Fluoride is a naturally occurring substance that is also added to drinking water, dental hygiene products, and food supplements for preventing dental caries. Concerns have been raised about several other potential health risks of fluoride. To conduct a robust synthesis of evidence regarding human health risks due to exposure to fluoride in drinking water, and to develop a point of departure (POD) for setting a health-based value (HBV) for fluoride in drinking water. A systematic review of evidence published since recent reviews of human, animal, and in vitro data was carried out. Bradford Hill considerations were used to weigh the evidence for causality. Several key studies were considered for deriving PODs. The current review identified 89 human studies, 199 animal studies, and 10 major in vitro reviews. The weight of evidence on 39 health endpoints was presented. In addition to dental fluorosis, evidence was considered strong for reduction in IQ scores in children, moderate for thyroid dysfunction, weak for kidney dysfunction, and limited for sex hormone disruptions. The current review identified moderate dental fluorosis and reduction in IQ scores in children as the most relevant endpoints for establishing an HBV for fluoride in drinking water. PODs were derived for these two endpoints, although there is still some uncertainty in the causal weight of evidence for causality for reducing IQ scores in children and considerable uncertainty in the derivation of its POD. Given our evaluation of the overall weight of evidence, moderate dental fluorosis is suggested as the key endpoint until more evidence is accumulated on possible reduction of IQ scores effects. A POD of 1.56 mg fluoride/L for moderate dental fluorosis may be preferred as a starting point for setting an HBV for fluoride in drinking water to protect against moderate and severe dental fluorosis. Although outside the scope of the current review, precautionary concerns for potential neurodevelopmental cognitive effects may warrant special consideration in the derivation of the HBV for fluoride in drinking water.

Long-term inhalation exposure to manganese (Mn) metal or its inorganic compounds can result in manganism or subclinical neurofunctional deficits. Studies have described affected workers in Mn dioxide mining, Mn-containing ore crushing and milling facilities, manufacturing of dry-cell batteries, Mn steel and alloy production plants, and in welders. The objective of this study was to critically review existing evidence on the reliability of potential biomarkers of Mn exposure, specifically the relationship between inhalation exposure to Mn particulates in different occupational settings and Mn concentrations in blood and other biological fluids and tissues, with a particular focus on whole blood as a potentially useful medium for measuring internal tissue dose. We also examined available evidence on the relationship between Mn levels in blood and adverse clinical and subclinical neurotoxic outcomes. Three bibliographic databases were searched for relevant studies and identified references were screened by two independent reviewers. Of the 6338 unique references identified, 76 articles were retained for data abstraction. Findings indicate that the relationships between Mn in blood and both external Mn exposure indices and neurofunctional impairments are limited and inconsistent. Different sources of exposure to Mn compounds, heterogeneity in the methodological approaches, and inadequate reporting of essential information limited direct comparison of the reported findings. Among the Mn-exposure biomarkers considered in this review – including biomarkers in blood, plasma, serum, erythrocytes, urine, bone, toenails, fingernails, hair, saliva – biomarkers in whole blood may provide to be most useful in Mn biomonitoring and risk assessment.

We conducted a critical review on biomarkers of environmental manganese (Mn) exposure to answer the following questions: 1) are there reliable biomarkers of internal Mn exposure (Mn in biological matrices) associated with external metrics of Mn exposure (Mn in environmental media)? and 2) are there accurate reference values (RVs) for Mn in biological matrices? Three bibliographic databases were searched for relevant references and identified references were screened by two independent reviewers. Of the 6342 unique references identified, 86 articles were retained for data abstraction. Our analysis of currently available evidence suggests that Mn levels in blood and urine are not useful biomarkers of Mn exposure in non-occupational settings. The strength of the association between Mn in environmental media and saliva was variable. Findings regarding the utility of hair Mn as a biomarker of environmental Mn exposure are inconsistent. Measurements of Mn in teeth are technically challenging and findings on Mn in tooth components are scarce. In non-occupationally exposed individuals, bone Mn measurements using in vivo neutron activation analysis (IVNAA) are associated with large uncertainties. Findings suggest that Mn in nails may reflect Mn in environmental media and discriminate between groups of individuals exposed to different environmental Mn levels, although more research is needed. Currently, there is no strong evidence for any biological matrix as a valid biomarker of Mn exposure in non-occupational settings. Because of methodological limitations in studies aimed at derivation of RVs for Mn in biological materials, accurate RVs are scarce.

