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Abstract Background Refeeding hypophosphatemia (RH) is a common complication of nutritional restoration in malnourished individuals, yet clear risk stratification remains elusive. Individuals with anorexia nervosa (AN) and avoidant/restrictive food intake disorder (ARFID) may be deficient in vitamin D, an important component of dietary phosphorus absorption in the gut. The relationship between vitamin D and RH in AN and ARFID is unknown. Therefore, the aims of this study were to (1) report rates of low serum 25-hydroxy vitamin D and RH in AN and ARFID; (2) describe associations between phosphorus and variables associated with RH identified in extant literature; (3) examine the relationship between 25-hydroxy vitamin D and RH and (4) investigate moderation by vitamin D between variables of interest and phosphorus level. Method Analyses included retrospective chart review of 307 individuals admitted to the ACUTE Center for Eating Disorders and Severe Malnutrition with a diagnosis of AN or ARFID. Variables of interest included admission laboratory values (vitamin D level, comprehensive metabolic panel, hemoglobin, point-of-care blood glucose), anthropometric measures (weight, body mass index [BMI], % ideal body weight [IBW]), age, duration of illness, length of stay, feeding method, and serum phosphorus nadir. Pearson and Spearman rank correlation, one-way ANOVA, and regression analyses were used to determine the relationship between variables and serum phosphorus. Results Over 1/3 of the sample (35.3%) had serum phosphorus levels ≤ 2.9 mg/dL. There were no significant differences between groups in phosphorus nadir (p = .17, η 2 = 0.12) or hypophosphatemia (p = .16, ϕc = 0.11). Thirty-five (35%) of individuals with ARFID were either deficient or insufficient in vitamin D, compared to 29% of individuals with AN. Individuals with AN had significantly higher mean vitamin D levels compared to those with ARFID (p = .03; η 2 = 0.015). Nadir phosphorus showed a positive association with weight, BMI, %IBW, potassium, and calcium on admission, and a negative association with length of stay, hemoglobin, and total number of tube-fed days. Higher levels of 25-hydroxy vitamin D moderated the relationship between serum phosphorus nadir and weight on admission (p = .0004). Conclusion Individuals diagnosed with ARFID are as nutritionally fragile as those with AN regarding vitamin D and RH. The negative feedback loop involving vitamin D that maintains phosphorus homeostasis may play a role in the development of RH in AN and ARFID.

Abstract Environmental DNA (eDNA) is increasingly used to detect animals in aquatic habitats, but uncertainty remains about the relationship between the present location of an animal relative to eDNA detections. In marine environments, physical characteristics—such as tides and currents—can influence the distribution of eDNA. In this study, we make use of hatchery net pens containing >46 million juvenile chum salmon (Oncorhynchus keta) in nearshore Southeast Alaska to test for dispersion of eDNA and the effects of tide. Initially, we collected and filtered surface water every 80 m along a 2 km transect to test eDNA attenuation over surface distance during incoming and outgoing tides on a single day. The following year, we sampled at three depths (0 m, 5 m, and 10 m) every 500 m along the same transect as well as along a perpendicular transect, to understand dispersion by depth and in additional directions. Chum salmon eDNA was quantified using species‐specific qPCR. We found that surface samples showed a consistent signal of decreasing chum salmon eDNA across the 2 km transect (R2 = 0.665), with the majority of eDNA detections within 1.5 km of the net pens. Tide had a significant effect, resulting in higher concentrations of chum DNA throughout the transect during incoming tide and a steeper decline in eDNA over distance during outgoing tide (R2 = 0.759). Depth affected chum salmon DNA concentration, with the majority of eDNA at the surface and a decreasing amount of DNA with increasing depth. This study addresses one of the critical knowledge gaps in applying eDNA to marine fisheries management by providing empirical evidence of eDNA dispersion and demonstrating that most eDNA detections are likely from nearby individuals that are either currently or recently present. Yet even at close proximity, eDNA signal strength fluctuates and depends on the physical environmental variables during a given sampling event.

