Inequities in COVID-19 Omicron infections and hospitalisations for Maori and Pacific people in Te Manawa Taki Midland region, New Zealand.

COVID-19 impacts population health equity. While mRNA vaccines protect against serious illness and death, little New Zealand (NZ) data exist about the impact of Omicron - and the effectiveness of vaccination - on different population groups. We aim to examine the impact of Omicron on Maori, Pacific, and Other ethnicities and how this interacts with age and vaccination status in the Te Manawa Taki Midland region of NZ. Daily COVID-19 infection and hospitalisation rates (1 February 2022 to 29 June 2022) were calculated for Maori, Pacific, and Other ethnicities for six age bands. A multivariate logistic regression model quantified the effects of ethnicity, age, and vaccination on hospitalisation rates. Per-capita Omicron cases were highest and occurred earliest among Pacific (9 per 1,000) and Maori (5 per 1,000) people and were highest among 12-24-year-olds (7 per 1,000). Hospitalisation was significantly more likely for Maori people (odds ratio (OR) = 2.03), Pacific people (OR = 1.75), over 75-year-olds (OR = 39.22), and unvaccinated people (OR = 4.64). Length of hospitalisation is strongly related to age. COVID-19 vaccination reduces hospitalisations for older individuals and Maori and Pacific populations. Omicron inequitably impacted Maori and Pacific people through higher per-capita infection and hospitalisation rates. Older people are more likely to be hospitalised and for longer.

Factors associated with naloxone availability and dispensing through Michigan's pharmacy standing order.

Background: Pharmacy standing order policies allow pharmacists to dispense naloxone, thereby increasing access to naloxone. Objectives: To describe pharmacy standing order participation and associations of pharmacy and community characteristics that predict naloxone availability and dispensing across eight counties in Michigan. Methods: We conducted a telephone survey of 662 standing order pharmacies with a response rate of 81% (n = 539). Pharmacies were linked with census tract-level demographics, overdose fatality rates, and dispensing data. County maps were created to visualize pharmacy locations relative to fatality rates. Regression models analyzed associations between pharmacy type, neighborhood characteristics, fatality rates, and these outcomes: naloxone availability, having ever dispensed naloxone, and counts of naloxone dispensed. Results: The prevalence of standing order pharmacies was 54% (n = 662/1231). Maps revealed areas with higher fatality rates had fewer pharmacies participating in the standing order or lacked any pharmacy access. Among standing order pharmacies surveyed, 85% (n = 458/539) had naloxone available and 82% had ever dispensed (n = 333/406). The mean out-of-pocket cost of Narcan® was $127.77 (SD: 23.93). National chains were more likely than regional chains to stock naloxone (AOR = 3.75, 95%CI = 1.77, 7.93) and to have ever dispensed naloxone (AOR 3.02, 95%CI = 1.21,7.57). Higher volume of naloxone dispensed was associated in neighborhoods with greater proportions of public health insurance (IRR = 1.38, 95%CI = 1.21, 1.58) and populations under 44 years old (IRR = 1.24, 95%CI = 1.04, 1.48). There was no association with neighborhood overdose fatality rates or race in regression models. Conclusion: As deaths from the opioid epidemic continue to escalate, efforts to expand naloxone access through greater standing order pharmacy participation are warranted.

Assessing how in vitro assay types predict in vivo toxicology data.

In vivo animal bioassays are increasingly being supplemented with in vitro assays to serve as the new standard for chemical toxicity tests. Despite this shift, investigators face challenges related to increased reliance on in vitro data. The aim of this study was to deploy a streamlined method to assess the ability of in vitro data to predict similar results as in vivo data by correlating chemical toxicity rankings obtained using Benchmark Doses and Benchmark Dose Lower Limits (BMD(L)s) derived from in vivo and in vitro assays. In vitro and in vivo assay characteristics were assessed for their impact on the predictive ability of in vitro data. Minimum best-fit BMD(L)s were calculated for chemicals using Environmental Protection Agency's (EPA's) Benchmark Dose Software (BMDS). Forty-one chemicals met the inclusion criteria of this study. Relative chemical toxicity rankings were assessed through Kappa statistics, Pearson correlations, and/or Ordinary Least Squares (OLS) regressions. Results illustrated likely ability of in vitro data to predict similar results as short-term in vivo data. Further, rankings derived from in vitro cytotoxicity assays, unlike stress response assays, significantly correlated with rankings derived from short-term in vivo assays. These results support the use of in vitro data as a prioritization tool within toxicity testing.

