Reactivity of renal and mesenteric resistance vessels to angiotensin II is mediated by NOXA1/NOX1 and superoxide signaling.

Activation of NADPH oxidase (NOX) enzymes and the generation of reactive oxygen species and oxidative stress regulate vascular and renal function and contribute to the pathogenesis of hypertension. The present study examined the role of NOXA1/NOX1 function in vascular reactivity of renal and mesenteric resistance arteries/arterioles of wild-type and Noxa1-/- mice. A major finding was that renal blood flow is less sensitive to acute stimulation by angiotensin II (ANG II) in Noxa1-/- mice compared with wild-type mice, with a direct action on resistance arterioles independent of nitric oxide (NO) bioavailability. These functional results were reinforced by immunofluorescence evidence of NOXA1/NOX1 protein presence in renal arteries, afferent arterioles, and glomeruli as well as their upregulation by ANG II. In contrast, the renal vascular response to the thromboxane mimetic U46619 was effectively blunted by NO and was similar in both mouse genotypes and thus independent of NOXA1/NOX1 signaling. However, phenylephrine- and ANG II-induced contraction of isolated mesenteric arteries was less pronounced and buffering of vasoconstriction after acetylcholine and nitroprusside stimulation was reduced in Noxa1-/- mice, suggesting endothelial NO-dependent mechanisms. An involvement of NOXA1/NOX1/O2•- signaling in response to ANG II was demonstrated with the specific NOXA1/NOX1 assembly inhibitor C25 and the nonspecific NOX inhibitor diphenyleneiodonium chloride in cultured vascular smooth muscle cells and isolated mesenteric resistance arteries. Collectively, our data indicate that the NOX1/NOXA1/O2•- pathway contributes to acute vasoconstriction induced by ANG II in renal and mesenteric vascular beds and may contribute to ANG II-induced hypertension.NEW & NOTEWORTHY Renal reactivity to angiotensin II (ANG II) is mediated by superoxide signaling produced by NADPH oxidase (NOX)A1/NOX1. Acute vasoconstriction of renal arteries by ANG was blunted in Noxa1-/- compared with wild-type mice. NOXA1/NOX1/O2•- signaling was also observed in ANG II stimulation of vascular smooth muscle cells and isolated mesenteric resistance arteries, indicating that it contributes to ANG II-induced hypertension. A NOXA1/NOX1 assembly inhibitor (C25) has been characterized that inhibits superoxide production and ameliorates the effects of ANG II.

Unique Cell Subpopulations and Disease Progression Markers in Canines with Atopic Dermatitis.

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with unclear molecular and cellular contributions behind the complex etiology. To unravel these differences between healthy control and AD skin we employed single-cell transcriptomics, utilizing the canine AD model for its resemblance to human clinical and molecular phenotypes. In this study, we show that there are overall increases in keratinocytes and T cells and decreases in fibroblast populations in AD dogs. Within immune cell types, we identified an enriched γδ T cell population in AD, which may contribute to cutaneous inflammation. A prominent IL26-positive fibroblast subpopulation in AD was detected, which may activate neighboring cells in the dermal-epidermal niche. Lastly, by comparing dogs with different disease severities, we found genes that follow disease progression and may serve as potential biomarkers. In this study, we characterized key AD cell types and cellular processes that can be further leveraged in diagnosis and treatment.

dCas9 fusion to computer-designed PRC2 inhibitor reveals functional TATA box in distal promoter region.

Bifurcation of cellular fates, a critical process in development, requires histone 3 lysine 27 methylation (H3K27me3) marks propagated by the polycomb repressive complex 2 (PRC2). However, precise chromatin loci of functional H3K27me3 marks are not yet known. Here, we identify critical PRC2 functional sites at high resolution. We fused a computationally designed protein, EED binder (EB), which competes with EZH2 and thereby inhibits PRC2 function, to dCas9 (EBdCas9) to allow for PRC2 inhibition at a precise locus using gRNA. Targeting EBdCas9 to four different genes (TBX18, p16, CDX2, and GATA3) results in precise H3K27me3 and EZH2 reduction, gene activation, and functional outcomes in the cell cycle (p16) or trophoblast transdifferentiation (CDX2 and GATA3). In the case of TBX18, we identify a PRC2-controlled, functional TATA box >500 bp upstream of the TBX18 transcription start site (TSS) using EBdCas9. Deletion of this TATA box eliminates EBdCas9-dependent TATA binding protein (TBP) recruitment and transcriptional activation. EBdCas9 technology may provide a broadly applicable tool for epigenomic control of gene regulation.

