Alternatives assessment: An analysis on progress and future needs for research and practice.

Alternatives assessment is a science-policy approach to support the informed substitution of chemicals of concern in consumer products and industries, with the intent of avoiding regrettable substitution and facilitating the transition to safer, more sustainable chemicals and products. The field of alternatives assessment has grown steadily in recent decades, particularly after the publication of specific frameworks and the inclusion of substitution and alternatives assessment requirements in a number of policy contexts. Previously, 14 research and practice needs for the field were outlined across five critical areas: comparative hazard assessment, comparative exposure characterization, lifecycle considerations, decision-making and decision analysis, and professional practice. The aim of the current article is twofold: to highlight methodological advances in the growing field of alternatives assessment based on identified research and practice needs and to propose areas for future developments. We assess advances in the field based on the analysis of a broad literature review that captured 154 sources published from 2013 to 2022. The results indicate that research conducted advanced many of the needs identified, but several remain underaddressed. Although the field has clearly grown and taken root over the past decade, there are still research and practice gaps, most notably on the hazard assessment of mixtures or different forms of chemicals, the integration of lifecycle considerations, and the development of practical approaches to address trade-offs in decision-making. We propose modifications to four of the prior research and practice needs in addition to new needs, including the development of standardized hazard assessment approaches for chemical mixtures as well as better integration of equity and/or justice considerations into assessments. Integr Environ Assess Manag 2024;00:1-18. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Monkeypox (Mpox) Vaccine Hesitancy Among Mpox Cases: A Qualitative Study.

Human mpox has been an increasing concern in the United States and California since late 2022. While the Jynneos vaccine offers a degree of cross-protection against the disease, vaccine hesitancy is common among those recommended for vaccination. The purpose of this study was to assess vaccine knowledge, facilitators, and barriers to vaccine uptake among individuals previously diagnosed with mpox, or mpox cases, in Santa Clara County, California. In-depth interviews were conducted by public health department staff among mpox cases diagnosed in Santa Clara County between July and September 2022. Responses were analyzed using a grounded theory data analysis approach. Among the 47 participants, 36 (77%) had heard of mpox before diagnosis, and of these, 20 (56%) did not think they were at risk of developing mpox, and 28 (78%) were aware that a vaccine was available. Those who did not receive the vaccine stated vaccine access and availability were the main barriers. Among the six participants not interested in the vaccine, the main hesitancies were lack of perceived risk, stigma of being branded by scarring and labeled gay, and vaccine safety. Overall, the following themes were attributed to reasons for vaccine hesitancy: (a) lack of awareness of the disease and vaccine, including perceived risks; (b) lack of vaccine availability and accessibility; and (c) stigma associated with receiving the vaccine, including being publicly labeled as "gay" and the scarring on forearm potentially seen as branding. We recommend tailoring outreach and educational campaigns to address reasons for mpox vaccine hesitancy.

The use of alternatives assessment in chemicals management policies: Needs for greater impact.

Alternatives assessment is a methodology used to identify, evaluate, and compare potential chemical and nonchemical solutions with a substance of concern. It is required in several chemicals management regulatory frameworks, with the objective of supporting the transition to safer chemistry and avoiding regrettable substitutions. Using expert input from symposium presentations and a discussion group hosted by the Association for the Advancement of Alternatives Assessment, four case examples of the use of alternatives assessment in regulatory frameworks were evaluated and compared: (1) the US Environmental Protection Agency Significant New Alternatives Policy (USEPA SNAP), (2) authorization provisions in the EU REACH (Registration, Evaluation, Authorisation, and Restriction of Chemicals) regulation, (3) the California (CA) Safer Consumer Products (SCP) Program, and (4) the Safer Products for Washington (WA) Program. Factors such as the purpose of the alternatives assessment, the timeline of actions, who completes the assessment, the role of stakeholder engagement, and the regulatory response options for each policy are outlined. Through these presentations and expert discussions, four lessons learned about the use of alternatives assessments in regulatory policy emerged: (1) the goal and purpose of the regulatory framework significantly affects its ability to result in safer substitution, (2) existing frameworks struggle with data access and insufficient stakeholder engagement, (3) some frameworks lack clear decision rules regarding what is a safer and feasible alternative, and (4) regulatory response options provide limited authority for enforcement and do not adequately address options where alternatives are unavailable or limited. Five recommendations address these lessons as well as how the application of alternatives assessment in regulatory settings could have greater impact in the future. This synthesis is not meant to be a comprehensive policy analysis, but rather an assessment based on the perspectives from experts in the field, which should be supplemented by formal policy analysis as policies are implemented over time. Integr Environ Assess Manag 2023;00:1-11. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Correction: Evaluation of kidney function among people living with HIV initiating antiretroviral therapy in Zambia.

