Search

Background: Systematic evidence maps are increasingly used to develop chemical risk assessments. These maps can provide an overview of available studies and relevant study information to be used for various research objectives and applications. Environmental epidemiological studies that examine the impact of chemical exposures on various 'omic profiles in human populations provide relevant mechanistic information and can be used for benchmark dose modeling to derive potential human health reference values., Objectives: To create a systematic evidence map of environmental epidemiological studies examining environmental contaminant exposures with 'omics in order to characterize the extent of available studies for future research needs., Methods: Systematic review methods were used to search and screen the literature and included the use of machine learning methods to facilitate screening studies. The Populations, Exposures, Comparators and Outcomes (PECO) criteria were developed to identify and screen relevant studies. Studies that met the PECO criteria after full-text review were summarized with information such as study population, study design, sample size, exposure measurement, and 'omics analysis., Results: Over 10,000 studies were identified from scientific databases. Screening processes were used to identify 84 studies considered PECO-relevant after full-text review. Various contaminants (e.g. phthalate, benzene, arsenic, etc.) were investigated in epidemiological studies that used one or more of the four 'omics of interest: epigenomics, transcriptomics, proteomics, and metabolomics . The epidemiological study designs that were used to explore single or integrated 'omic research questions with contaminant exposures were cohort studies, controlled trials, cross-sectional, and case-control studies. An interactive web-based systematic evidence map was created to display more study-related information., Conclusions: This systematic evidence map is a novel tool to visually characterize the available environmental epidemiological studies investigating contaminants and biological effects using 'omics technology and serves as a resource for investigators and allows for a range of applications in chemical research and risk assessment needs., (Published by Elsevier Ltd.)

Background: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS., Objective: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼ 150 PFAS that were prioritized in 2019 by the U.S. EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing., Methods: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement-only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥ 21 -d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata., Results: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams., Discussion: Many of the ∼ 150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343.

Rheumatoid arthritis (RA), a long-term auto-immune condition is a challenging condition for patients to manage. Goals of treatment include reducing pain, decreasing inflammation, and improving an individual's overall function. Increasingly technology is being utilised to support patients to self-manage their condition. The aim of this systematic narrative review was to synthesise and critically appraise published evidence concerning the effectiveness of tele-health interventions to support self-management in RA. Bibliographic databases searched from 2014 to March 2020 included MedLINE, Embase, Cochrane Library. Search strategy combined the following concepts: (1) rheumatoid arthritis, (2) tele-health interventions, and (3) self-management. Only randomised controlled trials (RCTs) involving adults with RA were included. Titles, abstracts, full-text articles were screened, any discrepancies were checked by a second reviewer. Risk of bias was assessed using Cochrane risk of bias tool and data were extracted utilising the Cochrane data collection form for RCT interventions along with the TiDier checklist. Due to high heterogeneity, results were not meta-analysed and instead data were synthesised narratively. The search identified 98 articles, seven were included. The completed RCTs varied in the nature of the interventions, duration/severity of RA, outcomes measured and effectiveness of the interventions. The completed RCTs included a total of 791 participants Disease duration was largely between 4 and 10 years and disease severity on average was moderate. There was extensive variation in intervention components, theories underpinning theories and outcomes measured. Five RCTs reported a positive effect on factors such as disease activity, medication adherence, physical activity and self-efficacy levels. This study suggests that tele-health interventions that are well-designed, tailored and multi-faceted can help to achieve positive self-management outcomes in RA. None of the studies showed evidence of harm.

Feed intake restriction impacts both humans and ruminants in late gestation, although it is unknown whether this adverse maternal environment influences the microbiome of the reproductive tract, and through it, the colonization of the fetal gut. A 2 × 2 factorial design including a 70% feed intake restriction (feed restricted 'FR' or control diets 'CON') and mineral supplementation (unsupplemented 'S-' or supplemented 'S+') was used to analyze these effects in multiparous cows ( n = 27). Vaginal swabs were obtained 60, 30, and 10 days prior to the estimated calving date, along with neonatal rumen fluid and meconium. Placental tissues and efficiency measurements were collected. Microbial DNA was extracted for 16S sequencing of the V4 region. Feed restriction decreased the diversity of the placental microbiome, but not the vagina, while mineral supplementation had little impact on these microbial communities. Mineral supplementation did improve the richness and diversity of the fetal gut microbiomes in relation to reproductive microbes. These differences within the placental microbiome may influence individual health and performance. Adequate maternal nutrition and supplementation yielded the greatest placental efficiency, which may aid in the establishment of a healthy placental microbiome and fetal microbial colonization.

