Exposomic Signatures of Tinnitus and/or Hearing Loss.

INTRODUCTION: We evaluated the risk factors associated with tinnitus and/or hearing loss (THL) among active duty (AD) members of the U.S. Army and Marine Aviation Community (AMAC) using an exposomic approach. Specifically, we aimed to determine the factors associated with the reported THL in the Military Health System. METHODS: Longitudinal data were obtained from the Medical Assessment and Readiness System housed at Womack Army Medical Center, Fort Bragg, NC, for a retrospective cohort study that included 78,546 AD AMAC members from October 2015 to December 2019. Multivariable mixed-effects logistic regression was used to assess the relationship between THL and numerous variables to include rank, service time, deployment, tobacco use, alcohol use, age, gender, race, ethnicity, and body mass index. RESULTS: Our analysis included a total of 220,044 person-years of observations. The THL incidence rate was 6.7 per 100 person-years, with an 8.1% period prevalence. THL was associated with age, gender, body mass index, race, deployment, service time, marital status, and tobacco use (all P < .05). Service time greater than 16 years had the greatest odds ratio of THL (4.46, 95% CI: 3.58-5.55, P < .001). CONCLUSIONS: Our assessment shows the utility of using an exposomic approach to create member-specific personalized clinical algorithms for health outcomes. We examined individuals with THL diagnoses and identified a combination of risk factors from biomedical, lifestyle, environmental, and stochastic sources. Taken together, the risk factors identified across the four exposomic domains could help understand the etiology of THL. Our exposomic methodology could be the foundation for generating predictive models. Finally, a specific evaluation of occupational risk factors may provide insight into aspects not readily available from civilian literature. In upcoming years, as the Medical Assessment and Readiness System matures, we will expand our analyses to include prospective, untargeted metabolites and biomarker data.

Exposomic Signatures of Cervical Pain.

INTRODUCTION: We evaluated risk factors associated with cervical pain (CP) among officers and enlisted members of the U.S. Army and Marine Aviation community using an exposomic approach. Specifically, we aimed to determine the factors associated with reported CP. MATERIALS AND METHODS: This is a retrospective cohort study that utilized the Medical Assessment and Readiness System housed at Womack Army Medical Center to evaluate the longitudinal data taken from medical and workforce resources. This study included 77,864 active duty AMAC members during October 2015-December 2019. Multivariable mixed-effects logistic regression was used to assess the relationship between the independent variables of rank, service time, deployment, Armed Forces Qualification Test score, tobacco use, alcohol use, age, gender, race, ethnicity, body mass index, marital status, and education level and the dependent variable, incidence occurrence of CP. RESULTS: The total analysis included 77,864 individuals with 218,180 person-years of observations. The incidence rate of CP was 18.8 per 100 person-years, with a 12% period prevalence. Cervical pain was independently associated with rank, service time, Armed Forces Qualification Test score, and alcohol use (all P < .05). CONCLUSIONS: Our longitudinal exposomic signatures-based approach aims to complement the outcomes of data science and analytics from Medical Assessment and Readiness System with validations of objective biochemical indicator species observed in Army and Marine Aviation community members suffering from CP. This initial approach using parallel track complementarity has the potential of substantiating the underlying mechanisms foundational to design prospective personalized algorithms that can be used as a predictive model. Finally, a specific evaluation of occupational risk factors may provide insight into factors not readily ascertained from the civilian literature.

"I did not see a need to get tested before, everything was going well with my health": a qualitative study of HIV-testing decision-making in KwaZulu-Natal, South Africa.