Renal NOXA1/NOX1 Signaling Regulates Epithelial Sodium Channel and Sodium Retention in Angiotensin II-induced Hypertension.

Aims: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are implicated in the pathophysiology of hypertension in chronic kidney disease patients. Genetic deletion of NOX activator 1 (Noxa1) subunit of NOX1 decreases ROS under pathophysiological conditions. Here, we investigated the role of NOXA1-dependent NOX1 activity in the pathogenesis of angiotensin II (Ang II)-induced hypertension (AIH) and possible involvement of abnormal renal function. Results: NOXA1 is present in epithelial cells of Henle's thick ascending limb and distal nephron. Telemetry showed lower basal systolic blood pressure (BP) in Noxa1-/-versus wild-type mice. Ang II infusion for 1 and 14 days increased NOXA1/NOX1 expression and ROS in kidney of male but not female wild-type mice. Mean BP increased 30 mmHg in wild-type males, with smaller increases in Noxa1-deficient males and wild-type or Noxa1-/- females. In response to an acute salt load, Na+ excretion was similar in wild-type and Noxa1-/- mice before and 14 days after Ang II infusion. However, Na+ excretion was delayed after 1-2 days of Ang II in male wild-type versus Noxa1-/- mice. Ang II increased epithelial Na+ channel (ENaC) levels and activation in the collecting duct principal epithelial cells of wild-type but not Noxa1-/- mice. Aldosterone induced ROS levels and Noxa1 and Scnn1a expression and ENaC activity in a mouse renal epithelial cell line, responses abolished by Noxa1 small-interfering RNA. Innovation and Conclusion: Ang II activation of renal NOXA1/NOX1-dependent ROS enhances tubular ENaC expression and Na+ reabsorption, leading to increased BP. Attenuation of AIH in females is attributed to weaker NOXA1/NOX1-dependent ROS signaling and efficient natriuresis. Antioxid. Redox Signal. 36, 550-566.

Epidemiology of Coronavirus Disease 2019 at a County Jail-Alameda County, California, March 2020-March 2021.

CONTEXT: Coronavirus disease 2019 (COVID-19) incidence rates are 2- to 5-fold higher among persons incarcerated in the United States than in the general population. PROGRAM OR POLICY: We describe an outbreak investigation of COVID-19 at a jail (jail A) in Alameda County during March 2020-March 2021. IMPLEMENTATION: To prevent COVID-19 cases among incarcerated persons and employees, staff at jail A and the county public health department worked to develop and recommend infection control measures implemented by jail A including, but not limited to, face covering use among incarcerated persons and staff; cohorting incarcerated persons at a higher risk of severe COVID-19 in dedicated housing units; quarantining all newly detained individuals for 14 days; and offering testing for all symptomatic incarcerated persons, newly incarcerated persons at day 2 and day 10, and all persons who resided in a housing unit where a COVID-19 case was detected. EVALUATION: A total of 571 COVID-19 cases were detected among incarcerated persons at jail A during March 2020-March 2021, which represented a total incidence of 280 per 1000 population, 5 times higher than the rate in Alameda County. Of the 571 cases among incarcerated persons, 557 (98%) were male; 415 (73%) were aged 18 to 40 years; 249 (44%) were Latino; and 180 (32%) were African American; 354 (62%) were not symptomatic; and 220 (39%) had no comorbidities. Less than 2% of infected incarcerated persons were hospitalized, and no deaths were reported. DISCUSSION: COVID-19 disproportionately impacted persons incarcerated at jail A, with higher numbers among Latinos and African Americans. Implementation of COVID-19 infection control and testing measures, and collaboration between public health, law enforcement, and health care providers may have, in part, led to reductions in morbidity and mortality associated with COVID-19 at jail A.

Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens.

