Accessible methods and tools to estimate chemical exposure in humans to support risk assessment: A systematic scoping review.

Exposure assessment is a crucial component of environmental health research, providing essential information on the potential risks associated with various chemicals. A systematic scoping review was conducted to acquire an overview of accessible human exposure assessment methods and computational tools to support and ultimately improve risk assessment. The systematic scoping review was performed in Sysrev, a web platform that introduces machine learning techniques into the review process aiming for increased accuracy and efficiency. Included publications were restricted to a publication date after the year 2000, where exposure methods were properly described. Exposure assessments methods were found to be used for a broad range of environmental chemicals including pesticides, metals, persistent chemicals, volatile organic compounds, and other chemical classes. Our results show that after the year 2000, for all the types of exposure routes, probabilistic analysis, and computational methods to calculate human exposure have increased. Sixty-three mathematical models and toolboxes were identified that have been developed in Europe, North America, and globally. However, only twelve occur frequently and their usefulness were associated with exposure route, chemical classes and input parameters used to estimate exposure. The outcome of the combined associations can function as a basis and/or guide for decision making for the selection of most appropriate method and tool to be used for environmental chemical human exposure assessments in Ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment (ONTOX) project and elsewhere. Finally, the choice of input parameters used in each mathematical model and toolbox shown by our analysis can contribute to the harmonization process of the exposure models and tools increasing the prospect for comparison between studies and consistency in the regulatory process in the future.

A systematic review of cancer risk among users of smokeless tobacco (Swedish snus) exclusively, compared with no use of tobacco.

The main objective of this systematic review was to assess cancer risk, and mortality after cancer diagnosis, for exclusive users of Swedish snus, compared with non-users of tobacco. We followed international standards for systematic reviews and graded our confidence in the risk estimates using the GRADE approach. Our search gave 2450 articles, of which 67 were assessed in full text against our inclusion criteria. Of these, 14 cohort-studies and one case-control study were included in the review. The studies investigated risk of cancer in the oral cavity or oropharynx (3 studies), esophagus (1 study), stomach (1 study), pancreas (2 studies), colorectum (2 studies), anus (1 study) and lung (1 study), as well as malignant lymphoma (1 study), leukemia and multiple myeloma (1 study), melanoma (1 study), any cancer (1 study) and mortality after cancer diagnosis (4 studies). Cancer risk could only be evaluated in men as there was a general lack of data for women. All included studies were evaluated to have a moderate risk of bias, mostly related to validity of exposure information. An increased risk of cancer of the esophagus, pancreas, stomach and rectum as well as an association between use of snus and increased mortality after a cancer diagnosis was reported. Our confidence in the various risk estimates varied from moderate through low to very low.

Use of Swedish smokeless tobacco during pregnancy: A systematic review of pregnancy and early life health risk.

BACKGROUND AND AIMS: Smokeless tobacco is a heterogeneous product group with diverse composition and prevalence globally. Tobacco use during pregnancy is concerning due to the risk of adverse pregnancy outcomes and effects on child health. Nicotine may mediate several of these effects. This systematic review measured health outcomes from Swedish smokeless tobacco (snus) use during pregnancy. METHOD: Literature search was conducted by an information specialist in May 2022. We included human studies of snus use during pregnancy compared with no tobacco use, assessed risk of bias, conducted a meta-analysis and assessed confidence in effect-estimates using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). RESULTS: We included 18 cohort studies (42 to 1 006 398 participants). Snus use during pregnancy probably (moderate confidence in risk estimates) increase the risk of neonatal apnea, adjusted odds ratio 95% confidence interval [aOR (95% CI)] 1.96 (1.30 to 2.96). Snus use during pregnancy possibly (low confidence in risk estimates) increase the risk of stillbirths aOR 1.43 (1.02 to 1.99), extremely premature births aOR 1.69 (1.17 to 2.45), moderately premature birth aOR 1.26 (1.15 to 1.38), SGA aOR 1.26 (1.09 to 1.46), reduced birth weight mean difference of 72.47 g (110.58 g to 34.35 g reduction) and oral cleft malformations aOR 1.48 (1.00 to 2.21). It is uncertain (low confidence in risk estimates, CI crossing 1) whether snus use during pregnancy affects risk of preeclampsia aOR 1.11 (0.97 to 1.28), antenatal bleeding aOR 1.15 (0.92 to 1.44) and very premature birth aOR 1.26 (0.95 to 1.66). Risk of early neonatal mortality and altered heart rate variability is uncertain, very low confidence. Snus using mothers had increased prevalence of caesarean sections, low confidence. CONCLUSIONS: This systematic review reveals that use of smokeless tobacco (snus) during pregnancy may adversely impact the developing child.