The Pebble Remains in the Master's Hand: Two Careers Spent Learning (Still) from John Evans.

In this article, we discuss four vexing problems in risk-based decision making that John Evans has addressed over the last nearly 40 years and has perennially challenged the two of us and others to think about. We tackle the role in decision making of potential thresholds in dose-response functions, how the lack of health reference values for many chemicals may distort risk management, the challenge of model uncertainty for risk characterization, and the yet-untapped potential for value-of-information analysis to enhance public health decision making. Our theme is that work remains to be done on each of these, but that some of that work would merely involve listening to ideas that John has already offered.

Stereochemical Dependences of 31P-13C Spin-Spin Coupling Constants of Heterocyclic Phosphines.

Phosphorus-carbon spin-spin coupling constants in a series of salient heterocyclic phosphines were calculated at the SOPPA(MP2) level including evaluation of relativistic and solvent effects. A number of the locally dense basis set schemes were thoroughly investigated in terms of their accuracy versus computational demands. The most effective computational scheme was tested in a benchmark series to provide a very good correlation between 2JPC calculated at the SOPPA(MP2) level and experiment. A marked dihedral angle dependence of 2JPC was demonstrated, and this could be used in stereochemical studies of a wide series of organophosphorus compounds based on the phosphorus-carbon coupling constants.

A review of prospective registration of trials published in nursing science journals in 2017.

AIM: To determine the proportion of trials published in nursing science journals in 2017 that were prospectively registered. DESIGN: A review of randomized controlled trials published in a Journal Citation Report nursing science journal in 2017. DATA SOURCE: Table of contents of included journals. REVIEW METHODS: Randomized controlled trials were identified by manually reviewing the title of all papers published in included journals. Included trials were classified as: (a) Prospectively registered; (b) Retrospectively registered; (c) Registered but registration not reported in the manuscript; (d) Indeterminate registration; and (e) Not registered. Additionally, we recorded if the trial registration number was reported in the manuscript abstract. RESULTS: Of 151 randomized controlled trials published in nursing science journals in 2017, 17 (11%) were prospectively registered. Thirty-six (24%) trials were retrospectively and 93 (62%) not registered. We could not determine the registration status of five (3%) trials. The registration number was included in the abstract of two prospectively and eight retrospectively registered studies. Compared with the rest of the world, trial registration rates were significantly lower in Asian countries. CONCLUSION: Two included trials were prospectively registered and reported a registration number in the abstract. Compared with other disciplines, rates of prospective trial registration are low. Nurse trialists must ensure that they prospectively register all trials. IMPACT: We intended to replicate this review in subsequent years with a view to reporting improvements in prospective registration rates over time.

Which is most sensitive? Assessing responses of mice and rats in toxicity bioassays.

Rodent species are commonly used in traditional toxicology testing guidelines to predict human health toxicity outcomes. The use of a consistent species in test guidelines is important for maintaining consistency and comparability between tests and testing guidelines. This recommendation was operationalized for this study as the implicit assumption of uniform species and species-sex sensitivities. This investigation analyzed the uniformity assumption using data from National Toxicology Program Technical Reports (and where applicable Toxicity Reports), which provide data from both short-term and chronic rodent toxicity tests. These data were extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Minimum best-fit benchmark doses (BMD) and benchmark dose lower limits (BMDL) were determined and a minimum best-fit BMD10 and BMDL10 estimated for every chemical and study duration. Endpoints of interest included non-neoplastic lesions, final mean body weights, and mean organ weights. The distribution of findings was then assessed to determine the most sensitive species and species-sex combinations associated with the minimum best-fit BMDL10. Data indicated that species and species-sex sensitivity for this group of chemicals is not uniform and that rats are significantly more sensitive than mice for non-cancerous outcomes observed, depending upon study duration. There are also indications that male rats may be more sensitive than other species-sex groups in certain situations.