[This corrects the article DOI: 10.1371/journal.pgph.0000124.].

Dietary exposure to the food preservative tert-Butylhydroquinone (tBHQ) impairs zebrafish (Danio rerio) survival, growth, organ development, and gene expression in Nrf2a-dependent and independent ways.

Tert-Butylhydroquinone (tBHQ), a preservative used to prevent oxidative deterioration of oil, fat, and meat products, has been linked to both chemoprotective and adverse effects. This study investigates the impact of dietary tBHQ consumption on survival, growth parameters, organ development, and gene expression in zebrafish (Danio rerio). As tBHQ activates the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2a), a zebrafish line with a mutation in the DNA-binding domain of Nrf2a was used to identify Nrf2a-dependent vs independent effects. Homozygous Nrf2a wildtype (wt) and mutant (m) larvae were fed a diet containing 5% tBHQ or a control diet. Survival and growth parameters were assessed at 15 days and at 5 months, and samples were collected for RNA sequencing at 5 months. Dietary exposure to tBHQ throughout the larval and juvenile periods negatively impacted growth and survival. RNA-seq analysis found differentially expressed genes related to growth and development and upregulation of several immune system-related pathways. The findings herein demonstrate that dietary tBHQ exposure may impair growth and survival in both Nrf2a dependent and independent manners.

The Zebrafish (Danio rerio) Embryo Model as a Tool to Assess Drinking Water Treatment Efficacy for Freshwater Impacted by Crude Oil Spill.

Traditional approaches toward evaluating oil spill mitigation effectiveness in drinking water supplies using analytical chemistry can overlook residual hydrocarbons and treatment byproducts of unknown toxicity. Zebrafish (Danio rerio) were used to address this limitation by evaluating the reduction in toxicity to fish exposed to laboratory solutions of dissolved crude oil constituents treated with 3 mg/L ozone (O3 ) with or without a peroxone-based advanced oxidation process using 0.5 M H2 O2 /M O3 or 1 M H2 O2 /M O3 . Crude oil water mixtures (OWMs) were generated using three mixing protocols-orbital (OWM-Orb), rapid (OWM-Rap), and impeller (OWM-Imp) and contained dissolved total aromatic concentrations of 106-1019 µg/L. In a first experiment, embryos were exposed at 24 h post fertilization (hpf) to OWM-Orb or OWM-Rap diluted to 25%-50% of full-strength samples and in a second experiment, to untreated or treated OWM-Imp mixtures at 50% dilutions. Toxicity profiles included body length, pericardial area, and swim bladder inflation, and these varied depending on the OWM preparation, with OWM-Rap resulting in the most toxicity, followed by OWM-Imp and then OWM-Orb. Zebrafish exposed to a 50% dilution of OWM-Imp resulted in 6% shorter body length, 83% increased pericardial area, and no swim bladder inflation, but exposure to a 50% dilution of OWM-Imp treated with O3 alone or with 0.5 M H2 O2 /M O3 resulted in normal zebrafish development and average total aromatic destruction of 54%-57%. Additional aromatic removal occurred with O3 + 1 M H2 O2 /M O3 but without further attenuation of toxicity to zebrafish. This study demonstrates using zebrafish as an additional evaluation component for modeling the effectiveness of freshwater oil spill treatment methods. Environ Toxicol Chem 2022;41:2822-2834. © 2022 SETAC.

