Hershey Medical Center Technical Workshop Report: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Importance Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, Design, and Participants Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features. Exposures Severe acute respiratory syndrome coronavirus 2. Main Outcomes and Measures Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19–related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and Relevance In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown

Case Study Report: Business Case for Implementing Battery-Powered Tools for Direct-Bury Line Workers at an Electric Power Utility

Cutting cable and crimping compression connections are the two most commonly performed tasks by direct-bury line workers who repair and bury underground cable for electric power utilities. Battery-powered tools, rather than manual (Figure 1), do the demanding work of cutting cable and crimping connectors while the worker holds the tool in place. The focus of this study is whether the cost of battery-powered tools for direct-bury line workers can be justified on injury and illness data and other factors

Case Study for Underground Workers at an Electric Utility: How a Research Institution, University, and Industry Collaboration Improved Occupational Health Through Ergonomics

This article describes a collaboration between a research institution, a university, and a medium-sized electric power utility. Two ergonomics teams were created at the host utility to identify tasks with risk factors for musculoskeletal disorders (MSDs) and propose ergonomic interventions for these tasks. Both ergonomics teams focused on tasks performed by underground workers: one team focused on manhole-vault tasks, and the other team focused on direct-buried cable job tasks. Several of the ergonomic interventions were tested in the ergonomics laboratory at the university. The results of one of the laboratory experiments indicated that a 2nd class lever tool reduced muscle forces required to remove and replace a manhole cover as compared with a T-handle attached to a hook and chain. The results of another laboratory experiment demonstrated that a battery-powered cutter reduced muscle forces to cut cable as compared to a manual cutting tool. A collaborative ergonomics effort is an effective method for identifying problematic tasks for workers in a particular industry, evaluating those tasks, and developing best work practices for that type of industry. This approach could be used by other industries in their effort to reduce the incidence, cost, and severity of MSDs in th

Physiologically based pharmacokinetic modeling of arsenic in the mouse

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process. [Authors]]]> eng oai:serval.unil.ch:BIB_814 2022-02-19T02:25:05Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_814 Shenyang apprend à gérer ses pauvres. Kernen, A info:eu-repo/semantics/article article 1997 Perspectives Chinoises, vol. 40, pp. 17-21 fre oai:serval.unil.ch:BIB_8140284AD5C8 2022-02-19T02:25:05Z openaire documents urnserval <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_8140284AD5C8 Mitochondrial respiratory states and rate info:doi:10.26124/mitofit:190001.v2 info:eu-repo/semantics/altIdentifier/doi/10.26124/mitofit:190001.v2 Gnaiger, E. Aasander Frostner, E. Abdul Karim, N. Abumrad, NA. Acuna-Castroviejo, D. Adiele, RC. Ahn, B. Ali, SS. Alton, L. Alves, MG. Amati, F. Amoedo, ND. Andreadou, I. Arago, M. Aral, C. Arandarcikaite, O. Armand, AS. Arnould, T. Avram, VF. Bailey, DM. Bajpeyi, S. Bajzikova, M. Bakker, BM. Barlow, J. Bastos Sant'Anna Silva, AC. Batterson, P. Battino, M. Bazil, J. Beard, DA. Bednarczyk, P. Bello, F. Ben-Shachar, D. Bergdahl, A. Berge, RK. Bergmeister, L. Bernardi, P. Berridge, MV. Bettinazzi, S. Bishop, D. Blier, PU. Blindheim, DF. Boardman, NT. Boetker, HE. Borchard, S. Boros, M. Borsheim, E. Borutaite, V. Botella, J. Bouillaud, F. Bouitbir, J. Boushel, RC. Bovard, J. Breton, S. Brown, DA. Brown, GC. Brown, RA. Brozinick, JT. Buettner, GR. Burtscher, J. Calabria, E. Calbet, JA. Calzia, E. Cannon, DT. Cano Sanchez, M. Canto, AC. Cardoso, LHD. Carvalho, E. Casado Pinna, M. Cassar, S. Cassina, AM. Castelo, MP. Castro, L. Cavalcanti-de-Albuquerque, JP. Cervinkova, Z. Chabi, B. Chakrabarti, L. Chakrabarti, S. Chaurasia, B. Chen, Q. Chicco, AJ. Chinopoulos, C. Chowdhury, SK. Cizmarova, B. Clementi, E. Coen, PM. Cohen, BH. Coker, RH. Collin, A. Crisostomo, L. Dahdah, N. Dalgaard, LT. Dambrova, M. Danhelovska, T. Darveau, CA. Das, AM. Dash, RK. Davidova, E. 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