Abstract Background Audit and feedback (A&F) is an implementation strategy that can facilitate implementation tailoring by identifying gaps between desired and actual clinical care. While there are several theory-based propositions on which A&F components lead to better implementation outcomes, many have not been empirically investigated, and there is limited guidance for stakeholders when applying A&F in practice. The current study aims to illustrate A&F procedures in six community mental health clinics, with an emphasis on reporting A&F components that are relevant to theories of how feedback elicits behavior change. Methods Six clinics from a larger trial using a tailored approach to implement measurement-based care (MBC) were analyzed for feedback content, delivery mechanisms, barriers to feedback, and outcomes of feedback using archival data. Pattern analysis was conducted to examine relations between A&F components and changes in MBC use. Results Several sites utilized both aggregate and individualized data summaries, and data accuracy concerns were common. Feedback cycles featuring individual-level clinician data, data relevant to MBC barriers, and information requested by data recipients were related to patterns of increased MBC use. Conclusions These findings support extant theory, such as Feedback Intervention Theory. Mental health professionals wishing to apply A&F should consider establishing reciprocal feedback mechanisms on the quality and amount of data being received and adopting specific roles communicating and addressing data quality concerns. Trial registration ClinicalTrials.gov Identifier: NCT02266134.

Background: The role of music in the NICU continues to evolve, with recent studies documenting the positive impact of music therapy for hospitalized infants and families. With many potential benefits and no substantial adverse effects reported to date in medically stable infants, we aimed to create a clinical guideline to integrate this therapy into the NICU operations. Methods: we launched and implemented a pilot music therapy clinical program within a subunit of a level-III NICU, building upon available evidence. Results: In this report, we describe our experience with initial program development and early outcomes in terms of population served, frequency of music therapy, and therapeutic modalities employed to implement service delivery. Conclusion: we highlight the importance of establishing practices that are aligned with currently available data and recommendations, in order to facilitate delivery of a safe, evidence-based, meaningful therapeutic experience with monitoring of preliminary effects of the therapy on all those involved in the experience.

Abstract Objective: To investigate whether food insecurity helps explain the association between income and psychological distress and if its role differs by disability status. Design: Using 2011–2017 National Health Interview Survey cross-sectional data (n 102 543), we conducted linear regression models, fully interacted with disability status, to estimate the association between income-to-poverty ratio (IPR) (

HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus. In this review, we have described the development path of the TAF/EVG insert up to its current point in clinical testing, highlighting findings from acceptability, preclinical safety, pharmacokinetics, and efficacy evaluations and early clinical studies. In summary, the TAF/EVG inserts are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention.

This study introduces a convenient and ultra-sensitive method of detection and quantification of the antiviral drug, tenofovir (TFV), by surface-enhanced Raman spectroscopy (SERS). Novel spatially resolved instrumentation for spectral acquisition and subsequent statistical analysis for hot spot selection was developed for convenient quantification of TFV in an aqueous matrix. Methods of statistical analysis include the use of partial least squares (PLS) regression vector analysis and spectral ranking by quality indices computed using CHAOS theory. Hydroxylamine-reduced Ag colloidal nanoparticles evaporated to dryness on an aluminum well-plate were used as the SERS substrate. To our knowledge, quantification of TFV down to 25 ng/mL by SERS, comprising clinically relevant concentrations, has not been previously reported. Furthermore, in this work we propose a novel method of quantification of aqueous TFV standards by SERS using statistical treatment of data by PLS and CHAOS theory. Based on these data, we propose future studies to develop a method of TFV detection and quantification in biological samples, beneficial to clinicians for rapid assessment of drug adherence during the treatment and prevention of viral diseases.