Correlation of Noncancer Benchmark Doses in Short- and Long-Term Rodent Bioassays.

This study investigated whether, in the absence of chronic noncancer toxicity data, short-term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose-response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best-fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012. Models were then developed at the chemical level using orthogonal regression techniques to predict chronic (two years) noncancer health effect levels using the results of the short-term (three months) toxicity data. The findings indicate that short-term animal studies may reasonably provide a quantitative estimate of a chronic BMD or BMDL. This can allow for faster development of human health toxicity values for risk assessment for chemicals that lack chronic toxicity data.

Part II: Quantitative Evaluation of Choices Used in Setting Noncancer Chronic Human Health Reference Values Across Organizations.

Environmental and public health organizations, including the World Health Organization (WHO) and the U.S. Environmental Protection Agency (USEPA), develop human health reference values (HHRV) that set "safe" levels of exposure to noncarcinogens. Here, we systematically analyze chronic HHRVs from four organizations: USEPA, Health Canada, RIVM (the Netherlands), and the U.S. Agency for Toxic Substances and Disease Registry. This study is an extension of our earlier work and both closely examines the choices made in setting HHRVs and presents a quantitative method for identifying the primary factors influencing HHRV agreement or disagreement.(1) We evaluated 171 organizational comparisons, developing a quantitative method for identifying the factors to which HHRV agreement (that is, when both organizations considering the same data set the identical HHRV values) is most sensitive. To conduct this analysis, a Bayesian belief network was built using expert judgment, including the specific science policy choices analysis made in the context of setting an HHRV. Based on a sensitivity of findings analysis, HHRV agreement is most sensitive to the point of departure value, followed by the total uncertainty factor (UF), critical study, critical effect, animal model, and point of departure approach. This analysis also considered the specific impacts of individual UFs, with the database UF and the subchronic-to-chronic UF being identified as primary factors impacting the total UF differences observed across organizations. The sensitivity of findings analysis results were strengthened and confirmed by frequency analyses evaluating which choices most often disagreed when the HHRV and the total UF disagreed.

Part I--Comparing Noncancer Chronic Human Health Reference Values: An Analysis of Science Policy Choices.

The goal of this study was to systematically evaluate the choices made in deriving a chronic oral noncancer human health reference value (HHRV) for a given chemical by different organizations, specifically those from the U.S. Environmental Protection Agency, Health Canada, RIVM (the Netherlands), and the U.S. Agency for Toxic Substances and Disease Registry. This analysis presents a methodological approach for comparing both the HHRVs and the specific choices made in the process of deriving an HHRV across these organizations. Overall, across the 96 unique chemicals and 171 two-way organizational comparisons, the HHRV agreed approximately 26% of the time. A qualitative method for identifying the primary factors influencing these HHRV differences was also developed, using arrays of HHRVs across organizations for the same chemical. The primary factors identified were disagreement on the critical or principal study and differential application of the total uncertainty factor across organizations. Of the cases where the total UF was the primary factor influencing HHRV disagreement, the database UF had the greatest influence.

Dialkyl phosphate urinary metabolites and chromosomal abnormalities in human sperm.