Protocol for designing INVITES-IN, a tool for assessing the internal validity of in vitro studies.

This protocol describes the design and development of a tool for evaluation of the internal validity of in vitro studies, which is needed to include the data as evidence in systematic reviews and chemical risk assessments. The tool will be designed specifically to be applied to cell culture studies, including, but not restricted to, studies meeting the new approach methodology (NAM) definition. The tool is called INVITES-IN (IN VITro Experimental Studies INternal validity). In this protocol, three of the four studies that will be performed to create the release version of INVITES-IN are described. In the first study, evaluation of existing assessment tools will be combined with focus group discussions to identify how characteristics of the design or conduct of an in vitro study can affect its internal validity. Bias domains and items considered to be of relevance for in vitro studies will be identified. In the second study, group agreement on internal validity domains and items of importance for in vitro studies will be identified via a modified Delphi methodology. In the third study, the draft version of the tool will be created, based on the data on relevance and importance of bias domains and items collected in Studies 1 and 2. A separate protocol will be prepared for the fourth study, which includes the user testing and validation of the tool, and collection of users' experience.

Polycyclic aromatic hydrocarbons (PAHs) may explain the paradoxical effects of cigarette use on preeclampsia (PE).

Tobacco smoking and use of snus (smokeless tobacco) are associated with adverse effects on pregnancy and neonatal outcomes. Nicotine is considered a key toxicant involved in effects caused by both smoking and snus, while pyrolysis products including polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke represents the constituents most unequally divided between these two groups of tobacco products. The aim of this review was: i) to compare the impact, in terms of relative effect estimates, of cigarette smoking and use of Swedish snus on pregnancy outcomes using similar non-tobacco user controls, and ii) to examine whether exposure to PAHs from smoking could explain possible differences in impact on pregnancy outcomes. We systematically searched MEDLINE, Embase, PsycInfo, Web of Science and the Cochrane Database of Systematic Reviews up to October 2021 and identified studies reporting risks for adverse pregnancy and neonatal outcomes associated with snus use and with smoking relative to pregnant women with no use of tobacco. Both snus use and smoking were associated with increased risk of stillbirth, preterm birth, and oral cleft malformation, with comparable point estimates. These effects were likely due to comparable nicotine exposure. We also found striking differences. While both smoking and snus increased the risk of having small for gestational age (SGA) infants, risk from maternal smoking was markedly higher as was the reduction in birthweight. In contrast, the risk of preeclampsia (PE) was markedly lower in smokers than in controls, while snus use was associated with a slightly increased risk. We suggest that PAHs acting via AhR may explain the stronger effects of tobacco smoking on SGA and also to the apparent protective effect of cigarette smoking on PE. Possible mechanisms involved include: i) disrupted endocrine control of fetal development as well as placental development and function, and ii) stress adaption and immune suppression in placenta and mother.

An evaluation of the COVID-19 recommendation map identified diverging clinical and public health guidance.

