Health Care Utilization and Direct Costs Prior to Subspecialty Care in Children with Chronic Pain Compared with Other Chronic Childhood Diseases: A Cohort Study.

OBJECTIVES: To understand the burden associated with pediatric chronic pain (CP) on the health care system compared with other costly chronic diseases prior to subspecialty care. STUDY DESIGN: In this retrospective cohort study, we assessed all-cause health care utilization and direct health care costs associated with pediatric CP (n = 91) compared with juvenile arthritis (n = 135), inflammatory bowel disease (n = 90), type 1 diabetes (n = 475) or type 2 diabetes (n = 289), anxiety (n = 7193), and controls (n = 273) 2 and 5 years prior to patients entering subspecialty care in Manitoba, Canada. Linked data from physician encounters, emergency department visits, hospitalizations, and prescriptions were extracted from administrative databases. Differences in health care utilization and direct health care costs associated with CP vs the other conditions were tested using negative binomial and zero-inflated negative binomial regression models, respectively. RESULTS: After adjustment for age at diagnosis, sex, location of residence, and socioeconomic status, CP continued to be associated with the highest number of consulted physicians and subspecialists and the highest number of physician billings compared with all other conditions (P < .01, respectively). CP was significantly associated with higher physician costs than juvenile arthritis, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, or controls (P < .01, respectively); anxiety was associated with the highest physician and prescription costs among all cohorts (P < .01, respectively). CONCLUSION: Compared with chronic inflammatory and endocrinologic conditions, pediatric CP and anxiety were associated with substantial burden on the health care system prior to subspecialty care, suggesting a need to assess gaps and resources in the management of CP and mental health conditions in the primary care setting.

Absolute thermometry of human brown adipose tissue by magnetic resonance with laser polarized 129Xe.

BACKGROUND: Absolute temperature measurements of tissues inside the human body are difficult to perform non-invasively. Yet, for brown adipose tissue (BAT), these measurements would enable direct monitoring of its thermogenic activity and its association with metabolic health. METHODS: Here, we report direct measurement of absolute BAT temperature in humans during cold exposure by magnetic resonance (MR) with laser polarized xenon gas. This methodology, which leverages on the sensitivity of the chemical shift of the 129Xe isotope to temperature-induced changes in fat density, is first calibrated in vitro and then tested in vivo in rodents. Finally, it is used in humans along with positron emission tomography (PET) scans with fluorine-18-fluorodeoxyglucose to detect BAT thermogenic activity during cold exposure. RESULTS: Absolute temperature measurements, obtained in rodents with an experimental error of 0.5 °C, show only a median deviation of 0.12 °C against temperature measurements made using a pre-calibrated optical temperature probe. In humans, enhanced uptake of 129Xe in BAT during cold exposure leads to background-free detection of this tissue by MR. Global measurements of supraclavicular BAT temperature, made over the course of four seconds and with an experimental error ranging from a minimum of 0.4 °C to more than 2 °C, in case of poor shimming, reveal an average BAT temperature of 38.8° ± 0.8 °C, significantly higher (p < 0.02 two-sided t test) than 37.7 °C. Hot BAT is also detected in participants with a PET scan negative for BAT. CONCLUSIONS: Non-invasive, radiation-free measurements of BAT temperature by MRI with hyperpolarized 129Xe may enable longitudinal monitoring of human BAT activity under various stimulatory conditions.

Brown adipose tissue (BAT) is a fat tissue specialized in heat production and considered a potential target for the treatment of obesity and diabetes. Detection of this tissue and its metabolic activity in adult humans is challenging as this tissue is often mixed with white fat, which makes up most of the fat in adult humans. Here we demonstrate that magnetic resonance imaging with laser-polarized xenon gas, a medical imaging technique used to assess lung ventilation function, can detect the presence of this tissue in humans and measure its temperature. These temperature measurements, which show that brown fat becomes significantly hotter than 37 °C when humans are exposed to cold, may be useful in future studies to assess the effects of drugs that aim to target BAT's heat-generating activity to regulate blood sugar level.

Protocol for a randomized control trial of the Building Regulation in Dual Generations Program (BRIDGE): preventing the intergenerational transmission of mental illness in at-risk preschool children.