CRISPR screens have been used to connect genetic perturbations with changes in gene expression and phenotypes. Here we describe a CRISPR-based, single-cell combinatorial indexing assay for transposase-accessible chromatin (CRISPR-sciATAC) to link genetic perturbations to genome-wide chromatin accessibility in a large number of cells. In human myelogenous leukemia cells, we apply CRISPR-sciATAC to target 105 chromatin-related genes, generating chromatin accessibility data for ~30,000 single cells. We correlate the loss of specific chromatin remodelers with changes in accessibility globally and at the binding sites of individual transcription factors (TFs). For example, we show that loss of the H3K27 methyltransferase EZH2 increases accessibility at heterochromatic regions involved in embryonic development and triggers expression of genes in the HOXA and HOXD clusters. At a subset of regulatory sites, we also analyze changes in nucleosome spacing following the loss of chromatin remodelers. CRISPR-sciATAC is a high-throughput, single-cell method for studying the effect of genetic perturbations on chromatin in normal and disease states.

A hybrid effectiveness/implementation trial of an evidence-based intervention for HIV-serodiscordant African American couples.

Couples-based behavioral HIV prevention interventions have demonstrated efficacy, but few are routinely available in community-based settings in the United States. The Eban intervention, designed for heterosexual African American serodiscordant couples and proven efficacious in a cluster randomized trial, was implemented in community-based HIV service organizations in two cities disproportionately affected by the HIV epidemic. This article reports primarily on the effectiveness results related to condom use and results related to retention challenges within a Hybrid Type 2 implementation/effectiveness trial. Ninety-one individuals enrolled at baseline; 39 completed the posttest, and 30 completed the 3-month follow-up. Although condom use did not monotonically increase from baseline to posttest and 3-month follow-up, it did increase from baseline (44%) to posttest (73%), and from baseline to 3-month follow-up with an overall positive slope of Time 0.13 to 0.14 (p < .001). There was a significant increase in the number of people who used condoms 100% of the time from baseline (36.3%) to posttest (56.4%; p = .04) but not from baseline to 3-month follow-up (46.7%; p = .2907). Challenges with resources as basic as housing, food, and transportation complicated participation (and therefore implementation) and may have impeded couples' maintenance of risk reduction strategies beyond the intervention. In light of couples' numerous observed vulnerabilities, we constructed a composite score of "critical vulnerability" and found that depression was persistently related to critical vulnerability and that retention was higher among those with less vulnerability. These findings highlight the important yet underaddressed role of patient-level factors in the process and outcomes of hybrid implementation/effectiveness research. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Barriers to Testing for Sexually Transmitted Infections among HIV-Serodiscordant Couples: The Influence of Discrimination.

Objectives: African Americans face challenges in accessing services for sexually transmitted infections (STIs). From 2012-2016, the EBAN II intervention was funded by the NIH to test the effectiveness of implementing a culturally congruent, evidence-based HIV/AIDS prevention program in Los Angeles and Oakland, California. This study examined the impact of personal characteristics and experiences of discrimination on the likelihood of being tested for STIs. Methods: Participants (N=91) completed a baseline survey. Descriptive statistics were used to test for differences between those who did and did not obtain STI testing. Factors included HIV serostatus, sociodemographic variables, STI history, the presence of outside partners, and discrimination experiences. Multiple logistic regressions were conducted for men and women separately. Results: Participants with no recent experiences of discrimination were more than 3 (3.4) times more likely to obtain a baseline STI test than those who reported discrimination experiences. HIV-positive women with no recent experiences of discrimination were 11 times more likely than those with reports of recent discrimination to obtain STI tests. Conclusions: It is often women who are the gatekeepers for health seeking in families and the same may be for these couples. Experiences of discrimination may impede STI testing, and heighten several health risks, particularly among HIV-positive African American women in HIV-serodiscordant relationships. Addressing the impact of discrimination experiences may be important for STI prevention and treatment efforts in interventions promoting health care utilization.

Combining surveillance systems to investigate local trends in tuberculosis-HIV co-infection.

Alameda County has some of the highest human immunodeficiency virus (HIV) and tuberculosis (TB) case rates of California counties. We identified TB-HIV co-infected patients in 2002-2015 by matching county TB and HIV registries, and assessed trends in TB-HIV case rates and estimated prevalence ratios for HIV co-infection. Of 2054 TB cases reported during 2002-2015, 91 (4%) were HIV co-infected. TB-HIV case rates were 0.29/100,000 and 0.40/100,000 in 2002 and 2015, respectively, with no significant change (P = 0.85). African-American TB case-patients were 9.77 times (95% confidence interval [CI] 5.90-16.17) more likely than Asians to be HIV co-infected, and men 2.74 times (95% CI 1.66-4.51) more likely co-infected than women. HIV co-infection was more likely among TB case-patients with homelessness (6.21, 95% CI 3.49-11.05) and injection drug use (11.75, 95% CI 7.61-18.14), but less common among foreign-born and older case-patients (both P < 0.05). Among foreign-born case-patients, 42% arrived in the U.S. within 5 years of TB diagnosis. TB-HIV case rates were low and stable in Alameda County, and co-infected patients were predominantly young, male, U.S.-born individuals with traditional TB risk factors. Efforts to reduce TB-HIV burden in Alameda County should target persons with traditional TB risk factors and recently arrived foreign-born individuals.