OBJECTIVES: To describe divergence between actionable statements issued by coronavirus disease 2019 (COVID-19) guideline developers cataloged on the "COVID-19 Recommendations and Gateway to Contextualization" platform. STUDY DESIGN AND SETTING: We defined divergence as at least two comparable actionable statements with different explicit judgments of strength, direction, or subgroup consideration of the population or intervention. We applied a content analysis to compare guideline development methods for a sample of diverging statements and to evaluate factors associated with divergence. RESULTS: Of the 138 guidelines evaluated, 85 (62%) contained at least one statement that diverged from another guideline. We identified 223 diverging statements in these 85 guidelines. We grouped statements into 66 clusters. Each cluster addressed the same population, intervention, and comparator group or just similar interventions. Clinical practice statements were more likely to diverge in an explicit judgment of strength or direction compared to public health statements. Statements were more likely to diverge in strength than direction. The date of publication, used evidence, interpretation of evidence, and contextualization considerations were associated with divergence. CONCLUSION: More than half of the assessed guidelines issued at least one diverging statement. This study helps in understanding the types of differences between guidelines issuing comparable statements and factors associated with their divergence.

Opioids for Treatment of Pre-hospital Acute Pain: A Systematic Review.

INTRODUCTION: Acute pain is a frequent symptom among patients in the pre-hospital setting, and opioids are the most widely used class of drugs for the relief of pain in these patients. However, the evidence base for opioid use in this setting appears to be weak. The aim of this systematic review was to explore the efficacy and safety of opioid analgesics in the pre-hospital setting and to assess potential alternative therapies. METHODS: The PubMed, EMBASE, Cochrane Library, Centre for Reviews and Dissemination, Scopus, and Epistemonikos databases were searched for studies investigating adult patients with acute pain prior to their arrival at hospital. Outcomes on efficacy and safety were assessed. Risk of bias for each included study was assessed according to the Cochrane approach, and confidence in the evidence was assessed using the GRADE method. RESULTS: A total of 3453 papers were screened, of which the full text of 125 was assessed. Twelve studies were ultimately included in this systematic review. Meta-analysis was not undertaken due to substantial clinical heterogeneity among the included studies. Several studies had high risk of bias resulting in low or very low quality of evidence for most of the outcomes. No pre-hospital studies compared opioids with placebo, and no studies assessed the risk of opioid administration for subgroups of frail patients. The competency level of the attending healthcare provider did not seem to affect the efficacy or safety of opioids in two observational studies of very low quality. Intranasal opioids had a similar effect and safety profile as intravenous opioids. Moderate quality evidence supported a similar efficacy and safety of synthetic opioid compared to morphine. CONCLUSIONS: Available evidence for pre-hospital opioid administration to relieve acute pain is scarce and the overall quality of evidence is low. Intravenous administration of synthetic, fast-acting opioids may be as effective and safe as intravenous administration of morphine. More controlled studies are needed on alternative routes for opioid administration and pre-hospital pain management for potentially more frail patient subgroups.

Using neural networks to support high-quality evidence mapping.

BACKGROUND: The Living Evidence Map Project at the Norwegian Institute of Public Health (NIPH) gives an updated overview of research results and publications. As part of NIPH's mandate to inform evidence-based infection prevention, control and treatment, a large group of experts are continously monitoring, assessing, coding and summarising new COVID-19 publications. Screening tools, coding practice and workflow are incrementally improved, but remain largely manual. RESULTS: This paper describes how deep learning methods have been employed to learn classification and coding from the steadily growing NIPH COVID-19 dashboard data, so as to aid manual classification, screening and preprocessing of the rapidly growing influx of new papers on the subject. Our main objective is to make manual screening scalable through semi-automation, while ensuring high-quality Evidence Map content. CONCLUSIONS: We report early results on classifying publication topic and type from titles and abstracts, showing that even simple neural network architectures and text representations can yield acceptable performance.

Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review.

Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in "low" or "very low" certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary, published animal and human trials failed to predict troglitazone's potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs' off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.

Ketamine for the treatment of prehospital acute pain: a systematic review of benefit and harm.