Background: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS., Methods: We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy, or death) and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations (ie, populations not used to develop the model) using internal-external cross-validation, and quantified the discrimination using the concordance (c) statistic (area under the receiver operator characteristic curve) and calibration using a calibration slope., Findings: Data were collected between Jan 1, 1992, and Sept 22, 2016 (the largest data-set included data from 1936 patients). The median follow-up time was 97·5 months (IQR 52·9-168·5). Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset (univariable hazard ratio [HR] 1·71, 95% CI 1·63-1·79), age at onset (1·03, 1·03-1·03), definite versus probable or possible ALS (1·47, 1·39-1·55), diagnostic delay (0·52, 0·51-0·53), forced vital capacity (HR 0·99, 0·99-0·99), progression rate (6·33, 5·92-6·76), frontotemporal dementia (1·34, 1·20-1·50), and presence of a C9orf72 repeat expansion (1·45, 1·31-1·61), all p<0·0001. The c statistic for external predictive accuracy of the model was 0·78 (95% CI 0·77-0·80; 95% prediction interval [PI] 0·74-0·82) and the calibration slope was 1·01 (95% CI 0·95-1·07; 95% PI 0·83-1·18). The model was used to define five groups with distinct median predicted (SE) and observed (SE) times in months from symptom onset to the composite survival outcome: very short 17·7 (0·20), 16·5 (0·23); short 25·3 (0·06), 25·2 (0·35); intermediate 32·2 (0·09), 32·8 (0·46); long 43·7 (0·21), 44·6 (0·74); and very long 91·0 (1·84), 85·6 (1·96)., Interpretation: We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only., Funding: Netherlands ALS Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose of Review: Amyotrophic lateral sclerosis (ALS) is a progressive, incurable and fatal neurodegenerative disease. Few interventions significantly alter the disease course, but many symptomatic treatments exist to improve patients' quality of life. In this review, we describe our approach to symptomatic management of ALS and discuss the underlying evidence base., Recent Findings: Discussion focuses predominantly on recently published articles. We cover management settings, disease-modifying treatment, vitamin D, respiratory management including noninvasive ventilation and diaphragmatic pacing, secretions, nutrition, dysphagia and gastrostomy, communication problems, mobility, spasticity, pain, cognition, depression and emotional lability, fatigue, sleep disturbance, head drop, prevention of deep venous thrombosis and end-of-life issues., Summary: Multidisciplinary specialist care appears to improve quality of life and survival. Riluzole remains the only available disease-modifying medication and confers a survival advantage of 2-3 months. Noninvasive ventilation improves quality of life and extends survival by approximately 7 months, at least in patients without severe bulbar problems. Nutrition is an independent prognostic factor; whether gastrostomy improves survival and quality of life remains unclear and further studies are underway. Many other symptomatic treatments appear helpful to individuals in clinic, but further randomized clinical trials are required to provide a more robust evidence base.

Background: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS., Methods: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31., Findings: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event., Interpretation: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments., Funding: The Motor Neurone Disease Association of Great Britain and Northern Ireland., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Placement of a gastrostomy tube remains the gold standard procedure to maintain nutrition in patients with motor neuron disease (MND) and bulbar muscle weakness. Percutaneous endoscopic gastrostomy (PEG) is the most commonly used procedure in this context. Per-oral image guided gastrostomy (PIG) is a new hybrid technique used successfully in non-MND patients. We have modified the PIG technique to improve patient tolerability and have undertaken a pilot evaluation of PIG compared to PEG in MND patients. Nineteen PIG and 16 PEG procedures performed over a period of four years were evaluated. Pre-procedural forced vital capacity (FVC), procedural oxygen saturation, post-procedural complications and survival duration were recorded. Results showed that a gastrostomy tube was successfully placed in 95% of the PIG group and 80% of the PEG group. Rates of minor complications were comparable in both groups (21% in PIG, 23% in PEG). No life-threatening complications occurred in either group. Procedural mean oxygen saturations were higher in the PIG group compared to the PEG group (p < 0.001). No significant survival differences were observed. This study provides evidence for the use of the PIG procedure as a safe and well tolerated alternative to PEG in MND patients.

Our objective was to establish the pattern of spread in lower limb-onset ALS (contra- versus ipsi-lateral) and its contribution to prognosis within a multivariate model. Pattern of spread was established in 109 sporadic ALS patients with lower limb-onset, prospectively recorded in Oxford and Sheffield tertiary clinics from 2001 to 2008. Survival analysis was by univariate Kaplan-Meier log-rank and multivariate Cox proportional hazards. Variables studied were time to next limb progression, site of next progression, age at symptom onset, gender, diagnostic latency and use of riluzole. Initial progression was either to the contralateral leg (76%) or ipsilateral arm (24%). Factors independently affecting survival were time to next limb progression, age at symptom onset, and diagnostic latency. Time to progression as a prognostic factor was independent of initial direction of spread. In a regression analysis of the deceased, overall survival from symptom onset approximated to two years plus the time interval for initial spread. In conclusion, rate of progression in lower limb-onset ALS is not influenced by whether initial spread is to the contralateral limb or ipsilateral arm. The time interval to this initial spread is a powerful factor in predicting overall survival, and could be used to facilitate decision-making and effective care planning.