Targeted demethylation at the CDKN1C/p57 locus induces human ß cell replication.

The loss of insulin-secreting ß cells is characteristic among type I and type II diabetes. Stimulating proliferation to expand sources of ß cells for transplantation remains a challenge because adult ß cells do not proliferate readily. The cell cycle inhibitor p57 has been shown to control cell division in human ß cells. Expression of p57 is regulated by the DNA methylation status of the imprinting control region 2 (ICR2), which is commonly hypomethylated in Beckwith-Wiedemann syndrome patients who exhibit massive ß cell proliferation. We hypothesized that targeted demethylation of the ICR2 using a transcription activator-like effector protein fused to the catalytic domain of TET1 (ICR2-TET1) would repress p57 expression and promote cell proliferation. We report here that overexpression of ICR2-TET1 in human fibroblasts reduces p57 expression levels and increases proliferation. Furthermore, human islets overexpressing ICR2-TET1 exhibit repression of p57 with concomitant upregulation of Ki-67 while maintaining glucose-sensing functionality. When transplanted into diabetic, immunodeficient mice, the epigenetically edited islets show increased ß cell replication compared with control islets. These findings demonstrate that epigenetic editing is a promising tool for inducing ß cell proliferation, which may one day alleviate the scarcity of transplantable ß cells for the treatment of diabetes.

A taxonomy of the scope and organization of local sexually transmitted disease services for policy and practice.

Local health departments (LHDs) and their organizational partners play a critical role in controlling sexually transmitted diseases (STDs) in the United States. We examine variation in the differentiation, integration, and concentration (DIC) of STD services and develop a taxonomy describing the scope and organization of local STD services. LHD STD programs (n = 115) in Alabama (AL) and California (CA) responded to surveys assessing STD services available in 2014. K-means cluster analysis identified LHD groupings based on DIC variation. Discriminant analysis validated cluster solutions. Differences in organizational partnerships and scope of STD services were compared by taxonomy category. Multivariable regression models estimated the association of the STD services organization taxonomy and five-year (2010­2014) gonorrhea incidence rates, controlling for county-level sociodemographics and resources. A three-cluster solution was identified: (1) low DIC (n = 74), (2) moderate DIC (n = 31), and (3) high DIC (n = 10). In discriminant analysis, 95% of jurisdictions were classified into the same types as originally assigned through K-means cluster analysis. High DIC jurisdictions were more likely (p < 0.001) to partner with most organizations than moderate and low DIC jurisdictions, and more likely (p < 0.001) to conduct STD needs assessment, comprehensive sex education, and targeted screening. In contrast, contact tracing, case management, and investigations were conducted similarly across jurisdictions. In adjusted analyses, there were no differences in gonorrhea incidence rates by category. Jurisdictions in CA and AL can be characterized into three distinct clusters based on the DIC of STD services. Taxonomic analyses may aid in improving the reach and effectiveness of STD services.

GABA and Artesunate Do Not Induce Pancreatic α-to-ß Cell Transdifferentiation In Vivo.

Recent reports identified activation of the GABA signaling pathway as a means to induce transdifferentiation of pancreatic α cells into ß cells. These reports followed several previous studies that found that α cells were particularly well suited to conversion into ß cells in mice, but only after nearly complete ß cell loss or forced overexpression of key transcriptional regulators. The possibility of increasing ß cell number via reprograming of α cells with a small molecule is enticing, as this could be a potential new pharmacologic therapy for diabetes. Here, we employed rigorous genetic lineage tracing of α cells, using Glucagon-CreERT2;Rosa-LSL-eYFP mice, to evaluate if activation of GABA signaling caused α-to-ß cell reprogramming. In contrast to previous reports, we found that even after long-term treatment of mice with artesunate or GABA, neither α-to-ß cell transdifferentiation nor insulin secretion were stimulated, putting into question whether these agents represent a viable path to a novel diabetes therapy.