IntroductionWe have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor–gamma coactivator 1-alpha (PGC1α) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1α expression and activity during IBD is not yet clear.MethodsMice (male; C57Bl/6, Villincre/+;Pgc1afl/fl mice, and Pgc1afl/fl) were subjected to experimental colitis and treated with nicotinamide riboside. Western blot, high-resolution respirometry, nicotinamide adenine dinucleotide (NAD+) quantification, and immunoprecipitation were used to in this study.ResultsWe demonstrate a significant depletion in the NAD+ levels within the intestinal epithelium of mice undergoing experimental colitis, as well as humans with ulcerative colitis. While we found no decrease in the levels of NAD+-synthesizing enzymes within the intestinal epithelium of mice undergoing experimental colitis, we did find an increase in the mRNA level, as well as the enzymatic activity, of the NAD+-consuming enzyme poly(ADP-ribose) polymerase-1 (PARP1). Treatment of mice undergoing experimental colitis with an NAD+ precursor reduced the severity of colitis, restored mitochondrial function, and increased active PGC1α levels; however, NAD+ repletion did not benefit transgenic mice that lack PGC1α within the intestinal epithelium, suggesting that the therapeutic effects require an intact PGC1α axis.DiscussionOur results emphasize the importance of PGC1α expression to both mitochondrial health and homeostasis within the intestinal epithelium and suggest a novel therapeutic approach for disease management. These findings also provide a mechanistic basis for clinical trials of nicotinamide riboside in IBD patients.

Abstract Background While oral pre-exposure prophylaxis (PrEP) has been shown to reduce the risk of HIV, challenges such as adhering to a daily-dosing regimen and persistence have emerged as barriers for at-risks populations in South Africa. This qualitative research sought to investigate perceptions of and preferences for a long-acting, biodegradable implantable PrEP product designed to address these barriers. Methods To identify and understand motivators, barriers, and preferences for the PrEP implant, we conducted qualitative in-depth interviews (IDIs) among health care providers (HCPs) and target end-users (young women, adolescent girls, and female sex workers) in urban and rural/peri-urban regions of Gauteng Province, South Africa. The IDIs focused on defining values, beliefs, habits, lifestyles, influencers, and information channels for potential PrEP implant end-users. Results We conducted 36 IDIs across health care providers and target end-user respondent segments. Respondents had generally positive reactions to the PrEP implant. Most end-users felt that some undesirable aspects of the implant (e.g., side effects, pain during insertion, potential scarring, and inability to remove implant) would be offset by having a highly effective, and long-lasting HIV prevention product. Although some HCPs believed the implantable PrEP would lead to increases in promiscuity and risky sexual behavior, most HCPs saw value in the PrEP implant’s long duration of protection, its biodegradability, and the likelihood of higher adherence relative to oral PrEP. Conclusions This study is a first step toward further research needed to demonstrate the demand for a biodegradable, long-acting implantable PrEP and suggests such a product would be accepted by end-users and HCPs in South Africa. This study indicates the need to develop more convenient, discreet, long-acting, and highly effective biomedical HIV prevention options for at-risk populations.

Abstract Background Tailored implementation approaches are touted as superior to standardized ones with the reasoning that tailored approaches afford opportunities to select strategies to resolve determinants of the local context. However, results from implementation trials on this topic are equivocal. Therefore, it is important to explore relevant contextual factors that function as determinants to evaluate if they are improved by tailoring and subsequently associated with changes in implementation outcomes (i.e., via statistical mediation) to better understand how tailoring achieves (or does not achieve) its effects. The present study examined the association between a tailored and standardized implementation approach, contextual factors that might mediate change, and a target implementation outcome in an initiative to implement measurement-based care (specifically the clinical integration of the Patient Health Questionnaire [PHQ-9] for depression) in a community mental health organization. Methods Using a cluster randomized control design, twelve community-based mental health clinics were assigned to a tailored or standardized implementation group. Clinicians completed a self-report battery assessing contextual factors that served as candidate mediators informed by the Framework for Dissemination at three time points: baseline, 5 months after active implementation support, and 10 months after sustainment monitoring. A subset of clinicians also participated in focus groups at 5 months. The routine use of the PHQ-9 (implementation outcome) was monitored during the 10-month sustainment period. Multi-level mediation analyses assessed the association between the implementation group and contextual factors and the association between contextual factors and PHQ-9 completion. Quantitative results were then elaborated by analyzing qualitative data from exemplar sites. Results Although tailored clinics outperformed standard clinics in terms of PHQ-9 completion at the end of active implementation, these group differences disappeared post sustainment monitoring. Perhaps related to this, no significant mediators emerged from our quantitative analyses. Exploratory qualitative analyses of focus group content emphasized the importance of support from colleagues, supervisors, and leadership when implementing clinical innovations in practice. Conclusions Although rates of PHQ-9 completion improved across the study, their sustained levels were roughly equivalent across groups and low overall. No mediators were established using quantitative methods; however, several partial quantitative pathways, as well as themes from the qualitative data, reveal fruitful areas for future research. Trial registration Standardized versus tailored implementation of measurement-based care for depression. ClinicalTrials.gov NCT02266134, first posted on October 16, 2014