BACKGROUND: Few publications have addressed prehospital use of ketamine in analgesic doses. We aimed to assess the effect and safety profile of ketamine compared with other analgesic drugs (or no drug) in adult prehospital patients with acute pain. METHODS: A systematic review of clinical trials assessing prehospital administration of ketamine in analgesic doses compared with other analgesic drugs or no analgesic treatment in adults. We searched PubMed, EMBASE, Cochrane Library and Epistemonikos from inception until 15 February 2020, including relevant articles in English and Nordic languages. We used the Cochrane and Grading of Recommendations Assessment, Development and Evaluation methodologies and exclusively assessed patient-centred outcomes. Two independent authors screened trials for eligibility, extracted data and assessed risk of bias. RESULTS: We included eight studies (2760 patients). Ketamine was compared with various opioids given alone, and intranasal ketamine given with nitrous oxide was compared with nitrous oxide given alone. Four randomised controlled trials (RCTs) and one cluster randomised trial included 699 patients. One prospective cohort included 27 patients and two retrospective cohorts included 2034 patients. Five of the eight studies had high risks of bias. Pain score with ketamine is probably lower than after opioids as demonstrated in a cluster-RCT (308 patients) and a retrospective cohort (158 patients) study, Δvisual analogue scale -0.4 (-0.8 to 0.0) and Δnumeric pain rating scale -3.0 (-3.86 to -2.14), respectively. Ketamine probably leads to less nausea and vomiting (risk ratio (RR) 0.24 (0.11 to 0.52)) but more agitation (RR 7.81 (1.85 to 33)) than opioids. CONCLUSIONS: This systematic literature review finds that ketamine probably reduces pain more than opioids and with less nausea and vomiting but higher risk of agitation. Risk of bias in included studies is high. OTHER: Scandinavian society of anaesthesiology and intensive care medicine funded meetings and software. The Norwegian Air Ambulance Foundation funded publication. Otherwise this research received no grant from any agency in the public, commercial or not-for-profit sectors. PROSPERO REGISTRATION NUMBER: CRD42018114399.

The mental health impact of the covid-19 pandemic on healthcare workers, and interventions to help them: A rapid systematic review.

The covid-19 pandemic has heavily burdened healthcare systems throughout the world. We performed a rapid systematic review to identify, assess and summarize research on the mental health impact of the covid-19 pandemic on HCWs (healthcare workers). We utilized the Norwegian Institute of Public Health's Live map of covid-19 evidence on 11 May and included 59 studies. Six reported on implementing interventions, but none reported on effects of the interventions. HCWs reported low interest in professional help, and greater reliance on social support and contact. Exposure to covid-19 was the most commonly reported correlate of mental health problems, followed by female gender, and worry about infection or about infecting others. Social support correlated with less mental health problems. HCWs reported anxiety, depression, sleep problems, and distress during the covid-19 pandemic. We assessed the certainty of the estimates of prevalence of these symptoms as very low using GRADE. Most studies did not report comparative data on mental health symptoms before the pandemic or in the general population. There seems to be a mismatch between risk factors for adverse mental health outcomes among HCWs in the current pandemic, their needs and preferences, and the individual psychopathology focus of current interventions.

Using GRADE in situations of emergencies and urgencies: certainty in evidence and recommendations matters during the COVID-19 pandemic, now more than ever and no matter what.

OBJECTIVES: The public, policy makers, and science communities are subject to many false, uninformed, overly optimistic, premature, or simply ridiculous health claims. The coronavirus disease 2019 (COVID-19) pandemic and its context is a paramount example for such claims. In this article, we describe why expressing the certainty in evidence to support a decision is critical and why the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach matters now, perhaps more than ever and no matter what the specific topic is in relation to COVID-19. We finally also offer suggestions for how it can be used appropriately to support decision-making at global, national, and local level when emergency, urgent or rapid responses are needed. STUDY DESIGN AND SETTING: This is an invited commentary to address the objectives above building on examples from the recent COVID-19 pandemic. This includes an iterative discussion of examples and development of guidance. RESULTS: The GRADE approach is a transparent and structured method for assessing the certainty of evidence and when developing recommendations that requires little additional time. We describe why emergency, urgent, or rapid responses do not justify omitting this critical assessment of the evidence. In situations of emergencies and urgencies, such as the COVID-19 pandemic, GRADE can similarly be used to express and convey certainty in intervention effects, test accuracy, risk and prognostic factors, consequences of public health measures, and qualitative bodies of evidence. CONCLUSIONS: Assessing and communicating the certainty of evidence during the COVID-19 pandemic is critical. Those offering evidence synthesis or making recommendations should use transparent ratings of the body of evidence supporting a claim regardless of time that is available or needed to provide this response.