Using a Social Network Strategy to Distribute HIV Self-Test Kits to African American and Latino MSM.

BACKGROUND: Men who have sex with men (MSM) continue to be disproportionately impacted globally by the HIV epidemic. Studies suggest that HIV self-testing (HIVST) is highly acceptable among MSM. Social network strategies to increase testing are effective in reaching MSM, particularly MSM of color, who may not otherwise test. We tested a social network-based strategy to distribute HIVST kits to African American MSM (AAMSM) and Latino MSM (LMSM). SETTING: This study was conducted in Alameda County, California, a large, urban/suburban county with an HIV epidemic mirroring the national HIV epidemic. METHODS: From January 2016 to March 2017, 30 AAMSM, LMSM, and transgender women were trained as peer recruiters and asked to distribute 5 self-test kits to MSM social network members and support those who test positive in linking to care. Testers completed an online survey after their test. We compared peer-distributed HIVST testing outcomes to outcomes from Alameda County's targeted, community-based HIV testing programs using χ tests. RESULTS: Peer-distributed HIVST to 143 social and sexual network members, of whom 110 completed the online survey. Compared with MSM who used the County's sponsored testing programs, individuals reached through the peer-based self-testing strategy were significantly more likely to have never tested for HIV (3.51% vs. 0.41%, P < 0.01) and to report a positive test result (6.14% vs. 1.49%, P < 0.01). CONCLUSION: Findings suggest that a network-based strategy for self-test distribution is a promising intervention to increase testing uptake and reduce undiagnosed infections among AAMSM and LMSM.

Strategies to Increase HIV Testing Among MSM: A Synthesis of the Literature.

More than 30 years into the HIV epidemic, men who have sex with men (MSM) continue to be disproportionately impacted. It is estimated that worldwide nearly half of MSM infected with HIV are unaware of their status, making HIV testing along with early linkage to care crucial to HIV prevention efforts. However, there remain significant barriers to HIV testing among MSM, due largely to complex issues of layered stigma that deter MSM from accessing traditional, clinic-based testing. We conducted a review and synthesis of the literature on strategies to increase uptake of HIV testing among MSM. We found that social network-based strategies, community-based testing, HIV self-testing, and modifications to the traditional clinic-based model can effectively reach a subset of MSM, but success was often context-specific and there are significant gaps in evidence. We provide recommendations for increasing HIV testing rates and status awareness among MSM.

TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury.

Understanding the molecular basis of the regenerative response following hepatic injury holds promise for improved treatment of liver diseases. Here, we report an innovative method to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury. We used the Fah-/- mouse, a model of hereditary tyrosinemia, which conditionally undergoes severe liver injury unless fumarylacetoacetate hydrolase (FAH) expression is reconstituted ectopically. We used translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs specific to repopulating hepatocytes. We uncovered upstream regulators and important signaling pathways that are highly enriched in genes changed in regenerating hepatocytes. Specifically, we found that glutathione metabolism, particularly the gene Slc7a11 encoding the cystine/glutamate antiporter (xCT), is massively upregulated during liver regeneration. Furthermore, we show that Slc7a11 overexpression in hepatocytes enhances, and its suppression inhibits, repopulation following toxic injury. TRAP-seq allows cell type-specific expression profiling in repopulating hepatocytes and identified xCT, a factor that supports antioxidant responses during liver regeneration. xCT has potential as a therapeutic target for enhancing liver regeneration in response to liver injury.

The RSVP Project: Factors Related to Disengagement From Human Immunodeficiency Virus Care Among Persons in San Francisco.