Gay, bisexual, and other men who have sex with men (MSM) are disproportionally impacted by HIV. Discrimination, violence, and psychological distress (PD) may influence engagement with HIV prevention services and amplify HIV vulnerability among this priority population. These dynamics are understudied in the Southern United States. Understanding how these relationships interact is critical to designing effective HIV programs. We examined associations between MSM-related discrimination, MSM-related violence, and severe PD with HIV status among 2017 National HIV Behavioral Surveillance study participants in Memphis, Tennessee. Eligible participants were aged ≥18 years, born and identified as male, and reported having sex with another man in their lifetime. Participants completed a Centers for Disease Control and Prevention–designed anonymous survey and self-reported discrimination and violence across their lifetime, and PD symptoms within the past month, scored on the Kessler-6 Scale. Optional HIV rapid tests were performed on-site. Logistic regressions examined the associations between the exposure variables and HIV antibody-positive results. Among 356 respondents, 66.9% were aged

Summary: Background: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. Methods: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). Findings: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%–98.8%) and 100% (95% CI = undefined), respectively. Interpretation: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. Funding: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.

Summary: Background: Topical on-demand forms for HIV pre-exposure prophylaxis (PrEP) may be a desirable alternative for people that prefer not to use daily PrEP. CONRAD has developed inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) for on-demand vaginal or rectal pericoital use. We assessed the pharmacokinetics (PK) and pre-exposure efficacy of rectally applied TAF/EVG inserts in macaques. Methods: PK was assessed in 12 pigtailed macaques. Tenofovir (TFV) and EVG levels were assayed in rectal biopsies and secretions, and tenofovir-diphosphate (TFV-DP) levels in biopsies and peripheral blood mononuclear cells (PBMC). Drug biodistribution was evaluated in 10 animals at necropsy 4 h post-dosing. For efficacy assessments, one or two TAF/EVG inserts were administered to macaques (n = 6) 4 h before repeated rectal SHIV162p3 challenges. Findings: One TAF/EVG insert resulted in rapid and high EVG and TFV-DP in rectal tissue 4 h after application. Adding a second insert led to a 10-fold increase in EVG and TFV-DP in rectal tissue. Efficacy of one and two TAF/EVG inserts were 72.6% (CI 24.5%–92.6%) and 93.1% (CI 73.3%–99.2%), respectively. Interpretation: Although high TFV-DP and EVG levels were observed with one rectal TAF/EVG insert, it only conferred partial protection from rectal SHIV challenges. Adding a second insert led to an increase in TFV and EVG in rectal tissues resulting in higher (>90%) efficacy. These results highlight the high efficacy of TAF/EVG inserts as topical on-demand rectal PrEP, as well as the need for appropriate drug coverage in the deep rectum and colon to achieve high protection. Funding: The work related to animal studies was funded by CDC intramural funds and an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002). The work related to the insert formulation was funded by U.S. PEPFAR through USAID under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. The findings and conclusions of this manuscript are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention (CDC), USAID, President's Emergency Plan for AIDS Relief (PEPFAR), Eastern Virginia Medical School (EVMS), or the US government.

