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Blood and urine are historically the most frequent matrices used for measuring chemical levels in human biomonitoring studies. As biomonitoring programs are refreshed, consideration of specific priority substances and specific population targets provide opportunities for inclusion of alternative non- or minimally invasive matrices. This review describes methods used in health risk assessment to characterize exposure and risk based upon biomarkers from noninvasive matrices other than urine or blood, including human milk, hair, fingernails, toenails, exhaled breath, deciduous teeth, sweat, semen, meconium, and feces. Illustrative examples of these methods relevant to chemical management are provided. This review suggests that, although these alternative noninvasive biomarkers are not frequently used in human health risk assessment at present, these biomarkers may prove useful in (1) characterizing exposure and health risk in vulnerable populations, (2) cumulative risk assessments, and (3) community-based risk assessments, depending upon the substance of concern. To incorporate alternative noninvasive biomarkers into human health risk assessments with confidence, more research is needed to improve our knowledge of the relationships between external dose, internal dose, and biologic consequent effects in matrices other than blood and urine. [ABSTRACT FROM AUTHOR]

BACKGROUND: Various drugs have been approved for the treatment of Alzheimer's disease (AD) in the United States and Canada, including donepezil and rivastigmine, although questions remain as to their efficacy, effectiveness, and long-term benefits. OBJECTIVE: The goal of this study was to conduct a best-evidence synthesis of data on the efficacy and cost-effectiveness of donepezil and rivastigmine in the treatment of AD. METHODS: Relevant published randomized controlled trials (RCTs) and Phase IV open-label extension studies (excluding abstracts) were identified through searches of MEDLINE, HealthSTAR, and PsycINFO for the period January 1984 to October 2001. The bibliographies of retrieved articles were searched for additional publications. For inclusion in the best-evidence synthesis, clinical trials had to pass a blinded quality assessment (score > or =5 on the Jadad scale) and use National Institute of Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria. Economic studies were selected using National Health Service Centre for Reviews and Dissemination criteria for reporting critical summaries of economic evaluations. RESULTS: Nine RCTs of donepezil and 2 of rivastigmine were identified and met inclusion criteria for the best-evidence synthesis. Eight donepezil trials and both rivastigmine trials included patients with mild AD (Mini-Mental State Examination [MMSE] score, 15-27) or moderate AD (MMSE score, 8-14); 1 donepezil trial included patients with moderate or severe AD (MMSE score, 0-7). In the RCTs of donepezil, the mean decrease in scores on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was greater with active treatment than with placebo (lower scores indicate less cognitive deterioration). In the RCTs of rivastigmine, ADAS-cog scores decreased over the follow-up period with both active treatment and placebo; however, scores decreased more with active treatment. Three Phase IV studies of donepezil and I Phase IV study of rivastigmine were identified. Their results were consistent with those of the RCTs. Ten economic studies (7 donepezil, 3 rivastigmine) were identified and reviewed. In 4 of the donepezil studies and all 3 rivastigmine studies, use of the drug cost less than a no-drug strategy. CONCLUSIONS: The efficacy data indicate that both donepezil and rivastigmine can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild to moderate AD. Patients receiving active treatment will have more favorable ADAS-cog scores for at least 6 months, after which their scores will begin to converge with those of patients receiving placebo. Differences in methodology, types of direct or indirect costs included, and sources of cost data made it difficult to compare and synthesize findings of the economic studies; therefore, the cost-effectiveness data are inconclusive. [ABSTRACT FROM AUTHOR]