BACKGROUND: In the United States, an estimated two-thirds of persons with human immunodeficiency virus (HIV) infection do not achieve viral suppression, including those who have never engaged in HIV care and others who do not stay engaged in care. Persons with an unsuppressed HIV viral load might experience poor clinical outcomes and transmit HIV. OBJECTIVE: The goal of the Re-engaging Surveillance-identified Viremic Persons (RSVP) project in San Francisco, CA, was to use routine HIV surveillance databases to identify, contact, interview, and reengage in HIV care persons who appeared to be out of care because their last HIV viral load was unsuppressed. We aimed to interview participants about their HIV care and barriers to reengagement. METHODS: Using routinely collected HIV surveillance data, we identified persons with HIV who were out of care (no HIV viral load and CD4 laboratory reports during the previous 9-15 months) and with their last plasma HIV RNA viral load >200 copies/mL. We interviewed the located persons, at baseline and 3 months later, about whether and why they disengaged from HIV care and the barriers they faced to care reengagement. We offered them assistance with reengaging in HIV care from the San Francisco Department of Public Health linkage and navigation program (LINCS). RESULTS: Of 282 persons selected, we interviewed 75 (26.6%). Of these, 67 (89%) reported current health insurance coverage, 59 (79%) had ever been prescribed and 45 (60%) were currently taking HIV medications, 59 (79%) had seen an HIV provider in the past year, and 34 (45%) had missed an HIV appointment in the past year. Reasons for not seeing a provider included feeling healthy, using alcohol or drugs, not having enough money or health insurance, and not wanting to take HIV medicines. Services needed to get to an HIV medical care appointment included transportation assistance, stable living situation or housing, sound mental health, and organizational help and reminders about appointments. A total of 52 (69%) accepted a referral to LINCS. Additionally, 64 (85%) of the persons interviewed completed a follow-up interview 3 months later and, of these, 62 (97%) had health insurance coverage and 47 (73%) reported having had an HIV-related care appointment since the baseline interview. CONCLUSIONS: Rather than being truly out of care, most participants reported intermittent HIV care, including recent HIV provider visits and health insurance coverage. Participants also frequently reported barriers to care and unmet needs. Health department assistance with HIV care reengagement was generally acceptable. Understanding why people previously in HIV care disengage from care and what might help them reengage is essential for optimizing HIV clinical and public health outcomes.

Invasive Obstetric Procedures and Cesarean Sections in Women With Known Herpes Simplex Virus Status During Pregnancy.

BACKGROUND: Neonatal herpes is a potentially devastating infection that results from acquisition of herpes simplex virus (HSV) type 1 or 2 from the maternal genital tract at the time of vaginal delivery. Current guidelines recommend (1) cesarean delivery if maternal genital HSV lesions are present at the time of labor and (2) antiviral suppressive therapy for women with known genital herpes to decrease HSV shedding from the genital tract at the time of vaginal delivery. However, most neonatal infections occur in infants born to women without a history of genital HSV, making current prevention efforts ineffective for this group. Although routine serologic HSV testing of women during pregnancy could identify women at higher risk of intrapartum viral shedding, it is uncertain how this knowledge might impact intrapartum management, and a potential concern is a higher rate of cesarean sections among women known to be HSV-2 seropositive. METHODS: To assess the effects of prenatal HSV-2 antibody testing, history of genital herpes, and use of suppressive antiviral medication on the intrapartum management of women, we investigated the frequency of invasive obstetric procedures and cesarean deliveries. We conducted a retrospective cohort study of pregnant women delivering at the University of Washington Medical center in Seattle, Washington. We defined the exposure of interest as HSV-2 antibody positivity or known history of genital herpes noted in prenatal records. The primary outcome was intrapartum procedures including fetal scalp electrode, artificial rupture of membranes, intrauterine pressure catheter, or operative vaginal delivery (vacuum or forceps). The secondary outcome was incidence of cesarean birth. Univariate and multivariable logistic regressions were performed. RESULTS: From a total of 449 women included in the analysis, 97 (21.6%) were HSV-2 seropositive or had a history of genital herpes (HSV-2/GH). Herpes simplex virus-2/GH women not using suppressive antiviral therapy were less likely to undergo intrapartum procedures than women without HSV-2/GH (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.25-0.95; P = .036), but this relationship was attenuated after adjustment for potential confounders (adjusted OR, 0.69; 95% CI, 0.34-1.41; P = .31). There was no difference in intrapartum procedures for women on suppressive therapy versus women without HSV-2/GH (OR, 1.17; 95% CI, 0.66-2.07; P = .60). Similar proportions of cesarean sections were performed within each group of women: 25% without history of HSV-2/GH, 30% on suppressive treatment, and 28.1% without suppressive treatment (global, P = .73). CONCLUSIONS: In this single-site study, provider awareness of genital herpes infection either by HSV serotesting or history was associated with fewer invasive obstetric procedures shown to be associated with neonatal herpes, but it was not associated with an increased rate of cesarean birth.

Dietary salt regulates uroguanylin expression and signaling activity in the kidney, but not in the intestine.