BACKGROUND: The past decade has seen numerous human health studies seeking to characterize the impacts of environmental exposures, such as organophosphate (OP) insecticides, on male reproduction. Despite an extensive literature on OP toxicology, many hormone-mediated effects on the testes are not well understood. OBJECTIVES: This study investigated environmental exposures to OPs and their association with the frequency of sperm chromosomal abnormalities (i.e., disomy) among adult men. METHODS: Men (n=159) from a study assessing the impact of environmental exposures on male reproductive health were included in this investigation. Multi-probe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine XX18, YY18, XY18 and total disomy in sperm nuclei. Urine was analyzed using gas chromatography coupled with mass spectrometry for concentrations of dialkyl phosphate (DAP) metabolites of OPs [dimethylphosphate (DMP); dimethylthiophosphate (DMTP); dimethyldithiophosphate (DMDTP); diethylphosphate (DEP); diethylthiophosphate (DETP); and diethyldithiophosphate (DEDTP)]. Poisson regression was used to model the association between OP exposures and disomy measures. Incidence rate ratios (IRRs) were calculated for each disomy type by exposure quartiles for most metabolites, controlling for age, race, BMI, smoking, specific gravity, total sperm concentration, motility, and morphology. RESULTS: A significant positive trend was seen for increasing IRRs by exposure quartiles of DMTP, DMDTP, DEP and DETP in XX18, YY18, XY18 and total disomy. A significant inverse association was observed between DMP and total disomy. Findings for total sum of DAP metabolites concealed individual associations as those results differed from the patterns observed for each individual metabolite. Dose-response relationships appeared nonmonotonic, with most of the increase in disomy rates occurring between the second and third exposure quartiles and without additional increases between the third and fourth exposure quartiles. CONCLUSIONS: This is the first epidemiologic study of this size to examine the relationship between environmental OP exposures and human sperm disomy outcomes. Our findings suggest that increased disomy rates were associated with specific DAP metabolites, suggesting that the impacts of OPs on testis function need further characterization in epidemiologic studies.

Concordance of Noncarcinogenic Endpoints in Rodent Chemical Bioassays.

Prediction of noncancer toxicologic outcomes in rodent bioassays of 37 chemicals from the National Toxicology Program was evaluated. Using the nonneoplastic lesions noted by NTP pathologists, we evaluate both agreement in toxic lesions across experiments and the predictive value of the presence (or absence) of a lesion in one group for other groups. We compare lesions between mice and rats, male mice and male rats, and female mice and female rats in both short-term and long-term bioassays. We also examine whether lesions found in a specific organ in a short-term test are also found in the long-term test of the same chemical. We find agreement (concordance) across species for specific lesions, as evaluated by the Kappa statistic, ranging from 0.58 (for concordance of nasal lesions between female mice and rats in long-term studies) to -0.14 (lung lesions between mice and rats in long-term studies). Predictive values are limited by the relatively small numbers of observations of each type of lesion. Positive predictive values range from 100% to 0%. Comparing the lesions found in short-term tests to those found in long-term tests resulted in Kappa statistic values from 0.76 (spleen lesions in male rats) to -0.61 (lung lesions in female mice). Positive predictive values of short-term tests for long-term tests range from 70% to 0%. Overall, there is considerable uncertainty in predicting the site of toxic lesions in different species exposed to the same chemical and from short-term to long-term tests of the same chemical.

Improving weight of evidence approaches to chemical evaluations.

Federal and other regulatory agencies often use or claim to use a weight of evidence (WoE) approach in chemical evaluation. Their approaches to the use of WoE, however, differ significantly, rely heavily on subjective professional judgment, and merit improvement. We review uses of WoE approaches in key articles in the peer-reviewed scientific literature, and find significant variations. We find that a hypothesis-based WoE approach, developed by Lorenz Rhomberg et al., can provide a stronger scientific basis for chemical assessment while improving transparency and preserving the appropriate scope of professional judgment. Their approach, while still evolving, relies on the explicit specification of the hypothesized basis for using the information at hand to infer the ability of an agent to cause human health impacts or, more broadly, affect other endpoints of concern. We describe and endorse such a hypothesis-based WoE approach to chemical evaluation.

Trends in pregnancy labeling and data quality for US-approved pharmaceuticals.