Abstract Background Strict adherence to antiretroviral-based microbicide use is important for effective HIV prevention. We previously developed a composite measure of product adherence, protocol compliance, and semen exposure for determining vaginal use of tenofovir (TFV) 1% gel applicators through biomarkers and residual drug analyses. In this study, we tested the ability of the composite measure in vaginally used TFV gel applicators from a Phase III HIV prevention clinical trial. Methods Used vaginal gel applicators from the FACTS 001 study were swabbed for detection of vaginal bacterial markers (vaginal insertion), semen DNA markers (semen exposure), and residual TFV gel (product use). Results Of 1,098 evaluable TFV and placebo applicators, 80% had detectable vaginal insertion biomarkers and 52% had semen biomarkers. Ninety-nine percent of vaginally inserted applicators TFV applicators had detectable residual TFV as measured by liquid chromatography with tandem mass spectroscopy (LC–MS/MS). Residual TFV levels were also successfully detected using Fourier Transform Infrared (FTIR)-based spectroscopy. Conclusions Vaginal insertion and semen exposure biomarkers were detectable on used TFV 1% gel applicators. Residual TFV on these gel applicators was detectable by LC–MS/MS and FTIR-based spectroscopy, which has potential to be a more convenient and quicker method for detecting drug use. With continual improvements, this composite measure of product adherence, protocol compliance, and semen exposure has potential to assess use of not only TFV gel but also other topical microbicides or products.

Abstract Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (DLPFC) has been shown to promote working memory (WM), however, its efficacy against time-on-task-related performance decline and associated cognitive fatigue remains uncertain. This study examined the impact of anodal tDCS of the left DLPFC on performance during a fatiguing visuospatial WM test. We adopted a repeated measures design, where 32 healthy adults (16 female), underwent anodal, control and sham tDCS on separate days. They completed an hour long two-back test, with stimulation intensity, onset, and duration set at 1 mA, at the 20th minute for 10 minutes respectively. Task performance, subjective responses, and heart rate variability (HRV) were captured during the experiment. Anodal tDCS substantially improved WM relative to sham tDCS and control in both sexes. These benefits lasted beyond the stimulation interval, and were unique across performance measures. However, no perceptual changes in subjective effort or fatigue levels were noted between conditions, although participants reported greater discomfort during stimulation. While mood and sleepiness changed with time-on-task, reflecting fatigue, these were largely similar across conditions. HRV increased under anodal tDCS and control, and plateaued under sham tDCS. We found that short duration anodal tDCS at 1 mA was an effective countermeasure to time-on-task deficits during a visuospatial two-back task, with enhancement and preservation of WM capacity. However, these improvements were not available at a perceptual level. Therefore, wider investigations are necessary to determine “how” such solutions will be operationalized in the field, especially within human-centered systems.

Background: Brief educational trainings are often used for disseminating and implementing evidence-based practices (EBPs). However, many accessible trainings are ubiquitously standardized. Tailored training focused on modifying individual or contextual factors that may hinder EBP implementation is recommended, but there is a dearth of research comparing standardized versus tailored training. This study sought to: (a) assess the impact of MBC training on clinician intention to use measurement-based care (MBC); (b) compare the effect of standardized versus tailored training on clinician intention to MBC; and (c) identify clinician-level predictors of intention. Methods: Clinicians ( n = 152) treating adult clients with depression at 12 community mental health clinics were randomized to either tailored or standardized MBC training. Clinic-specific barriers and facilitators were used to inform training content and structure tailoring. Linear mixed modeling tested the association between training condition and post-training intention to use MBC, as well as hypothesized individual-level predictors of post-training intention (e.g., age, gender). Results: Clinician intention pre- and post-training increased across training conditions ( B = 0.38, t = −5.95, df = 36.99, p .05, Cohen's d = .15). Only baseline intention emerged as a predictor of post-training intention ( B = 0.39, SE = .05, p