Few studies have examined HIV-testing decision-making since the South African national HIV counseling and testing campaign in 2010-2011 and subsequent expansion in antiretroviral therapy (ART) eligibility in 2012. We describe HIV-testing decision-making and pathways to testing among participants in Pathways to Care, a cohort study of newly-diagnosed HIV-positive adults in KwaZulu-Natal. Our analysis is embedded within a theoretical framework informed by Arthur Kleinman's work on pluralistic healthcare systems, and the concept of diagnostic itineraries (i.e., the route taken to HIV testing). We conducted 26 semi-structured interviews in 2012, within one month of participants' diagnosis. Most (n = 22) deferred testing until they had developed symptoms, and then often sought recourse in non-biomedical settings. Of the eleven symptomatic participants who accessed professional medical services prior to testing, only three reported that a healthcare professional had offered or recommended an HIV test. Although ART emerged as an important motivator, offering hope of health and normalcy, fear of death and HIV-related stigma remained key barriers. Despite national policy changes in testing and treatment, health system and individual factors contributed to ongoing high levels of late diagnosis of HIV in this study population. Encouraging local health systems to direct clients toward HIV testing, and continuing to raise awareness of the benefits of routine testing remain important strategies to reduce delayed diagnoses.

Immediate Blood Draw for CD4+ Cell Count Is Associated with Linkage to Care in Durban, South Africa: Findings from Pathways to Engagement in HIV Care.

BACKGROUND: Timely linkage to care by newly-diagnosed HIV+ individuals remains a significant challenge to achieving UNAIDS 90-90-90 goals. Current World Health Organization (WHO) guidelines recommend initiating anti-retroviral treatment (ART) regardless of CD4+ count, with priority given to those with CD4+ <350 cells/µl. We evaluated the impact of not having a day-of-diagnosis CD4+ count blood draw, as recommended by South African guidelines, on time to linkage, using data from a prospective cohort study. METHODS: Individuals (N = 2773) were interviewed prior to HIV counseling and testing at three public sector primary care clinics in the greater Durban area; 785 were newly-diagnosed and eligible for the cohort study; 459 (58.5%) joined and were followed for eight months with three structured assessments. Linkage to care, defined as returning to clinic for CD4+ count results, and day-of-diagnosis blood draw were self-reported. RESULTS: Overall, 72.5% did not have a day-of-diagnosis CD4+ count blood draw, and 19.2% of these never returned. Compared with a day-of-diagnosis blood draw, the adjusted hazard ratio of linkage (AHRlinkage) associated with not having day-of-diagnosis blood draw was 0.66 (95%CI: 0.51, 0.85). By 4 months, 54.8% of those without day-of-diagnosis blood draw vs. 75.2% with one were linked to care (chi-squared p = 0.004). Of those who deferred blood draw, 48.3% cited clinic-related and 51.7% cited personal reasons. AHRlinkage was 0.60 (95%CI: 0.44, 0.82) for clinic-related and 0.53 (95%CI: 0.38, 0.75) for personal reasons relative to having day-of-diagnosis blood draw. CONCLUSIONS: Newly-diagnosed HIV+ individuals who did not undergo CD4+ count blood draw on the day they were diagnosed-regardless of the reason for deferring-had delayed linkage to care relative to those with same-day blood draw. To enhance prompt linkage to care even when test and treat protocols are implemented, all diagnostic testing required before ART initiation should be performed on the same day as HIV testing/diagnosis. This may require modifying clinic procedures to enable overnight blood storage if same-day draws cannot be performed, and providing additional counseling to encourage newly-diagnosed individuals to complete day-of-diagnosis testing. Tracking HIV+ individuals via clinic registries should commence immediately from diagnosis to reduce these early losses to care.

Characteristics of Women Enrolled into a Randomized Clinical Trial of Dapivirine Vaginal Ring for HIV-1 Prevention.

INTRODUCTION: Women in sub-Saharan Africa are a priority population for evaluation of new biomedical HIV-1 prevention strategies. Antiretroviral pre-exposure prophylaxis is a promising prevention approach; however, clinical trials among young women using daily or coitally-dependent products have found low adherence. Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges. METHODS: ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection. We describe the baseline characteristics of African women enrolled in the ASPIRE trial. RESULTS: Between August 2012 and June 2014, 5516 women were screened and 2629 HIV-1 seronegative women between 18-45 years of age were enrolled from 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe. The median age was 26 years (IQR 22-31) and the majority (59%) were unmarried. Nearly 100% of participants reported having a primary sex partner in the prior three months but 43% did not know the HIV-1 status of their primary partner; 17% reported additional concurrent partners. Nearly two-thirds (64%) reported having disclosed to primary partners about planned vaginal ring use in the trial. Sexually transmitted infections were prevalent: 12% had Chlamydia trachomatis, 7% Trichomonas vaginalis, 4% Neisseria gonorrhoeae, and 1% syphilis. CONCLUSIONS: African HIV-1 seronegative women at risk of HIV -1 infection were successfully enrolled into a phase III trial of dapivirine vaginal ring for HIV-1 prevention.