OBJECTIVE: Over the past decades, there have been significant efforts in the United States to improve pharmaceutical labeling pertaining to pregnancy. The goal of this study was to describe trends in pregnancy labeling at the time of drug approval and over time. STUDY DESIGN: The labeling data of 213 new pharmaceutical approvals between January 2003 and December 2012 were systematically reviewed. Initial approval data and subsequent labeling revisions were evaluated for pregnancy category, source of pregnancy and breast-feeding data, data in labor and delivery, presence of a registry, black-box warnings, and utilization of the new labeling format. RESULTS: The most commonly approved pregnancy category was C (51.6%). Most pharmaceuticals (92.9%) had pregnancy data based on animal studies and 5.2% had human pregnancy data. For breast-feeding, there were no data in 47.9% of labels, animal data in 42.7%, and human data in 4.7%. There were no labor and delivery data in 85.9% of labels. Only 2.8% of medications had human data, with the remainder having animal data. The majority of medications (85%) did not have a pregnancy registry. Of those that had a registry, 68.7% were by therapeutic category, not agent specific. Seven medications had black-box warnings related to teratogenicity. Since the new labeling recommendations, 4.7% of medications incorporated the new format into the labeling, primarily approvals that occurred in 2012. CONCLUSION: Despite significant efforts to improve drug labeling for pregnancy and lactation, there remains a paucity of human data in this understudied population.

Workshop report: strategies for setting occupational exposure limits for engineered nanomaterials.

Occupational exposure limits (OELs) are important tools for managing worker exposures to chemicals; however, hazard data for many engineered nanomaterials (ENMs) are insufficient for deriving OELs by traditional methods. Technical challenges and questions about how best to measure worker exposures to ENMs also pose barriers to implementing OELs. New varieties of ENMs are being developed and introduced into commerce at a rapid pace, further compounding the issue of OEL development for ENMs. A Workshop on Strategies for Setting Occupational Exposure Limits for Engineered Nanomaterials, held in September 2012, provided an opportunity for occupational health experts from various stakeholder groups to discuss possible alternative approaches for setting OELs for ENMs and issues related to their implementation. This report summarizes the workshop proceedings and findings, identifies areas for additional research, and suggests potential avenues for further progress on this important topic.

The work environment disability-adjusted life year for use with life cycle assessment: a methodological approach.

BACKGROUND: Life cycle assessment (LCA) is a systems-based method used to determine potential impacts to the environment associated with a product throughout its life cycle. Conclusions from LCA studies can be applied to support decisions regarding product design or public policy, therefore, all relevant inputs (e.g., raw materials, energy) and outputs (e.g., emissions, waste) to the product system should be evaluated to estimate impacts. Currently, work-related impacts are not routinely considered in LCA. The objectives of this paper are: 1) introduce the work environment disability-adjusted life year (WE-DALY), one portion of a characterization factor used to express the magnitude of impacts to human health attributable to work-related exposures to workplace hazards; 2) outline the methods for calculating the WE-DALY; 3) demonstrate the calculation; and 4) highlight strengths and weaknesses of the methodological approach. METHODS: The concept of the WE-DALY and the methodological approach to its calculation is grounded in the World Health Organization's disability-adjusted life year (DALY). Like the DALY, the WE-DALY equation considers the years of life lost due to premature mortality and the years of life lived with disability outcomes to estimate the total number of years of healthy life lost in a population. The equation requires input in the form of the number of fatal and nonfatal injuries and illnesses that occur in the industries relevant to the product system evaluated in the LCA study, the age of the worker at the time of the fatal or nonfatal injury or illness, the severity of the injury or illness, and the duration of time lived with the outcomes of the injury or illness. RESULTS: The methodological approach for the WE-DALY requires data from various sources, multi-step instructions to determine each variable used in the WE-DALY equation, and assumptions based on professional opinion. CONCLUSIONS: Results support the use of the WE-DALY in a characterization factor in LCA. Integrating occupational health into LCA studies will provide opportunities to prevent shifting of impacts between the work environment and the environment external to the workplace and co-optimize human health, to include worker health, and environmental health.