Importance: Among cancer surgeries, patients requiring open radical cystectomy have the highest risk of red blood cell (RBC) transfusion. Prophylactic tranexamic acid (TXA) reduces blood loss during cardiac and orthopedic surgery, and it is possible that similar effects of TXA would be observed during radical cystectomy., Objective: To determine whether TXA, administered before incision and for the duration of radical cystectomy, reduced the number of RBC transfusions received by patients up to 30 days after surgery., Design, Setting, and Participants: The Tranexamic Acid During Cystectomy Trial (TACT) was a double-blind, placebo-controlled, randomized clinical trial with enrollment between June 2013 and January 2021. This multicenter trial was conducted in 10 academic centers. A consecutive sample of patients was eligible if the patients had a planned open radical cystectomy for the treatment of bladder cancer., Intervention: Before incision, patients in the intervention arm received a loading dose of intravenous TXA, 10 mg/kg, followed by a maintenance infusion of 5 mg/kg per hour for the duration of the surgery. In the control arm, patients received indistinguishable matching placebo., Main Outcomes and Measures: The primary outcome was receipt of RBC transfusion up to 30 days after surgery., Results: A total of 386 patients were assessed for eligibility, and 33 did not meet eligibility. Of 353 randomized patients (median [IQR] age, 69 [62-75] years; 263 male [74.5%]), 344 were included in the intention-to-treat analysis. RBC transfusion up to 30 days occurred in 64 of 173 patients (37.0%) in the TXA group and 64 of 171 patients (37.4%) in the placebo group (relative risk, 0.99; 95% CI, 0.83-1.18). There were no differences in secondary outcomes among the TXA group vs placebo group including mean (SD) number of RBC units transfused (0.9 [1.5] U vs 1.1 [1.8] U; P = .43), estimated blood loss (927 [733] mL vs 963 [624] mL; P = .52), intraoperative transfusion (28.3% [49 of 173] vs 24.0% [41 of 171]; P = .08), or venous thromboembolic events (3.5% [6 of 173] vs 2.9% [5 of 171]; P = .57). Non-transfusion-related adverse events were similar between groups., Conclusions and Relevance: Results of this randomized clinical trial reveal that TXA did not reduce blood transfusion in patients undergoing open radical cystectomy for bladder cancer. Based on this trial, routine use of TXA during open radical cystectomy is not recommended., Trial Registration: ClinicalTrials.gov Identifier: NCT01869413.

Asbestos is a group of naturally occurring fibrous minerals that were commonly used in the construction of cement pipes for drinking water distribution systems. These pipes deteriorate and can release asbestos fibers into drinking water, raising concerns about potential risk to human health. The objective of this work was to synthesize human, animal, and in vitro evidence on potential health risks due to ingested asbestos in drinking water and evaluate the weight of evidence (WoE) of human health risk. A systematic review of epidemiological evidence was conducted, along with critical review of animal and in vitro evidence, followed by WoE evaluation that integrated human, animal, and in vitro evidence. The systematic review included 17 human studies with health outcomes mostly related to various cancer sites, with the majority focusing on the gastrointestinal system. The WoE evaluation resulted in very low levels of confidence or insufficient evidence of a health effect for cancers in 15 organ systems and for three non-cancer endpoints. While eight studies reported possible associations with stomach cancer in males, few high-quality studies were available to verify a causal relationship. Based on high-quality animal studies, an increased risk for cancer or non-cancer endpoints was not supported, aligning with findings from human studies. Overall, the currently available body of evidence is insufficient to establish a clear link between asbestos contamination in drinking water and adverse health effects. Due to the lack of both high-quality epidemiological studies and a validated kinetic model for ingested asbestos, additional research on this association is warranted.

Potential differential and non-differential recall error in mobile phone use (MPU) in the multinational MOBI-Kids case-control study were evaluated. We compared self-reported MPU with network operator billing record data up to 3 months, 1 year, and 2 years before the interview date from 702 subjects aged between 10 and 24 years in eight countries. Spearman rank correlations, Kappa coefficients and geometric mean ratios (GMRs) were used. No material differences in MPU recall estimates between cases and controls were observed. The Spearman rank correlation coefficients between self-reported and recorded MPU in the most recent 3 months were 0.57 and 0.59 for call number and for call duration, respectively. The number of calls was on average underestimated by the participants (GMR = 0.69), while the duration of calls was overestimated (GMR = 1.59). Country, years since start of using a mobile phone, age at time of interview, and sex did not appear to influence recall accuracy for either call number or call duration. A trend in recall error was seen with level of self-reported MPU, with underestimation of use at lower levels and overestimation of use at higher levels for both number and duration of calls. Although both systematic and random errors in self-reported MPU among participants were observed, there was no evidence of differential recall error between cases and controls. Nonetheless, these sources of exposure measurement error warrant consideration in interpretation of the MOBI-Kids case-control study results on the association between children's use of mobile phones and potential brain cancer risk., (© 2024 The Author(s). Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.)