Are the health risks of moist oral snuff (snus) underestimated? / Er helserisikoen ved snus undervurdert?

The use of moist oral snuff (snus) has increased significantly, particularly among young adults who have not previously smoked. Snus increases the risk of cancer, cardiovascular disease, type-2 diabetes and birth defects.

Femoral nerve blocks for the treatment of acute pre-hospital pain: A systematic review with meta-analysis.

BACKGROUND: Pain management is one of the most important interventions in the emergency medical services. The femoral nerve block (FNB) is, among other things, indicated for pre- and post-operative pain management for patients with femoral fractures but its role in the pre-hospital setting has not been determined. The aim of this review was to assess the effect and safety of the FNB in comparison to other forms of analgesia (or no treatment) for managing acute lower extremity pain in adult patients in the pre-hospital setting. METHODS: A systematic review (PROSPERO registration (CRD42018114399)) was conducted. The Cochrane and GRADE methods were used to assess outcomes. Two authors independently reviewed each study for eligibility, extracted the data and performed risk of bias assessments. RESULTS: Four studies with a total of 252 patients were included. Two RCTs (114 patients) showed that FNB may reduce pain more effectively than metamizole (mean difference 32 mm on a 100 mm VAS (95% CI 24 to 40)). One RCT (48 patients) compared the FNB with lidocaine and magnesium sulphate to FNB with lidocaine alone and was only included here for information regarding adverse effects. One case series included 90 patients. Few adverse events were reported in the included studies. The certainty of evidence was very low. We found no studies comparing FNB to inhaled analgesics, opioids or ketamine. CONCLUSIONS: Evidence regarding the effectiveness and adverse effects of pre-hospital FNB is limited. Studies comparing pre-hospital FNB to inhaled analgesics, opioids or ketamine are lacking.

GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA). STUDY DESIGN AND SETTING: We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overview of the domains, and describe risk of bias and indirectness specifically. RESULTS: Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies. CONCLUSION: Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.

GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias, and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables. STUDY DESIGN AND SETTING: We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. RESULTS: Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies. CONCLUSION: Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. Although several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.

A systematic review of the agreement between chronological age and skeletal age based on the Greulich and Pyle atlas.

OBJECTIVES: This systematic review examines the agreement between assessed skeletal age by the Greulich and Pyle atlas (GP skeletal age) and chronological age. METHODS: We searched electronic databases until January 2017 for studies reporting GP skeletal age and confirmed chronological age in healthy individuals aged 10-25 years. Results are presented as forest plots and meta-analyses (random-effects models). RESULTS: In separate meta-analyses for each age group and sex (14-18 years for girls, 14-19 years for boys), the pooled mean differences between GP skeletal age and chronological age varied from -0.52 years to 0.47 years. In individual studies, age group and sex-specific mean differences between GP skeletal age and chronological age rarely exceeded 1 year, but between-study heterogeneities were large in most age groups. Few studies examined mean chronological age and distribution for each GP skeletal age. One study of good methodological quality indicates that 95% prediction intervals for chronological age from given GP skeletal ages are typically around 4 years. CONCLUSIONS: There is still good correlation between GP skeletal age and mean chronological age in modern populations. However, the individual variation of development within a population and heterogeneities between studies are substantial. KEY POINTS: • The GP atlas still corresponds well with mean chronological age in modern populations. • The substantial variation within a population must be considered. • The heterogeneity between studies is relatively large and of unknown origin.