Nrf2a dependent and independent effects of early life exposure to 3,3'-dichlorobiphenyl (PCB-11) in zebrafish (Danio rerio).

The environmental pollutant 3,3'-dichlorobiphenyl (PCB-11) is a lower-chlorinated polychlorinated biphenyl (PCB) congener present in air and water samples. Both PCB-11 and its metabolite, 4-PCB-11-Sulfate, are detected in humans, including in pregnant women. Previous research in zebrafish (Danio rerio) has shown that 0.2 µM exposures to 4-PCB-11-Sulfate starting at 1 day post fertilization (dpf) increase hepatic neutral lipid accumulation in larvae at 15 dpf. Here, we explored whether nuclear factor erythroid 2-related factor 2 (Nrf2), known as the master-regulator of the adaptive response to oxidative stress, contributes to metabolic impacts of 4-PCB-11-Sulfate. For this work, embryos were collected from homozygous wildtype or Nrf2a mutant adult zebrafish that also express GFP in pancreatic ß-cells, rendering Tg(ins:GFP;nrf2afh318+/+) and Tg(ins:GFP;nrf2afh318-/-) lines. Exposures were conducted from 1-15 dpf to either 0.05% DMSO or DMSO-matched 0.2 µM 4-PCB-11-Sulfate, and at 15 dpf subsets of larvae were imaged for overall morphology, primary pancreatic islet area, and collected for fatty acid profiling and RNAseq. At 15 dpf, independent of genotype, fish exposed to 4-PCB-11-Sulfate survived significantly more at 80-85% compared to 65-73% survival for unexposed fish, and had primary pancreatic islets 8% larger compared to unexposed fish. Fish growth at 15 dpf was dependent on genotype, with Nrf2a mutant fish a significant 3-5% shorter than wildtype fish, and an interaction effect was observed where Nrf2a mutant fish exposed to 4-PCB-11-Sulfate experienced a significant 29% decrease in the omega-3 fatty acid DHA compared to unexposed mutant fish. RNAseq revealed 308 differentially expressed genes, most of which were dependent on genotype. These findings suggest that Nrf2a plays an important role in growth as well as for DHA production in the presence of 4-PCB-11-Sulfate. Further research would be beneficial to understand the importance of Nrf2a throughout the lifecourse, especially in the context of toxicant exposures.

Evaluation of kidney function among people living with HIV initiating antiretroviral therapy in Zambia.

As the response to the HIV epidemic in sub-Saharan Africa continues to mature, a growing number of people living with HIV (PLHIV) are aging and risk for non-communicable diseases increases. Routine laboratory tests of serum creatinine have been conducted to assess HIV treatment (ART) suitability. Here we utilize those measures to assess kidney function impairment among those initiating ART. Identification of non-communicable disease (NCD) risks among those in HIV care creates opportunity to improve public health through care referral and/or NCD/HIV care integration. We estimated glomerular filtration rates (eGFR) using routinely collected serum creatinine measures among a cohort of PLHIV with an HIV care visit at one of 113 Centre for Infectious Disease Research Zambia (CIDRZ) supported sites between January 1, 2011 and December 31, 2017, across seven of the ten provinces in Zambia. We used mixed-effect Poisson regression to assess predictors of eGFR <60ml/min/1.73m2 allowing random effects at the individual and facility level. Additionally, we assessed agreement between four eGFR formulae with unadjusted CKD-EPI as a standard using Scott/Fleiss method across five categories of kidney function. A total of 72,933 observations among 68,534 individuals met the inclusion criteria for analysis. Of the 68,534, the majority were female 41,042 (59.8%), the median age was 34 (interquartile range [IQR]: 28-40), and median CD4 cell count was 292 (IQR: 162-435). The proportion of individuals with an eGFR <60ml/min/1.73m2 was 6.9% (95% CI: 6.7-7.1%) according to the unadjusted CKD-EPI equation. There was variation in agreement across eGFR formulas considered compared to unadjusted CKD-EPI (χ2 p-value <0.001). Estimated GFR less than 60ml/min/1.73m2, per the unadjusted CKD-EPI equation, was significantly associated with age, sex, body mass index, and blood pressure. Using routine serum creatinine measures, we identified a significant proportion of individuals with eGFR indicating moderate or great kidney function impairment among PLHIV initiating ART in Zambia. It is possible that differentiated service delivery models could be developed to address this subset of those in HIV care with increased risk of chronic kidney disease.