This experimental study explored the use of online expressive writing interventions to cope with distress from heterosexist events among a sample of autistic-LBGQ + individuals. This study included an open writing condition and an emotion focused therapy guided writing condition. Over 89% of the participants indicated that the writing exercises were helpful in processing the event, with significant decreases for measures of depressive and trauma/stressor symptoms. A thematic analysis identified specific aspects of each condition that were helpful for participants in coping with heterosexist distress, such as the development of insight through the emotion-focused exercises. This low-demand exercise is promising as a solo exercise or as a therapy homework assignment, especially given the accessibility of this online intervention for autistic-LGBQ + people.

BackgroundA relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported.ObjectiveCONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK.MethodsThe study screened 68 participants and randomized 47 (37 TFV/LNG, 10 placebo), assessing the vaginal microbiota by sequencing the V3–V4 regions of 16S rRNA genes prior to IVR insertion and monthly for 3 months. Concentrations of TFV in vaginal fluid (VF), and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue, and modeled PD against HIV-1 in vitro were measured before and after treatment.ResultsThere were no clinically significant changes in relative abundance of vaginal bacterial phylotypes from pre-insertion baseline at any month among active and placebo IVR users. There were no significant changes in community state type (CST) with IVR use. Participants with diverse, anaerobic CST IVA/B microbiota had higher in vivo release of TFV from the IVR compared to women with Lactobacillus-dominated (LbD) microbiota, who had expected in vivo TFV release rates. Median VF TFV concentrations were significantly higher among women with CST IVA/B microbiota in months 1 (3,135 ng/mg VF) and 2 (3,800 ng/mg). Women with LbD microbiota had significantly higher median VF TFV concentration (1,423 ng/mg) and median TFV (103 ng/mg) and TFV-DP (5,877 fmol/mg) tissue concentrations versus women with CST IVA/B microbiota at month 3. All women demonstrated a significant increase from pre-insertion baseline of in vitro HIV-1 inhibition by VF (p values

Multipurpose prevention technologies (MPTs), which prevent sexually transmitted infection(s) and unintended pregnancy, are highly desirable to women. In this randomized, placebo-controlled, phase I study, women used a placebo or tenofovir (TFV) and levonorgestrel (LNG) intravaginal ring (IVR), either continuously or cyclically (three, 28-day cycles with a 3 day interruption in between each cycle), for 90 days. Sixty-eight women were screened; 47 were randomized to 4 arms: TFV/LNG or placebo IVRs used continuously or cyclically (4:4:1:1). Safety was assessed by adverse events and changes from baseline in mucosal histology and immune mediators. TFV concentrations were evaluated in multiple compartments. LNG concentration was determined in serum. Modeled TFV pharmacodynamic antiviral activity was evaluated in vaginal and rectal fluids and cervicovaginal tissue ex vivo. LNG pharmacodynamics was assessed with cervical mucus quality and anovulation. All IVRs were safe with no serious adverse events nor significant changes in genital tract histology, immune cell density or secreted soluble proteins from baseline. Median vaginal fluid TFV concentrations were >500 ng/mg throughout 90d. TFV-diphosphate tissue concentrations exceeded 1,000 fmol/mg within 72hrs of IVR insertion. Mean serum LNG concentrations exceeded 200 pg/mL within 2h of TFV/LNG use, decreasing quickly after IVR removal. Vaginal fluid of women using TFV-containing IVRs had significantly greater inhibitory activity (87–98% versus 10% at baseline; p10-fold reduction in HIV p24 antigen production from ectocervical tissues after TFV/LNG exposure. TFV/LNG IVR users had significantly higher rates of anovulation, lower Insler scores and poorer/abnormal cervical mucus sperm penetration. Most TFV/LNG IVR users reported no change in menstrual cycles or fewer days of and/or lighter bleeding. All IVRs were safe. Active rings delivered high TFV concentrations locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. Trial registration: ClinicalTrials.gov #NCT03279120.