Background: The impact of delirium on cognition has not been well-studied in long-term care (LTC) residents. This study examined changes in cognition 1 year after a probable delirium episode among LTC residents, compared to LTC residents without probable delirium. We also evaluated whether the relationship between probable delirium and cognitive change differed according to a diagnosis of dementia., Methods: We conducted a population-based retrospective cohort study using linked health administrative data. The study population included adults aged 65+ residing in LTC in Ontario, Canada and assessed via the Resident Assessment Instrument-Minimum Dataset between January 1, 2016 and December 31, 2018. Probable delirium was ascertained via the delirium Clinical Assessment Protocol on the index assessment. Cognition was measured quarterly using the Cognitive Performance Scale (range 0-6, higher values indicate greater impairment). Cognitive decline up to 1 year after index was evaluated using multivariable proportional odds regression models., Results: Of 92,005 LTC residents, 2816 (3.1%) had probable delirium at index. Residents with probable delirium had an increased odds of cognitive decline compared to those without probable delirium, with adjusted odds ratios of 1.64 (95% confidence interval [CI] 1.35-1.99), 1.56 (95% CI 1.34-1.85), 1.57 (95% CI 1.32-1.86) and 1.50 (95% CI 1.25-1.80) after 1-3, 4-6, 7-9, and 10-12 months of follow-up. Residents with probable delirium and a comorbid dementia diagnosis had the highest adjusted odds of cognitive decline (adjusted odds ratio 5.57, 95% CI 4.79-6.48) compared to those without probable delirium or dementia. Residents with probable delirium were also more likely to die within 1 year than those without probable delirium (52.5% vs. 23.4%)., Conclusions: Probable delirium is associated with increased mortality and worsened cognition in LTC residents that is sustained months after the probable delirium episode. Efforts to prevent delirium in this population may help limit these adverse effects., (© 2023 The American Geriatrics Society.)

With declining exposures to manganese (Mn) in occupational settings, there is a need for more sensitive exposure assessments and clinical diagnostic criteria for manganism and Mn neurotoxicity. To address this issue, a workshop was held on November 12-13, 2020, with international experts on Mn toxicity. The workshop discussions focused on the history of the diagnostic criteria for manganism, including those developed by the Institut de Recherche Robert-Sauvé en Santé et en Sécurité du Travail (IRSST) in Quebec in 2005 and criteria developed by the Chinese government in 2002 and updated in 2006; the utility of biomarkers of exposure; recent developments in magnetic resonance imaging (MRI) for assessing Mn accumulation in the brain and diagnosing manganism; and potential future applications of metabolomics. The suggestions of the participants for updating manganism diagnostic criteria included the consideration of: i) A history of previous occupational and environmental exposure to Mn; ii) relevant clinical symptoms such as dystonia; iii) MRI imaging to document Mn accumulation in the neural tissues, including the basal ganglia; and iv) criteria for the differential diagnosis of manganism and other neurological conditions. Important research gaps include the characterization of Mn exposure and other co-exposures, exploration of the roles of different brain regions with MRI, understanding the complexity of metal ion transporters involved in Mn homeostasis, and a need for information on other neurotransmitter systems and brain regions underlying the pathophysiology of manganism., Competing Interests: MB and UD have received funding from the International Manganese Institute (IMnI). DK is the Natural Sciences and Engineering Research Council of Canada Chair in Risk Science at the University of Ottawa. CA, DK, DM, FM, NK, NS and SR are affiliated with Risk Sciences International (www.risksciences.com), a Canadian company established in 2006 in partnership with the University of Ottawa. RSI has provided consulting services on manganese to public and private sector clients. Although IMnI contributed funding, they did not actively participate in the planning of the workshop or in the development of the workshop report. The workshop deliberations summarized in this report represent the independent views of the authors alone., (Copyright: © Mattison et al.)

Introduction: 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., Objective: 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., Methods: 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., Results: 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., Conclusion: 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.

Objectives: To synthesize evidence relevant for informed decisions concerning cognitive testing of older physicians., Methods: Relevant literature was systematically searched in Medline, EMBASE, PsycInfo, and ERIC, with key findings abstracted and synthesized., Results: 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., Conclusion: 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.