A controlled study to assess the effects of a Fast Track (FT) service delivery model among stable HIV patients in Lusaka Zambia.

Fast Track models-in which patients coming to facility to pick up medications minimize waiting times through foregoing clinical review and collecting pre-packaged medications-present a potential strategy to reduce the burden of treatment. We examine effects of a Fast Track model (FT) in a real-world clinical HIV treatment program on retention to care comparing two clinics initiating FT care to five similar (in size and health care level), standard of care clinics in Zambia. Within each clinic, we selected a systematic sample of patients meeting FT eligibility to follow prospectively for retention using both electronic medical records as well as targeted chart review. We used a variety of methods including Kaplan Meier (KM) stratified by FT, to compare time to first late pick up, exploring late thresholds at >7, >14 and >28 days, Cox proportional hazards to describe associations between FT and late pick up, and linear mixed effects regression to assess the association of FT with medication possession ratio. A total of 905 participants were enrolled with a median age of 40 years (interquartile range [IQR]: 34-46 years), 67.1% were female, median CD4 count was 499 cells/mm3 (IQR: 354-691), and median time on ART was 5 years (IQR: 3-7). During the one-year follow-up period FT participants had a significantly reduced cumulative incidence of being >7 days late for ART pick-up (0.36, 95% confidence interval [CI]: 0.31-0.41) compared to control participants (0.66; 95% CI: 0.57-0.65). This trend held for >28 days late for ART pick-up appointments, at 23% (95% CI: 18%-28%) among intervention participants and 54% (95% CI: 47%-61%) among control participants. FT models significantly improved timely ART pick up among study participants. The apparent synergistic relationship between refill time and other elements of the FT suggest that FT may enhance the effects of extending visit spacing/multi-month scripting alone. ClinicalTrials.gov Identifier: NCT02776254 https://clinicaltrials.gov/ct2/show/NCT02776254.

Dibenzyl trisulfide binds to and competitively inhibits the cytochrome P450 1A1 active site without impacting the expression of the aryl hydrocarbon receptor.

The toxicological manifestation of many pollutants relies upon their binding to the aryl hydrocarbon receptor (AHR), and it follows a cascade of reactions culminating in an elevated expression of cytochrome P450 (CYP) 1 enzymes. CYP1A1 and CYP1B1 are associated with enhanced carcinogenesis when chronically exposed to certain polyaromatic hydrocarbons, and their inhibition may lead to chemoprevention. We evaluated dibenzyl trisulfide (DTS), expressed in the ethnomedical plant, Petiveria alliacea, for such potential chemoprevention. Using recombinant human CYP1A1 and CYP1B1 bactosomes on a fluorogenic assay, we first demonstrated that DTS moderately inhibited both enzymes with half maximal inhibitory concentration (IC50) values of 1.3 ± 0.3 and 1.7 ± 0.3 µM, respectively. Against CYP1A1, DTS was a reversible, competitive inhibitor with an apparent inhibitory constant (Ki) of 4.55 ± 0.37 µM. In silico molecular modeling showed that DTS binds with an affinity of -39.8 kJ·mol-1, situated inside the binding pocket, approximately 4.3 Å away from the heme group, exhibiting interactions with phenylalanine residue 123 (Phe-123), Phe-224, and Phe-258. Lastly, zebrafish (Danio rerio) embryos were exposed to 0.08-0.8 µM DTS from 24 to 96 h post fertilization (hpf) with the in vivo ethoxyresorufin-O-deethylase (EROD) assay, and, at 96 hpf, DTS significantly suppressed EROD CYP1A activity in a dose-dependent manner, with up to 60% suppression in the highest 0.8 µM exposure group. DTS had no impact on gene transcription levels for cyp1a and aryl hydrocarbon receptor 2 (ahr2). In co-exposure experiments, DTS suppressed CYP1A activity induced by both B[a]P and PCB-126, although these reductions were not significant. Taken together, these results demonstrate that DTS is a direct, reversible, competitive inhibitor of the carcinogen-activating CYP1A enzyme, binding in the active site pocket close to the heme site, and shows potential in chemoprevention.

