Vinyl Chloride: A Case Study of Data Suppression and Misrepresentation

When the U.S. Environmental Protection Agency (EPA) finalized its 2000 update of the toxicological effects of vinyl chloride (VC), it was concerned with two issues: the classification of VC as a carcinogen and the numerical estimate of its potency. In this commentary we describe how the U.S. EPA review of VC toxicology, which was drafted with substantial input from the chemical industry, weakened safeguards on both points. First, the assessment downplays risks from all cancer sites other than the liver. Second, the estimate of cancer potency was reduced 10-fold from values previously used for environmental decision making, a finding that reduces the cost and extent of pollution reduction and cleanup measures. We suggest that this assessment reflects discredited scientific practices and recommend that the U.S. EPA reverse its trend toward ever-increasing collaborations with the regulated industries when generating scientific reviews and risk assessments

A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study.

BACKGROUND: Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications. METHODS AND FINDINGS: From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735-0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658-0.768). A predicted probability ≥25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability. CONCLUSIONS: The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Heat-inducible and constitutive expression of the 90 kD heat shock protein gene, Hsp90, during zebrafish embryogenesis

The objective of my thesis work is to examine the in vivo transcript accumulation of the 90 kD heat shock protein, 'hsp90α' during zebrafish embryogenesis in order to identify stage- and tissue-dependent localization. Northern blot analysis indicated that 'hsp90β' mRNA was visible at high levels constitutively, and only mildly up-regulated following heat shock, whereas, 'hsp90α' mRNA was undetectable at control temperatures (28.5°C), but was dramatically upregulated following heat shock (1 hr at 37°C). Whole mount in situ hybridization with gene specific riboprobes demonstrated that constitutive accumulation of ' hsp90β' mRNA was evident in a wide range of tissues throughout the embryo, whereas 'hsp90α' mRNA was localized within putative myogenic tissue of the zebrafish trunk and pectoral fin bud during myogenesis. Observation of tissue sections confirmed high levels of ' hsp90α' mRNA within cells of the presegmental and segmental plate mesoderm, and not within the axial structures (neural tube and notochord). Similar tissue- and stage-specific accumulation of 'hsp90α' mRNA was also seen in mid-somitogenic chicken embryos. Following exposure of zebrafish and chicken embryos to heat shock ' hsp90α' was dramatically upregulated throughout all embryonic tissues, demonstrating that heat-induced expression of 'hsp90α ' is regulated independent of constitutive expression, and that the expression of the two 'hsp90' genes are regulated separately during vertebrate embryogenesis. I examined the altered pattern of 'hsp90α' transcript accumulation within three zebrafish mutant embryo types, 'spadetail, no tail', and 'floating head', which exhibit aberrant myogenesis. In all cases 'hsp90α' mRNA was localized within cells of the paraxial mesoderm which are fated to form striated trunk muscle (identified by expression of 'myoD'), suggesting that its upregulation within myogenic tissue is regulated as part of myogenesis. The work presented in this dissertation demonstrates for the first time the independent regulation of 'hsp90α' and 'hsp90β ' gene expression at the mRNA level during embryogenesis. Further, the highly restricted pattern of 'hsp90α' mRNA localization during myogenesis, in contrast to its ubiquitous high level accumulation following heat shock, suggests that the protein may perform a specific function during skeletal myogenesis in addition to a more general protective function during periods of environmental stress

_113N7_Science_809-893

When the U.S. Environmental Protection Agency (EPA) finalized its 2000 update of the toxicological effects of vinyl chloride (VC), it was concerned with two issues: the classification of VC as a carcinogen and the numerical estimate of its potency. In this commentary we describe how the U.S. EPA review of VC toxicology, which was drafted with substantial input from the chemical industry, weakened safeguards on both points. First, the assessment downplays risks from all cancer sites other than the liver. Second, the estimate of cancer potency was reduced 10-fold from values previously used for environmental decision making, a finding that reduces the cost and extent of pollution reduction and cleanup measures. We suggest that this assessment reflects discredited scientific practices and recommend that the U.S. EPA reverse its trend toward ever-increasing collaborations with the regulated industries when generating scientific reviews and risk assessments

Lessons from health hazards | Vinyl chloride: a saga of secrecy 8 Vinyl chloride: a saga of secrecy

This chapter is about how early warnings in the 1950s and 1960s concerning the short-term harm of vinyl chloride (VC) to the skin and bones of workers, and to the livers of laboratory animals, were initially hidden from other workers and regulators. This was despite some early misgivings by company experts whose advice was initially ignored by their employers. This pattern was repeated when the later, more devastating news of a rare liver cancer in workers was revealed by long-term animal studies and by an attentive and concerned company physician. Unlike many other histories, however, this story features a very prompt response from the global chemical industry to the publication of the liver cancer evidence, a response that included funding cancer testing and later compliance with a large reduction in the permissible exposure limits. The case also provides early evidence of reproductive effects of vinyl chloride monomer (VCM). Other features of this story presage the later and common responses of the corporate world to heightened public awareness and pressure from non-governmental organisations (NGOs) and trade unions, including greatly exaggerated estimates of the likely costs of complying with tighter pollution controls; a frequent mismatch between the position of the trade association and tha