Objectives: This study examined potentially inappropriate prescribing (PIP) of medication and its association with probable delirium among long-term care (LTC) residents in Ontario, Canada., Design: Population-based cross-sectional study using provincial health administrative data, including LTC assessment data via the Resident Assessment Instrument-Minimum Dataset version 2.0 (RAI-MDS 2.0)., Setting and Participants: LTC residents in Ontario between January 1, 2016, and December 31, 2019., Methods: We used residents' first RAI-MDS 2.0 assessment in the study period as the index assessment. Probable delirium was identified via the delirium Clinical Assessment Protocol. Medication use in the 2 weeks preceding assessment was captured using medication claims data. PIP was measured using the STOPP/START criteria and 2015 Beers criteria, with residents classified as having 0, 1, 2, or 3+ instances of PIP. Relationships between PIP and probable delirium was assessed via bivariate and multivariable logistic regression models., Results: The study population included 171,190 LTC residents (mean age 84.5 years, 66.8% female, 62.9% with dementia). More than half (51.8%) of residents had 1+ instances of PIP and 21% had 3+ instances of PIP according to the STOPP/START criteria; PIP prevalence was slightly lower when assessed using Beers criteria (36.5% with 1+, 11.1% with 3+). Overall, 3.7% of residents had probable delirium. The prevalence of probable delirium increased as the number of instances of PIP increased, with residents with 3+ instances of STOPP/START PIP being 1.66 times more likely (95% CI 1.56-1.77) to have probable delirium compared to those with no instances of PIP. Similar findings were observed when PIP was measured using the Beers criteria. Central nervous system (CNS)-related PIP criteria showed a stronger association with probable delirium than non-CNS-related PIP criteria., Conclusions and Implications: This population-based study highlighted that PIP was highly prevalent in long-term care residents and was associated with an increased prevalence of probable delirium., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: First Nations children in Canada experience health inequities. We aimed to determine whether a self-report health app identified children's needs for support earlier in their illness than would typically occur., Methods: Children (aged 8 to 18 yr) were recruited from a rural First Nation community. Children completed the Aaniish Naa Gegii: the Children's Health and Well-being Measure (ACHWM) and then met with a local mental health worker who determined their risk status. ACHWM Emotional Quadrant Scores (EQS) were compared between 3 groups of children: healthy peers (HP) who were not at risk, those with newly identified needs (NIN) who were at risk and not previously identified, and a typical treatment (TT) group who were at risk and already receiving support., Results: We included 227 children (57.1% girls), and the mean age was 12.9 (standard deviation [SD] 2.9) years. The 134 children in the HP group had a mean EQS of 80.1 (SD 11.25), the 35 children in the NIN group had a mean EQS of 67.2 (SD 13.27) and the 58 children in the TT group had a mean EQS of 66.2 (SD 16.30). The HP group had significantly better EQS than the NIN and TT groups ( p < 0.001). The EQS did not differ between the NIN and TT groups ( p = 0.8)., Interpretation: The ACHWM screening process identified needs for support among 35 children, and the associated triage process connected them to local services; the similarity of EQS in the NIN and TT groups highlights the value of community screening to optimize access to services. Future research will examine the impact of this process over the subsequent year in these groups., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

Introduction: Reference intervals and reference curves provide clinicians with a point of reference when evaluating patients' laboratory test results. In practical applications, the 2.5th and 97.5th percentiles of healthy reference population are typically used as lower and upper reference limits. Guidelines outlining analytical and methodological steps involved in reference intervals and curves estimation are available and there have been large-scale world-wide initiatives to provide reference intervals and curves for children. However, there is a lack of synthesised evidence regarding the results of such initiatives in general, but specifically in iron-related biomarkers, ferritin (in serum and plasma) and haemoglobin. Objectives of this review are to identify studies that have produced reference intervals and curves for ferritin and haemoglobin in paediatric populations and to synthesise all available evidence. We also aim to quantify heterogeneity across reference intervals and curves and identify and elucidate sources of heterogeneity, including heterogeneity in the methods employed in their development., Methods and Analysis: Using a comprehensive search strategy, we will identify eligible studies. Following electronic databases will be searched from inception: EMBASE, MEDLINE, SCOPUS and The Cochrane Library. We will also perform grey literature search to capture unpublished reference intervals and curves from healthy cohorts. Two researchers will independently screen retrieved citations against eligibility criteria in two stages, focusing first on titles and abstracts and then on full-text articles. Studies that provide reference intervals and curves for ferritin and haemoglobin for paediatric population will be eligible. Data extraction will include study characteristics, characteristics of reference population, methodological and analytical considerations and estimated reference intervals and curves. We will consider narrative synthesis and quantitative synthesis when appropriate., Ethics and Dissemination: Ethical approval is not required as data from already published studies will be used. Results will be disseminated through peer-reviewed publications and conference presentations., Prospero Registration Number: CRD42023399802., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Recent case reports have suggested that sodium-glucose co-transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins., Methods: We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two-criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor-statin pairs with higher interaction potential (canagliflozin-rosuvastatin, empagliflozin-rosuvastatin) and accounted for stimulated reporting., Results: There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor-statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting., Conclusion: There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)