Abstract Background Understanding the mechanisms of implementation strategies (i.e., the processes by which strategies produce desired effects) is important for research to understand why a strategy did or did not achieve its intended effect, and it is important for practice to ensure strategies are designed and selected to directly target determinants or barriers. This study is a systematic review to characterize how mechanisms are conceptualized and measured, how they are studied and evaluated, and how much evidence exists for specific mechanisms. Methods We systematically searched PubMed and CINAHL Plus for implementation studies published between January 1990 and August 2018 that included the terms “mechanism,” “mediator,” or “moderator.” Two authors independently reviewed title and abstracts and then full texts for fit with our inclusion criteria of empirical studies of implementation in health care contexts. Authors extracted data regarding general study information, methods, results, and study design and mechanisms-specific information. Authors used the Mixed Methods Appraisal Tool to assess study quality. Results Search strategies produced 2277 articles, of which 183 were included for full text review. From these we included for data extraction 39 articles plus an additional seven articles were hand-entered from only other review of implementation mechanisms (total = 46 included articles). Most included studies employed quantitative methods (73.9%), while 10.9% were qualitative and 15.2% were mixed methods. Nine unique versions of models testing mechanisms emerged. Fifty-three percent of the studies met half or fewer of the quality indicators. The majority of studies (84.8%) only met three or fewer of the seven criteria stipulated for establishing mechanisms. Conclusions Researchers have undertaken a multitude of approaches to pursue mechanistic implementation research, but our review revealed substantive conceptual, methodological, and measurement issues that must be addressed in order to advance this critical research agenda. To move the field forward, there is need for greater precision to achieve conceptual clarity, attempts to generate testable hypotheses about how and why variables are related, and use of concrete behavioral indicators of proximal outcomes in the case of quantitative research and more directed inquiry in the case of qualitative research.

Abstract Background Urbanization is occurring rapidly on a global scale and is altering mosquito communities, creating assemblages that are characteristically less diverse. Despite high rates of urbanization and ample examples of vector-borne diseases transmitted by multiple species, the effects of urbanization-driven mosquito diversity losses on disease transmission has not been well explored. We investigated this question using the dog heartworm, a filarial parasite vectored by numerous mosquito species. Methods We trapped host-seeking mosquitoes in undeveloped areas and neighborhoods of different ages in Wake County, North Carolina, USA, analyzing captured mosquitoes for heartworm DNA. We compared within-mosquito heartworm infection across land-use types by Kruskal–Wallis and likelihood ratio tests. Using zip code level data acquired from dogs in a local shelter, we performed linear regressions of within-host heartworm prevalence by within-mosquito heartworm prevalence as well as by three mosquito diversity measures. We also determined the best predictor of host-level prevalence among models including within-mosquito infection, mosquito diversity and abundance, and socioeconomic status as variables. Results Suburban areas had lower within-mosquito heartworm prevalence and lower likelihood of heartworm-positive mosquitoes than did undeveloped field sites, although no differences were seen between suburban and undeveloped wooded sites. No relationships were noted between within-mosquito and within-host heartworm prevalence. However, mosquito diversity metrics were positively correlated with host heartworm prevalence. Model selection revealed within-host prevalence was best predicted by a positive relationship with mosquito Shannon–Wiener diversity and a negative relationship with household income. Conclusions Our results demonstrate that decreases in mosquito diversity due to urbanization alter vector-borne disease risk. With regard to dog heartworm disease, this loss of mosquito diversity is associated with decreased heartworm prevalence within both the vector and the host. Although the response is likely different for diseases transmitted by one or few species, mosquito diversity losses leading to decreased transmission could be generalizable to other pathogens with multiple vectors. This study contributes to better understanding of the effects of urbanization and the role of vector diversity in multi-vectored pathosystems.

