Windows of sensitivity to toxic chemicals in the motor effects development.

Many chemicals currently used are known to elicit nervous system effects. In addition, approximately 2000 new chemicals introduced annually have not yet undergone neurotoxicity testing. This review concentrated on motor development effects associated with exposure to environmental neurotoxicants to help identify critical windows of exposure and begin to assess data needs based on a subset of chemicals thoroughly reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR) in Toxicological Profiles and Addenda. Multiple windows of sensitivity were identified that differed based on the maturity level of the neurological system at the time of exposure, as well as dose and exposure duration. Similar but distinct windows were found for both motor activity (GD 8-17 [rats], GD 12-14 and PND 3-10 [mice]) and motor function performance (insufficient data for rats, GD 12-17 [mice]). Identifying specific windows of sensitivity in animal studies was hampered by study designs oriented towards detection of neurotoxicity that occurred at any time throughout the developmental process. In conclusion, while this investigation identified some critical exposure windows for motor development effects, it demonstrates a need for more acute duration exposure studies based on neurodevelopmental windows, particularly during the exposure periods identified in this review.

Medicaid Expansion and Restriction Policies for Hepatitis C Treatment.

Importance: Hepatitis C can be cured with direct-acting antivirals (DAAs), but Medicaid programs have implemented fibrosis, sobriety, and prescriber restrictions to control costs. Although restrictions are easing, understanding their association with hepatitis C treatment rates is crucial to inform policies that increase access to lifesaving treatment. Objective: To estimate the association of jurisdictional (50 states and Washington, DC) DAA restrictions and Medicaid expansion with the number of Medicaid recipients with filled prescriptions for DAAs. Design, Setting, and Participants: This cross-sectional study used publicly available Medicaid documents and claims data from January 1, 2014, to December 31, 2021, to compare the number of unique Medicaid recipients treated with DAAs in each jurisdiction year with Medicaid expansion status and categories of fibrosis, sobriety, and prescriber restrictions. Medicaid recipients from all 50 states and Washington, DC, during the study period were included. Multilevel Poisson regression was used to estimate the association between Medicaid expansion and DAA restrictive policies on jurisdictional Medicaid DAA prescription fills. Data were analyzed initially from August 15 to November 15, 2023, and subsequently from April 15 to May 9, 2024. Exposures: Jurisdictional Medicaid expansion status and fibrosis, sobriety, and prescriber DAA restrictions. Main Outcomes and Measures: Number of people treated with DAAs per 100 000 Medicaid recipients per year. Results: A total of 381 373 Medicaid recipients filled DAA prescriptions during the study period (57.3% aged 45-64 years; 58.7% men; 15.2% non-Hispanic Black and 52.2% non-Hispanic White). Medicaid nonexpansion jurisdictions had fewer filled DAA prescriptions per 100 000 Medicaid recipients per year than expansion jurisdictions (38.6 vs 86.6; adjusted relative risk [ARR], 0.56 [95% CI, 0.52-0.61]). Jurisdictions with F3 to F4 (34.0 per 100 000 Medicaid recipients per year; ARR, 0.39 [95% CI, 0.37-0.66]) or F1 to F2 fibrosis restrictions (61.9 per 100 000 Medicaid recipients per year; ARR, 0.62 [95% CI, 0.59-0.66]) had lower treatment rates than jurisdictions without fibrosis restrictions (94.8 per 100 000 Medicaid recipients per year). Compared with no sobriety restrictions (113.5 per 100 000 Medicaid recipients per year), 6 to 12 months of sobriety (38.3 per 100 000 Medicaid recipients per year; ARR, 0.65 [95% CI, 0.61-0.71]) and screening and counseling requirements (84.7 per 100 000 Medicaid recipients per year; ARR, 0.87 [95% CI, 0.83-0.92]) were associated with reduced treatment rates, while 1 to 5 months of sobriety was not statistically significantly different. Compared with no prescriber restrictions (97.8 per 100 000 Medicaid recipients per year), specialist consult restrictions was associated with increased treatment (66.2 per 100 000 Medicaid recipients per year; ARR, 1.05 [95% CI, 1.00-1.10]), while specialist required restrictions were not statistically significant. Conclusions and Relevance: In this cross-sectional study, Medicaid nonexpansion status, fibrosis, and sobriety restrictions were associated with a reduction in the number of people with Medicaid who were treated for hepatitis C. Removing DAA restrictions might facilitate treatment of more people diagnosed with hepatitis C.