Chemical Characterization of a Legacy Aqueous Film-Forming Foam Sample and Developmental Toxicity in Zebrafish (Danio rerio).

BACKGROUND: Drinking water contamination related to the use of aqueous film-forming foam (AFFF) has been documented at hundreds of military bases, airports, and firefighter training facilities. AFFF has historically contained high levels of long-chain per- and polyfluoroalkyl substances (PFAS), which pose serious health concerns. However, the composition and toxicity of legacy AFFF mixtures are unknown, presenting great uncertainties in risk assessment and affected communities. OBJECTIVES: This study aimed to determine the fluorinated and nonfluorinated chemical composition of a legacy AFFF sample and its toxicity in zebrafish embryos. METHODS: A sample of legacy AFFF (3% application formulation, manufactured before 2001) was provided by the Massachusetts Department of Environmental Protection. High resolution mass spectrometry (HRMS) was used to identify PFAS and nonfluorinated compounds, and a commercial laboratory measured 24 PFAS by a modified U.S. EPA Method 537.1. AFFF toxicity was assessed in zebrafish embryos in comparison with four major constituents: perfluorooctanesulfonic acid (PFOS); perfluorohexanesulfonic acid (PFHxS); sodium dodecyl sulfate (SDS); and sodium tetradecyl sulfate (TDS). End points included LC50 values, and sublethal effects on growth, yolk utilization, and pancreas and liver development. RESULTS: We identified more than 100 PFAS. Of the PFAS detected, PFOS was measured at the highest concentration (9,410mg/L) followed by PFHxS (1,500mg/L). Fourteen nonfluorinated compounds were identified with dodecyl sulfate and tetradecyl sulfate the most abundant at 547.8 and 496.4mg/L, respectively. An LC50 of 7.41×10-4% AFFF was calculated, representing a dilution of the 3% formulation. TDS was the most toxic of the constituents tested but could not predict the AFFF phenotype in larval zebrafish. PFOS exposure recapitulated the reduction in length but could not predict effects on development of the liver, which was the tissue most sensitive to AFFF. DISCUSSION: To our knowledge, this research is the first characterization of the chemical composition and toxicity of legacy AFFF, which has important implications for regulatory toxicology. https://doi.org/10.1289/EHP6470.

The sulfate metabolite of 3,3'-dichlorobiphenyl (PCB-11) impairs Cyp1a activity and increases hepatic neutral lipids in zebrafish larvae (Danio rerio).

The environmental contaminant 3,3'-dichlorobiphenyl (PCB-11) is widely detected in environmental samples, and this parent compound along with its metabolites 4-OH-PCB-11 and 4-PCB-11-Sulfate are detected in human serum. Our previous research in zebrafish (Danio rerio) embryos shows exposure to 20 µM PCB-11 inhibits Cyp1a enzyme activity and perturbs lipid metabolism pathways. In this study, wildtype AB embryos underwent acute exposures from 1 to 4 days post fertilization (dpf) to 0.002-20 µM 4-OH-PCB-11 or 0.2-20 µM 4-PCB-11-Sulfate, with and without co-exposures to 100 µg/L benzo[a]pyrene (B[a]P) or 5 nM 3,3',4,4',5-pentachlorobiphenyl (PCB-126), and were assessed for in vivo EROD activity and morphometrics. Chronic exposures from 1 to 15 dpf to assess lipid accumulation using Oil-Red-O staining were also conducted with 0.2 µM parent or metabolite compounds, alongside a co-exposure experiment of 0.002-0.2 µM 4-PCB-11-Sulfate and 10 µg/L B[a]P. For acute experiments, 2 and 20 µM 4-OH-PCB-11 was lethal but no Cyp1a or morphological effects were observed at lower concentrations; 20 µM 4-PCB-11-Sulfate significantly lowered the Cyp1a activity of B[a]P and PCB-126 but did not alter morphological development. For chronic experiments, 0.2 µM 4-PCB-11-Sulfate significantly increased lipid accumulation 30% in single exposures and 44% in co-exposures with B[a]P. Further long-term studies would better elucidate the effects of this contaminant, particularly in the context of environmentally-relevant mixtures.

