care continuum: (1) voluntary counseling and testing, (2) pre-anti-retroviral therapy (ART) linkage to care, (3) loss to follow-up and mortality, and (4) ART adherence and/or viral suppression. We identified 34 studies containing 52 unique estimates of association between a geographic or transportation-related barrier and an HIV outcome. There was an inverse effect in 23 estimates (44 %), a null association in 26 (50 %), and a paradoxical beneficial impact in 3 (6 %). We conclude that geographic and transportation-related barriers are associated with poor outcomes across the continuum of HIV care.

Role of glucocorticoid receptor in acclimation of killifish (Fundulus heteroclitus) to seawater and effects of arsenic.

Objective Studies of the association between transportation barriers and HIV-related health outcomes have shown both positive and negative effects, possibly because a reliable, validated measure of transportation barriers has not been identified. Design Prospective cohort study of HIV-infected patients in rural Uganda. Methods Participants were enrolled from the HIV clinic at the regional referral hospital in Mbarara, Uganda as part of the Uganda AIDS Rural Treatment Outcomes (UARTO) Study. We collected the following measures of transportation barriers to HIV clinic: global positioning systems (GPS)-tracked distance measured by driving participants to their homes along their typical route; straight-line GPS distance from clinic to home, calculated with the Great Circle Formula; self-reported travel time; and self-reported travel cost. We assessed inter-measure agreement using linear regression, correlation coefficients and κ statistics (by measure quartile) and validated measures by fitting linear regression models to estimate associations with days late for clinic visits. Results One hundred and eighty-eight participants were tracked with GPS. Seventy-six percent were women, with a median age of 40 years and median CD4 cell count of 193 cells/μl. We found a high correlation between GPS-based distance measures (β = 0.74, P < 0.001, R2 = 0.92, k = 0.73), but little correlation between GPS-based and self-reported measures (all R2 ≤ 0.4). GPS-based measures were associated with days late to clinic (P < 0.001); but neither self-reported measure was associated (P > 0.85). Conclusion GPS-measured distance to clinic is associated with HIV clinic absenteeism and should be prioritized over self-reported measures to optimally risk-stratify patients accessing care in rural, resource-limited settings.

Killifish are euryhaline teleosts that adapt to increased salinity by up regulating CFTR mediated Cl^- secretion in the gill and opercular membrane. Although many studies have examined the mechanisms responsible for long term (days) adaptation to increased salinity, little is known about the mechanisms responsible for acute (hours) adaptation. Thus, studies were conducted to test the hypotheses that the acute homeostatic regulation of NaCl balance in killifish involves a translocation of CFTR to the plasma membrane and that this effect is mediated by serum-and glucocorticoid-inducible kinase (SGK1). Cell surface biotinyation and Ussing chamber studies revealed that freshwater to seawater transfer rapidly (1 hour) increased CFTR Cl^- secretion and the abundance of CFTR in the plasma membrane of opercular membranes. Q-RT-PCR and Western blot studies demonstrated that the increase in plasma membrane CFTR was preceded by an increase in SGK1 mRNA and protein levels. Seawater rapidly (1 hr) increases cortisol and plasma tonicity, potent stimuli of SGK1 expression, yet RU486, a glucocorticoid receptor antagonist, did not block the increase in SGK1 expression. Thus, in killifish SGK1 does not appear to be regulated by the glucocorticoid receptor. Since SGK1 has been shown to increase the plasma membrane abundance of CFTR in Xenopus oocytes, these observations suggest that acute adaptation (hours) to increased salinity in killifish involves translocation of CFTR from an intracellular pool to the plasma membrane, and that this effect may be mediated by SGK1.

BackgroundUp to 50 % of HIV-infected persons in sub-Saharan Africa are lost from care between HIV diagnosis and antiretroviral therapy (ART) initiation. Structural barriers, including cost of transportation to clinic and poor communication systems, are major contributors.MethodsWe conducted a prospective, pragmatic, before-and-after clinical trial to evaluate a combination mobile health and transportation reimbursement intervention to improve care at a publicly operated HIV clinic in Uganda. Patients undergoing CD4 count testing were enrolled, and clinicians selected a result threshold that would prompt early return for ART initiation or further care. Participants enrolled in the pre-intervention period (January – August 2012) served as a control group. Participants in the intervention period (September 2012 – November 2013) were randomized to receive daily short message service (SMS) messages for up to seven days in one of three formats: 1) messages reporting an abnormal result directly, 2) personal identification number-protected messages reporting an abnormal result, or 3) messages reading “ABCDEFG” to confidentially convey an abnormal result. Participants returning within seven days of their first message received transportation reimbursements (about $6USD). Our primary outcomes of interest were time to return to clinic and time to ART initiation.ResultsThere were 45 participants in the pre-intervention period and 138 participants in the intervention period (46, 49, and 43 in the direct, PIN, and coded groups, respectively) with low CD4 count results. Median time to clinic return was 33 days (IQR 11–49) in the pre-intervention period and 6 days (IQR 3–16) in the intervention period (P < 0.001); and median time to ART initiation was 47 days (IQR 11–75) versus 12 days (IQR 5–19), (P < 0.001). In multivariable models, participants in the intervention period had earlier return to clinic (AHR 2.32, 95 %CI 1.53 to 3.51) and earlier time to ART initiation (AHR 2.27, 95 %CI 1.38 to 3.72). All three randomized message formats improved time to return to clinic and time to ART initiation (P < 0.01 for all comparisons versus the pre-intervention period).ConclusionsA combination of an SMS laboratory result communication system and transportation reimbursements significantly decreased time to clinic return and time to ART initiation after abnormal CD4 test results.Trial registrationsClinicaltrials.gov NCT01579214, approved 13 April 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0397-1) contains supplementary material, which is available to authorized users.

Killifish are euryhaline teleosts that normally experience rapid changes in the salinity of the swim water. Acclimation to seawater is mediated by cortisol, which by activating glucocorticoid receptors, upregulates CFTR mediated Cl^- secretion in the gill and operculum. Arsenic, a toxic metalloid that naturally occurs in the aquatic environment, has been shown to disrupt glucocorticoid hormone-mediated regulation of genes. Because little is known about the effects of environmentally relevant levels of arsenic on ion channels and salt homeostasis, studies were conducted to examine the effects of arsenic on the ability of killifish to acclimate to increased salinity. Arsenic in the swim water or administered by intraperitoneal injection prevented acclimation. To determine if arsenic blocked acclimation by inhibiting CFTR mediated Cl^- secretion (Isc), opercular membranes were isolated and mounted in Ussing chambers and the effects of arsenic on Isc were measured. Arsenic (24 hr exposure) reduced Isc in opercular membranes isolated from salt water acclimated killifish. In addition, arsenic acutely (5-10 minutes) and reversibly inhibited Isc with an IC₅₀ = 4.1 µM (305 ppb) when applied to the apical (seawater) side of the operculum, but not when added to the basolateral side of the operculum. Arsenic (4 µM for 60 minutes) also reduced mitochondrial respiration. Thus, environmentally relevant levels of arsenic block acclimation to seawater in killifish by reversibly inhibiting CFTR-mediated Cl^- secretion by the opercular membrane, in part by inhibiting mitochondrial respiration.

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