Vaccines effectively protect against COVID-19, but vaccine hesitancy and refusal hinder vaccination rates. This systematic review aimed to (1) review and describe current interventions for addressing COVID-19 vaccine hesitancy/refusal and (2) assess whether these interventions are effective for increasing vaccine uptake. The protocol was registered prospectively on PROSPERO and comprehensive search included Medline, Embase, CINAHL, PsycInfo, and Web of Science databases. Only studies that evaluated the effectiveness of non-financial interventions to address COVID-19 vaccine hesitancy were included, while those focusing intentions or financial incentive were excluded. Risk of bias for all included studies was evaluated using Cochrane risk of bias tools. In total, six articles were included in the review (total participants n = 200,720). A narrative synthesis was performed due to the absence of common quantitative metrics. Except for one randomized controlled trial, all studies reported that interventions were effective, increasing COVID-19 vaccination rates. However, non-randomized studies were subject to confounding biases. Evidence on the effectiveness of COVID-19 vaccine hesitancy interventions remains limited and further evidence is needed for the development of clear guidance on effective interventions to increase vaccine uptake.

To synthesize evidence relevant for informed decisions concerning cognitive testing of older physicians. Relevant literature was systematically searched in Medline, EMBASE, PsycInfo, and ERIC, with key findings abstracted and synthesized. Cognitive abilities of physicians may decline in an age range where they are still practicing. Physician competence and clinical performance may also decline with age. Cognitive scores are lower in physicians referred for assessment because of competency or performance concerns. Many physicians do not accurately self-assess and continue to practice despite declining quality of care; however, perceived cognitive decline, although not an accurate indicator of ability, may accelerate physicians' decision to retire. Physicians are reluctant to report colleagues' cognitive problems. Several issues should be considered in implementing cognitive screening. Most cognitive assessment tools lack normative data for physicians. Scientific evidence linking cognitive test results with physician performance is limited. There is no known level of cognitive decline at which a doctor is no longer fit to practice. Finally, relevant domains of cognitive ability vary across medical specialties. Physician cognitive decline may impact clinical performance. If cognitive assessment of older physicians is to be implemented, it should consider challenges of cognitive test result interpretation.

Excessive exposure to manganese (Mn) is linked to its accumulation in the brain and adverse neurological effects. Paramagnetic properties of Mn allow the use of magnetic resonance imaging (MRI) techniques to identify it in biological tissues. A critical review was conducted to evaluate whether MRI techniques could be used as a diagnostic tool to detect brain Mn accumulation as a quantitative biomarker of inhaled exposure. A comprehensive search was conducted in MEDLINE, EMBASE, and PubMed to identify potentially relevant studies published prior to 9 May 2022. Two reviewers independently screened identified references using a two-stage process. Of the 6452 unique references identified, 36 articles were retained for data abstraction. Eligible studies used T1-weighted MRI techniques and reported direct or indirect T1 measures to characterize Mn accumulation in the brain. Findings demonstrate that, in subjects exposed to high levels of Mn, deposition in the brain is widespread, accumulating both within and outside the basal ganglia. Available evidence indicates that T1 MRI techniques can be used to distinguish Mn-exposed individuals from unexposed. Additionally, T1 MRI may be useful for semi-quantitative evaluation of inhaled Mn exposure, particularly when interpreted along with other exposure indices. T1 MRI measures appear to have a nonlinear relationship to Mn exposure duration, with R1 signal only increasing after critical thresholds. The strength of the association varied depending on the regions of interest imaged and the method of exposure measurement. Overall, available evidence suggests potential for future clinical and risk assessment applications of MRI as a diagnostic tool.