Participation in adherence clubs and on-time drug pickup among HIV-infected adults in Zambia: A matched-pair cluster randomized trial.

BACKGROUND: Current models of HIV service delivery, with frequent facility visits, have led to facility congestion, patient and healthcare provider dissatisfaction, and suboptimal quality of services and retention in care. The Zambian urban adherence club (AC) is a health service innovation designed to improve on-time drug pickup and retention in HIV care through off-hours facility access and pharmacist-led group drug distribution. Similar models of differentiated service delivery (DSD) have shown promise in South Africa, but observational analyses of these models are prone to bias and confounding. We sought to evaluate the effectiveness and implementation of ACs in Zambia using a more rigorous study design. METHODS AND FINDINGS: Using a matched-pair cluster randomized study design (ClinicalTrials.gov: NCT02776254), 10 clinics were randomized to intervention (5 clinics) or control (5 clinics). At each clinic, between May 19 and October 27, 2016, a systematic random sample was assessed for eligibility (HIV+, age ≥ 14 years, on ART >6 months, not acutely ill, CD4 count not <200 cells/mm3) and willingness to participate in an AC. Clinical and antiretroviral drug pickup data were obtained through the existing electronic medical record. AC meeting attendance data were collected at intervention facilities prospectively through October 28, 2017. The primary outcome was time to first late drug pickup (>7 days late). Intervention effect was estimated using unadjusted Kaplan-Meier survival curves and a Cox proportional hazards model to derive an adjusted hazard ratio (aHR). Medication possession ratio (MPR) and implementation outcomes (adoption, acceptability, appropriateness, feasibility, and fidelity) were additionally evaluated as secondary outcomes. Baseline characteristics were similar between 571 intervention and 489 control participants with respect to median age (42 versus 41 years), sex (62% versus 66% female), median time since ART initiation (4.8 versus 5.0 years), median CD4 count at study enrollment (506 versus 533 cells/mm3), and baseline retention (53% versus 55% with at least 1 late drug pickup in previous 12 months). The rate of late drug pickup was lower in intervention participants compared to control participants (aHR 0.26, 95% CI 0.15-0.45, p < 0.001). Median MPR was 100% in intervention participants compared to 96% in control participants (p < 0.001). Although 18% (683/3,734) of AC group meeting visits were missed, on-time drug pickup (within 7 days) still occurred in 51% (350/683) of these missed visits through alternate means (use of buddy pickup or early return to the facility). Qualitative evaluation suggests that the intervention was acceptable to both patients and providers. While patients embraced the convenience and patient-centeredness of the model, preference for traditional adherence counseling and need for greater human resources influenced intervention appropriateness and feasibility from the provider perspective. The main limitations of this study were the small number of clusters, lack of viral load data, and relatively short follow-up period. CONCLUSIONS: ACs were found to be an effective model of service delivery for reducing late ART drug pickup among HIV-infected adults in Zambia. Drug pickup outside of group meetings was relatively common and underscores the need for DSD models to be flexible and patient-centered if they are to be effective. TRIAL REGISTRATION: ClinicalTrials.gov NCT02776254.

The emerging contaminant 3,3'-dichlorobiphenyl (PCB-11) impedes Ahr activation and Cyp1a activity to modify embryotoxicity of Ahr ligands in the zebrafish embryo model (Danio rerio).