Rapid effects of hearing song on catecholaminergic activity in the songbird auditory pathway.

Catecholaminergic (CA) neurons innervate sensory areas and affect the processing of sensory signals. For example, in birds, CA fibers innervate the auditory pathway at each level, including the midbrain, thalamus, and forebrain. We have shown previously that in female European starlings, CA activity in the auditory forebrain can be enhanced by exposure to attractive male song for one week. It is not known, however, whether hearing song can initiate that activity more rapidly. Here, we exposed estrogen-primed, female white-throated sparrows to conspecific male song and looked for evidence of rapid synthesis of catecholamines in auditory areas. In one hemisphere of the brain, we used immunohistochemistry to detect the phosphorylation of tyrosine hydroxylase (TH), a rate-limiting enzyme in the CA synthetic pathway. We found that immunoreactivity for TH phosphorylated at serine 40 increased dramatically in the auditory forebrain, but not the auditory thalamus and midbrain, after 15 min of song exposure. In the other hemisphere, we used high pressure liquid chromatography to measure catecholamines and their metabolites. We found that two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, increased in the auditory forebrain but not the auditory midbrain after 30 min of exposure to conspecific song. Our results are consistent with the hypothesis that exposure to a behaviorally relevant auditory stimulus rapidly induces CA activity, which may play a role in auditory responses.

A qualitative study of obstacles to diaphragm and condom use in an HIV prevention trial in sub-Saharan Africa.

Consistent condom use and the substitution of condoms with potential HIV prevention methods of lower or unknown effectiveness are important concerns in the development of new prevention technologies. This qualitative study explored obstacles to consistent condom use with the diaphragm in MIRA, an HIV prevention trial in South Africa and Zimbabwe. We conducted 26 focus group discussions (FGDs) with 206 women and 7 FGDs and 10 in-depth interviews with 41 male partners of intervention-arm women. The belief that the diaphragm/gel prevented HIV, women's difficulties negotiating condom use, and men's unawareness that using the products together was recommended were obstacles to consistent condom use with the diaphragm/gel. Concerns about protection from HIV and pregnancy, recognition that the diaphragm was not yet proven to prevent HIV or sexually transmitted infections, and the trial context were facilitators. Understanding selective study product use in HIV prevention trials may inform improved adherence counseling and male involvement strategies.

Enzymatic synthesis of TDP-deoxysugars.

Many biologically active bacterial natural products contain highly modified deoxysugar residues that are often critical for the activity of the parent compounds. Most of these deoxysugars are secondary metabolites that are biosynthesized in the form of nucleotide diphosphate (NDP) sugars prior to their transfer to natural product aglycones by glycosyltransferases. Over the past decade, many biosynthetic pathways that lead to the formation of these unusual sugars have been unraveled, and the mechanisms of many key enzymatic transformations involved in these pathways have been elucidated. However, obtaining workable quantities of NDP-deoxysugars for in vitro studies is often a difficult task. This limitation has hindered an in-depth investigation of the substrate specificity of deoxysugar biosynthetic enzymes, many of which are promiscuous with respect to their NDP-sugar substrates and are, thus, potentially useful catalysts for natural product glycoengineering. Presented in this review are procedures for the enzymatic synthesis and purification of a variety of NDP-deoxysugars, including some early intermediates in NDP-deoxysugar biosynthetic pathways, and highly modified NDP-deoxysugars that are late intermediates in their respective biosynthetic pathways. The procedures described herein could be used as general guidelines for the development of specific protocols for the synthesis of other NDP-deoxysugars.