DDT/DDE and breast cancer: a meta-analysis.

The biological basis for investigating dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk stems from in vitro and animal studies indicating that DDT has estrogenic properties. The objective of this study was to update a meta-analysis from 2004 which found no association between dichlorodiphenyldichloroethylene (DDE) and breast cancer. We searched PubMed and Web of Science for studies published through June 2012 assessing DDT/DDE exposure and breast cancer. Summary Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated for the prevalence of breast cancer in the highest versus the lowest exposed groups for DDT and DDE. Difference of means of exposure for cases versus controls was analyzed for DDT and DDE. From the 500 studies screened, 46 were included in the meta-analysis. Slightly elevated, but not statistically significant summary ORs were found for DDE (1.05; 95% CI: 0.93-1.18) and DDT (1.02; 95% CI: 0.92-1.13). Lipid adjusted difference of means analysis found a significantly higher DDE concentration in cases versus controls (11.30 ng/g lipid; p=0.01). No other difference of means analysis found significant relationships. The existing information does not support the hypothesis that exposure to DDT/DDE increases the risk of breast cancer in humans.

Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations.

UNLABELLED: Human leukocyte antigen B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant, HLA-B27-restricted, HCV-specific, cluster of differentiation (CD)8(+) T-cell epitope, nonstructural protein (NS)5B(2841-2849) (ARMILMTHF), has been shown to be limited by viral fitness costs as well as broad T-cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27-restricted epitope, NS5B(2936-2944) (GRAAICGKY), to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a-infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T-cell receptor contact site, neither of which impaired viral replication capacity, as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27(+) subjects, rare escape mutations arose at the HLA-B27 anchor residue, R(2937) , which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Coexpression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from <5% to ≥ 70% of wild-type levels. CONCLUSION: The selection of rare CTL escape mutations in this HLA-B27-restricted epitope dramatically impairs viral replicative fitness, unless properly compensated. These data support a role for the targeting of highly constrained regions by HLA-B27 in its ability to assert immune control of HCV and other highly variable pathogens.

An Evaluation of the Text Illness Monitoring (TIM) Platform for COVID-19: Cross-sectional Online Survey of Public Health Users.

BACKGROUND: The US public health response to the COVID-19 pandemic has required contact tracing and symptom monitoring at an unprecedented scale. The US Centers for Disease Control and Prevention and several partners created the Text Illness Monitoring (TIM) platform in 2015 to assist US public health jurisdictions with symptom monitoring for potential novel influenza virus outbreaks. Since May 2020, 142 federal, state, and local public health agencies have deployed TIM for COVID-19 symptom monitoring. OBJECTIVE: The aim of this study was to evaluate the utility, benefits, and challenges of TIM to help guide decision-making for improvements and expansion to support future public health emergency response efforts. METHODS: We conducted a brief online survey of previous and current TIM administrative users (admin users) from November 28 through December 21, 2020. Closed- and open-ended questions inquired about the onboarding process, decision to use TIM, groups monitored with TIM, comparison of TIM to other symptom monitoring systems, technical challenges and satisfaction with TIM, and user support. A total of 1479 admin users were invited to participate. RESULTS: A total of 97 admin users from 43 agencies responded to the survey. Most admin users represented the Indian Health Service (35/97, 36%), state health departments (26/97, 27%), and local or county health departments (18/97, 19%), and almost all were current users of TIM (85/94, 90%). Among the 43 agencies represented, 11 (26%) used TIM for monitoring staff exclusively, 13 (30%) monitored community members exclusively, and 19 (44%) monitored both staff and community members. Agencies most frequently used TIM to monitor symptom development in contacts of cases among community members (28/43, 65%), followed by symptom development among staff (27/43, 63%) and among staff contacts of cases (24/43, 56%). Agencies also reported using TIM to monitor patients with COVID-19 for the worsening of symptoms among staff (21/43, 49%) and community members (18/43, 42%). When asked to compare TIM to previous monitoring systems, 78% (40/51) of respondents rated TIM more favorably than their previous monitoring system, 20% (10/51) said there was no difference, and 2% (1/51) rated the previous monitoring system more favorably than TIM. Most respondents found TIM favorable in terms of time burden, staff burden, timeliness of the data, and the ability to monitor large population sizes. TIM compared negatively to other systems in terms of effort to enroll participants (ie, persons TIM monitors) and accuracy of the data. Most respondents (76/85, 89%) reported that they would highly or somewhat recommend TIM to others for symptom monitoring. CONCLUSIONS: This evaluation of TIM showed that agencies used TIM for a variety of purposes and rated TIM favorably compared to previously used monitoring systems. We also identified opportunities to improve TIM; for example, enhancing the flexibility of alert deliveries would better meet admin users' varying needs. We also suggest continuous program evaluation practices to assess and respond to implementation gaps.