3,3'-dichlorobiphenyl (PCB-11) is an emerging PCB congener widely detected in environmental samples and human serum, but its toxicity potential is poorly understood. We assessed the effects of three concentrations of PCB-11 on embryotoxicity and Aryl hydrocarbon receptor (Ahr) pathway interactions in zebrafish embryos (Danio rerio). Wildtype AB or transgenic Tg(gut:GFP) strain zebrafish embryos were exposed to static concentrations of PCB-11 (0, 0.2, 2, or 20 µM) from 24 to 96 h post fertilization (hpf), and gross morphology, Cytochrome P4501a (Cyp1a) activity, and liver development were assessed via microscopy. Ahr interactions were probed via co-exposures with PCB-126 or beta-naphthoflavone (BNF). Embryos exposed to 20 µM PCB-11 were also collected for PCB-11 body burden, qRT-PCR, RNAseq, and histology. Zebrafish exposed to 20 µM PCB-11 absorbed 0.18% PCB-11 per embryo at 28 hpf and 0.61% by 96 hpf, and their media retained 1.36% PCB-11 at 28 hpf and 0.84% at 96 hpf. This concentration did not affect gross morphology, but altered the transcription of xenobiotic metabolism and liver development genes, impeded liver development, and increased hepatocyte vacuole formation. In co-exposures, 20 µM PCB-11 prevented deformities caused by PCB-126 but exacerbated deformities in co-exposures with BNF. This study suggests that PCB-11 can affect liver development, act as a partial agonist/antagonist of the Ahr pathway, and act as an antagonist of Cyp1a activity to modify the toxicity of compounds that interact with the Ahr pathway.

A Review of Differentiated Service Delivery for HIV Treatment: Effectiveness, Mechanisms, Targeting, and Scale.

PURPOSE OF REVIEW: Differentiated service delivery (DSD) models were initially developed as a means to combat suboptimal long-term retention in HIV care, and to better titrate limited health systems resources to patient needs, primarily in low-income countries. The models themselves are designed to streamline care along the HIV care cascade and range from individual to group-based care and facility to community-based health delivery systems. However, much remains to be understood about how well and for whom DSD models work and whether these models can be scaled, are sustainable, and can reach vulnerable and high-risk populations. Implementation science is tasked with addressing some of these questions through systematic, scientific inquiry. We review the available published evidence on the implementation of DSD and suggest further health systems innovations needed to maximize the public health impact of DSD and future implementation science research directions in this expanding field. RECENT FINDINGS: While early observational data supported the effectiveness of various DSD models, more recently published trials as well as evaluations of national scale-up provide more rigorous evidence for effectiveness and performance at scale. Deeper understanding of the mechanism of effect of various DSD models and generalizability of studies to other countries or contexts remains somewhat limited. Relative implementability of DSD models may differ based on patient preference, logistical complexity of model adoption and maintenance, human resource and pharmacy supply chain needs, and comparative cost-effectiveness. However, few studies to date have evaluated comparative implementation or cost-effectiveness from a health systems perspective. While DSD represents an exciting and promising "next step" in HIV health care delivery, this innovation comes with its own set of implementation challenges. Evidence on the effectiveness of DSD generally supports the use of most DSD models, although it is still unclear which models are most relevant in diverse settings and populations and which are the most cost-effective. Challenges during scale-up highlight the need for accurate differentiation of patients, sustainable inclusion of a new cadre of health care worker (the community health care worker), and substantial strengthening of existing pharmacy supply chains. To maximize the public health impact of DSD, systems need to be patient-centered and adaptive, as well as employ robust quality improvement processes.

Differentiated Care Preferences of Stable Patients on Antiretroviral Therapy in Zambia: A Discrete Choice Experiment.