The peptide uroguanylin (Ugn) is expressed at significant levels only in intestine and kidney, and is stored in both tissues primarily (perhaps exclusively) as intact prouroguanylin (proUgn). Intravascular infusion of either Ugn or proUgn evokes well-characterized natriuretic responses in rodents. Furthermore, Ugn knockout mice display hypertension and salt handling deficits, indicating that the Na(+) excretory mechanisms triggered when the peptides are infused into anesthetized animals are likely to operate under normal physiological conditions, and contribute to electrolyte homeostasis in conscious animals. Here, we provide strong corroborative evidence for this hypothesis, by demonstrating that UU gnV (the rate of urinary Ugn excretion) approximately doubled in conscious, unrestrained rats consuming a high-salt diet, and decreased by ~15% after salt restriction. These changes in UU gnV were not associated with altered plasma proUgn levels (shown here to be an accurate index of intestinal proUgn secretion). Furthermore, enteric Ugn mRNA levels were unaffected by salt intake, whereas renal Ugn mRNA levels increased sharply during periods of increased dietary salt consumption. Together, these data suggest that diet-evoked Ugn signals originate within the kidney, rather than the intestine, thus strengthening a growing body of evidence against a widely cited hypothesis that Ugn serves as the mediator of an entero-renal natriuretic signaling axis, while underscoring a likely intrarenal natriuretic role for the peptide. The data further suggest that intrarenal Ugn signaling is preferentially engaged when salt intake is elevated, and plays only a minor role when salt intake is restricted.

Screening Yield of HIV Antigen/Antibody Combination and Pooled HIV RNA Testing for Acute HIV Infection in a High-Prevalence Population.

IMPORTANCE: Although acute HIV infection contributes disproportionately to onward HIV transmission, HIV testing has not routinely included screening for acute HIV infection. OBJECTIVE: To evaluate the performance of an HIV antigen/antibody (Ag/Ab) combination assay to detect acute HIV infection compared with pooled HIV RNA testing. DESIGN, SETTING, AND PARTICIPANTS: Multisite, prospective, within-individual comparison study conducted between September 2011 and October 2013 in 7 sexually transmitted infection clinics and 5 community-based programs in New York, California, and North Carolina. Participants were 12 years or older and seeking HIV testing, without known HIV infection. EXPOSURES: All participants with a negative rapid HIV test result were screened for acute HIV infection with an HIV Ag/Ab combination assay (index test) and pooled human immunodeficiency virus 1 (HIV-1) RNA testing. HIV RNA testing was the reference standard, with positive reference standard result defined as detectable HIV-1 RNA on an individual RNA test. MAIN OUTCOMES AND MEASURES: Number and proportion with acute HIV infections detected. RESULTS: Among 86,836 participants with complete test results (median age, 29 years; 75.0% men; 51.8% men who have sex with men), established HIV infection was diagnosed in 1158 participants (1.33%) and acute HIV infection was diagnosed in 168 participants (0.19%). Acute HIV infection was detected in 134 participants with HIV Ag/Ab combination testing (0.15% [95% CI, 0.13%-0.18%]; sensitivity, 79.8% [95% CI, 72.9%-85.6%]; specificity, 99.9% [95% CI, 99.9%-99.9%]; positive predictive value, 59.0% [95% CI, 52.3%-65.5%]) and in 164 participants with pooled HIV RNA testing (0.19% [95% CI, 0.16%-0.22%]; sensitivity, 97.6% [95% CI, 94.0%-99.4%]; specificity, 100% [95% CI, 100%-100%]; positive predictive value, 96.5% [95% CI, 92.5%-98.7%]; sensitivity comparison, P < .001). Overall HIV Ag/Ab combination testing detected 82% of acute HIV infections detectable by pooled HIV RNA testing. Compared with rapid HIV testing alone, HIV Ag/Ab combination testing increased the relative HIV diagnostic yield (both established and acute HIV infections) by 10.4% (95% CI, 8.8%-12.2%) and pooled HIV RNA testing increased the relative HIV diagnostic yield by 12.4% (95% CI, 10.7%-14.3%). CONCLUSIONS AND RELEVANCE: In a high-prevalence population, HIV screening using an HIV Ag/Ab combination assay following a negative rapid test detected 82% of acute HIV infections detectable by pooled HIV RNA testing, with a positive predictive value of 59%. Further research is needed to evaluate this strategy in lower-prevalence populations and in persons using preexposure prophylaxis for HIV prevention.