Abstract Background Adherence to topical microbicides for HIV prevention has been a challenge for women using them and those developing novel products. The Quatro Clinical Crossover Study investigated user preference and acceptability of four different placebo‐based vaginal delivery forms among young African women. The objective of this sub‐study was to test the ability of objective adherence measures in assessing placebo product usage. Methods A total of two hundred women from Zimbabwe and South Africa used placebo vaginal gel, insert, and film once per week, with or without sex, for 1 month and an intravaginal ring continuously for one month (Months 1–4). Women then chose their preferred product and used it with sex each week during Month 5. Women self‐collected vaginal swabs after using the gel, insert and film. Collected vaginal swabs and used intravaginal rings were analysed for placebo‐based adherence measures using spectroscopy and excipient‐based analyses to determine product use. Vaginal insertion and semen exposure was determined using previously developed and published adherence biomarkers. Intravaginal rings were extracted for residual excipient (glycerin) and penetrated bioanalytes. Results Both methodologies showed that women used gel the most during Months 1–4 (75% by excipient methods, 85% by spectroscopy). The methodologies also determined that nearly all swabs from both sites were vaginally inserted, and 51–86% had detectable placebo product. Semen was detected in more swabs collected during Month 5 from women in Zimbabwe than the swabs from women in South Africa, and most of those swabs had placebo product present as well. The majority of women used the ring for the required four weeks. Sixty‐eight per cent of women who used the ring for the required 4 weeks increased to 78% during Month 5. Conclusion This sub‐study demonstrated how these objective placebo‐based measures of adherence determined product use of various microbicide delivery forms.

The COVID-19 (coronavirus disease–2019) pandemic disrupted the education of students across the globe in the spring of 2020. Students who were previously at most risk for falling behind their peers and through the cracks because of academic, financial, racial, and/or generational disadvantage faced a wide range of additional obstacles in the pursuit of their college goals. This qualitative study sought to uncover postsecondary advising implications for students through the perspectives of near-peer college advisers (n = 23) serving in high-need schools in two different states as intensive, in-person advising was forced to adapt to virtual formats. Two key thematic findings reveal that advisers faced new communication challenges and existing systemic barriers for marginalized students became even larger. For seniors who had not yet made final postsecondary decisions or who had remaining to-dos, the impact of school closures and distanced advising may have fatally widened existing cracks in the path to college.

Abstract This study examined an urban school readiness initiative that developed parent leadership as a key strategy for increasing the likelihood that all children enter kindergarten ready to succeed. Parent Leaders were primarily immigrant mothers who conducted outreach activities and child developmental screenings with low income, under-served, urban and immigrant families with young children. Using a rigorous case study design, this qualitative study investigated what strategies Parent Leaders used to engage families and how their leadership influenced families, neighborhoods, and the Parent Leaders themselves. The study found that Parent Leaders (1) used highly relational strategies to engage families, (2) shifted community norms about parent leadership, and (3) developed their own identities as leaders. These findings contribute to an increased understanding of how and why parent leadership matters for school readiness research, practice, and policy, particularly in immigrant and under-served communities.

This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (Ci) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (Ci-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked Ci-polyvinyl alcohol-boric acid (Ci-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to Ci gelling properties) on vaginal application (at acidic pH of ~3.5–4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7–8 of seminal fluid, thereby acting as a physical barrier to motile sperm. The gels were characterized for dynamic rheology, physicochemical properties, and impact on sperm functionality (motility, viability, penetration). The rheology data confirmed that the Ci-PBA gel was formed by ionic interactions whereas Ci-PVA-BA gel was chemically cross-linked and became more elastic at basic pH. Based on the screening data, lead gels were selected for in vitro sperm functionality testing. The in vitro results confirmed that the Ci-PBA and Ci-PVA-BA gels created a barrier at the sperm-gel interface, providing sperm blocking properties. For preclinical proof-of-concept, the Ci-PBA gels were applied vaginally and tested for contraceptive efficacy in rabbits, demonstrating only partial efficacy (40–60%). Overall, the in vitro and in vivo results support the development and further optimization of cross-linked gels using commercially available materials as vaginal contraceptives.