BACKGROUND: Although differentiated service delivery (DSD) models for stable patients on antiretroviral therapy (ART) offer a range of health systems innovations, their comparative desirability to patients remains unknown. We conducted a discrete choice experiment to quantify service attributes most desired by patients to inform model prioritization. METHODS: Between July and December 2016, a sample of HIV-positive adults on ART at 12 clinics in Zambia were asked to choose between 2 hypothetical facilities that differed across 6 DSD attributes. We used mixed logit models to explore preferences, heterogeneity, and trade-offs. RESULTS: Of 486 respondents, 59% were female and 85% resided in urban locations. Patients strongly preferred infrequent clinic visits [3- vs. 1-month visits: ß (ie, relative utility) = 2.84; P < 0.001]. Milder preferences were observed for waiting time for ART pick-up (1 vs. 6 hours.; ß = -0.67; P < 0.001) or provider (1 vs. 3 hours.; ß = -0.41; P = 0.002); "buddy" ART collection (ß = 0.84; P < 0.001); and ART pick-up location (clinic vs. community: ß = 0.35; P = 0.028). Urban patients demonstrated a preference for collecting ART at a clinic (ß = 1.32, P < 0.001), and although most rural patients preferred community ART pick-up (ß = -0.74, P = 0.049), 40% of rural patients still preferred facility ART collection. CONCLUSIONS: Stable patients on ART primarily want to attend clinic infrequently, supporting a focus in Zambia on optimizing multimonth prescribing over other DSD features-particularly in urban areas. Substantial preference heterogeneity highlights the need for DSD models to be flexible, and accommodate both setting features and patient choice in their design.

Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Permanently Alters Blood-Liver Balance of Lipids in Male Mice.

Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives starting 1965 and were recently withdrawn from commerce in North America and Europe. Approximately 1/5 of the total U.S. population were born when environmental concentrations of PBDE plateaued at their maximum. Accumulating evidence suggests that developmental exposures to PBDE may result in long-lasting programming of liver metabolism. In this study, CD-1 mice were exposed prenatally or neonatally to 1 mg/kg body weight of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), and changes in liver histology, transcriptome, and liver-blood balance of triglycerides were analyzed in 10 months old male offspring. In both exposure groups, long-term reprogramming of lipid metabolism was observed, including increased liver triglycerides and decreased blood triglycerides, and altered expression of metabolic genes in the liver. Significant upregulation of lipid influx transporter Cd36 2.3- and 5.7-fold in pre- and neonatal exposure groups, respectively was identified as a potential mechanism of blood/liver imbalance of triglycerides. Analysis of our and previously published all-genome gene expression data identified changes in expression of ribosomal protein genes as a transcriptomic signature of PBDE exposure. Further comparison of our new data and published data demonstrate that low doses (0.2 mg/kg body weight) of PBDE induce long-lasting up-regulation of ribosomal genes, suppression of Cd36 in liver and increase circulating triglycerides in blood, while moderated doses (≥1 mg/kg body weight) produce opposite long-lasting effects. To conclude, this study shows that an environmentally relevant developmental exposures to BDE-47 permanently alter lipid uptake and accumulation in the liver, with low and moderate doses having opposite effect on liver transcriptomics and triglyceride balance. Similar effects of pre- and neonatal exposures point at hepatocyte maturation as a sensitive window of the liver metabolism programming. These results suggest that PBDE exposure may be an important factor increasing risks of cardio-vascular disease and non-alcoholic fatty liver disease via modulation of liver/blood balance of lipids. The translational relevance of these findings for human remain to be studied.

A Metagenomic Approach to Evaluating Surface Water Quality in Haiti.

The cholera epidemic that occurred in Haiti post-earthquake in 2010 has resulted in over 9000 deaths during the past eight years. Currently, morbidity and mortality rates for cholera have declined, but cholera cases still occur on a daily basis. One continuing issue is an inability to accurately predict and identify when cholera outbreaks might occur. To explore this surveillance gap, a metagenomic approach employing environmental samples was taken. In this study, surface water samples were collected at two time points from several sites near the original epicenter of the cholera outbreak in the Central Plateau of Haiti. These samples underwent whole genome sequencing and subsequent metagenomic analysis to characterize the microbial community of bacteria, fungi, protists, and viruses, and to identify antibiotic resistance and virulence associated genes. Replicates from sites were analyzed by principle components analysis, and distinct genomic profiles were obtained for each site. Cholera toxin converting phage was detected at one site, and Shiga toxin converting phages at several sites. Members of the Acinetobacter family were frequently detected in samples, including members implicated in waterborne diseases. These results indicate a metagenomic approach to evaluating water samples can be useful for source tracking and the surveillance of pathogens such as Vibrio cholerae over time, as well as for monitoring virulence factors such as cholera toxin.