Historical View on Lead: Guidelines and Regulations.

Lead has been used in many commodities for centuries. As a result, human exposure has occurred through the production and use of these lead-containing products. For example, leaded gasoline, lead-based paint, and lead solder/pipes in water distribution systems have been important in terms of exposure potential to the general population. Worker exposures occur in various industrial activities such as lead smelting and refining, battery manufacturing, steel welding or cutting operations, printing, and construction. Some industrial locations have also been a source of exposure to the surrounding communities. While the toxicity of relatively high lead exposures has been recognized for centuries, modern scientific studies have shown adverse health effects at very low doses, particularly in the developing nervous system of fetuses and children. This chapter reflects on historical and current views on lead toxicity. It also addresses the development and evolution of exposure prevention policies. As discussed here, these lead policies target a variety of potential exposure routes and sources. The changes reflect our better understanding of lead toxicity. The chapter provides lead-related guidelines and regulations currently valid in the U. S. and in many countries around the world. The reader will learn about the significant progress that has been made through regulations and guidelines to reduce exposure and prevent lead toxicity.

Dataset for human sensitivity to chemicals during development of motor function.

The authors reviewed human data related to motor development following exposure to a subset of chemicals thoroughly reviewed in Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profiles and Addenda. The resulting dataset includes the following variables and confounders: chemical name, exposure route, exposure duration and frequency, study design, cohort name and/or geographic location, sex of cohort subjects, NOAEL, and LOAEL. This data summary can help validate motor development outcomes observed in animal exposure studies; it can also aid in determining whether these outcomes and corresponding exposure windows are relevant to humans.

Urinary and blood cadmium and lead and kidney function: NHANES 2007-2012.

BACKGROUND: Cadmium (Cd) and lead (Pb) are widespread environmental contaminants that are known nephrotoxins. However, their nephrotoxic effects at low-environmental exposure levels are debated. OBJECTIVE: We examined the association of blood Pb (B-Pb), blood Cd (B-Cd), urinary Pb (U-Pb) and urinary Cd (U-Cd) with estimated glomerular filtration rate (eGFR) and urinary albumin (ALB). METHODS: We used multivariate linear regression to analyze the association between B-Pb, B-Cd, U-Pb, and U-Cd with eGFR and ALB in adult participants (≥20 years of age) in NHANES 2007-2012. The dataset was limited to NHANES individuals with both blood and urinary metal measurements. RESULTS: We found a statistically significant inverse association between eGFR and B-Cd and statistically significant positive associations between eGFR and both U-Cd and U-Pb, as well as statistically significant associations between ALB and the 3rd and 4th quartiles of U-Cd. CONCLUSIONS: The inverse association between eGFR and B-Cd, in conjunction with positive associations between eGFR and ALB with U-Cd, suggest that U-Cd measurement at low levels of exposure may result from changes in renal excretion of Cd due to kidney function and protein excretion. However, renal effects such as hyperfiltration from Cd-mediated kidney damage or creatinine-specific Cd effects cannot be excluded with this cross-sectional design.