BACKGROUND: Since the onset of the COVID-19 pandemic, the worldwide prevalence of maternal depression has risen sharply; it is now estimated that one quarter of mothers experience clinically significant depression symptoms. Exposure to maternal depression during early childhood increases the risk for the development of childhood mental illness (MI) in offspring, with altered parenting practices mediating the association between maternal depression and child outcomes. Dual-generation interventions, which aim to simultaneously treat parent and child mental health, show promise for improving outcomes for mothers with depression and their young children. The Building Regulation in Dual Generations (BRIDGE) program combines Dialectical Behavior Therapy (DBT) and parenting skills training to concurrently treat maternal depression and improve parenting practices. In pilot within-group studies, BRIDGE has led to large reductions in maternal depression and child MI symptoms. The aim of the current study is to evaluate the efficacy of BRIDGE in reducing maternal depression and child MI symptoms (primary outcomes) as well as parenting stress and harsh parenting (secondary outcomes). METHODS: A three-armed randomized control trial with equal group sizes will be conducted to compare the efficacy of (1) BRIDGE (DBT + parenting skills), (2) DBT skills training, and (3) services-as-usual. Participants (n = 180) will be mothers of 3- to 5-year-old children who report elevated depression symptoms. Those randomized to BRIDGE or DBT skills training will complete a 16-week group therapy intervention. Assessments will be administered at pre-intervention(T1) post-intervention (T2), and 6-month follow-up (T3). DISCUSSION: Dual-generation programs offer an innovative approach to prevent the intergenerational transmission of mental illness. The current study will add to the evidence base for BRIDGE by comparing it to a stand-alone mental health intervention and a services-as-usual group. These comparisons will provide valuable information on the relative efficacy of including parenting support in a mental health intervention for parents. The results will contribute to our understanding of how maternal depression affects children's development and how intervening at both a mental health and parenting level may affect child and family outcomes. TRIAL REGISTRATION: Name of registry: Clinical Trials Protocol Registration and Results System; trial registration number: NCT05959538; date of registry: July 24, 2023; available: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05959538.

The Building Emotional Awareness and Mental health (BEAM) program developed with a community partner for mothers of infants: protocol for a feasibility randomized controlled trial.

BACKGROUND: Drastic increases in the rates of maternal depression and anxiety have been reported since the COVID-19 pandemic began. Most programs aim to improve maternal mental health or parenting skills separately, despite it being more effective to target both concurrently. The Building Emotional Awareness and Mental health (BEAM) program was developed to address this gap. BEAM is a mobile health program aiming to mitigate the impacts of pandemic stress on family well-being. Since many family agencies lack infrastructure and personnel to adequately treat maternal mental health concerns, a partnership will occur with Family Dynamics (a local family agency) to address this unmet need. The study's objective is to examine the feasibility of the BEAM program when delivered with a community partner to inform a larger randomized controlled trial (RCT). METHODS: A pilot RCT will be conducted with mothers who have depression and/or anxiety with a child 6-18 months old living in Manitoba, Canada. Mothers will be randomized to the 10 weeks of the BEAM program or a standard of care (i.e., MoodMission). Back-end App data (collected via Google Analytics and Firebase) will be used to examine feasibility, engagement, and accessibility of the BEAM program; cost-effectiveness will also be examined. Implementation elements (e.g., maternal depression [Patient Health Questionnaire-9] and anxiety [Generalized Anxiety Disorder-7]) will be piloted to estimate the effect size and variance for future sample size calculations. DISCUSSION: In partnership with a local family agency, BEAM holds the potential to promote maternal-child health via a cost-effective and an easily accessible program designed to scale. Results will provide insight into the feasibility of the BEAM program and will inform future RCTs. TRIAL REGISTRATION {2A}: This trial was retrospectively registered with ClinicalTrial.gov ( NCT05398107 ) on May 31st, 2022.

The Building Regulation in Dual-Generations Program (BRIDGE): A Mixed-Methods Feasibility Pilot of a Parenting Program for Depressed Mothers of Preschoolers, Matched with Dialectical Behavior Therapy Skills.

Early exposure to maternal depression is a key risk factor for child mental illness (MI), but there are limited programs that interrupt intergenerational transmission. The BRIDGE "Building Regulation in Dual Generations" Program treats maternal MI using Dialectical Behavior Therapy Skills with a paired curriculum that promotes non-reactive and emotionally validating parenting designed to improve child mental health and ultimately prevent MI. The pilot feasibility trial (n = 28 dyads) included mothers and their preschool-aged children. The 20-week program was completed in a group-based format using mixed methods questionnaires and interviews. Results indicate high feasibility and acceptability (86% retention). Consistent improvements were seen across program targets and outcomes including maternal depression (d = 1.02) and child mental health (d = 1.08), with clinically significant symptom reductions for 85% of clients. Mothers with higher adversity exhibited greater reductions in parenting stress. Qualitative results highlighted efficacy in promoting positive parent-child relationships, rewarding parenting experiences, competence, and child development. Evidence suggests high feasibility and accessibility for BRIDGE in addressing intergenerational mental health needs. There was strong satisfaction with the program material and efficacy across key outcomes. BRIDGE holds promise for offering a transdiagnostic approach to preventing child MI in families of at-risk preschool aged children.

Walking in two worlds with type 2 diabetes: a scoping review of prevention and management practices incorporating traditional indigenous approaches.

Type 2 diabetes is a complex chronic disease rapidly increasing among young people and disproportionately impacting Indigenous youth. Treatment programs are often inadequate for this population as they lack cultural relevance. A scoping review was conducted to explore traditional Indigenous approaches for diabetes prevention and management, to inform a program aimed at supporting Indigenous youth and families with type 2 diabetes. We seek to answer the following question: "Which traditional medicines and practices have been incorporated into intervention or prevention strategies for Indigenous people living with diabetes?" Search was done June 2021 using Ovid Medline, ESBCO and ProQuest databases. Terms included wellbeing, intervention, diabetes, and traditional approaches. Of the 2138 titles screened, 34 met inclusion criteria. Three studies integrated traditional Indigenous approaches into Western-based intervention programming. Content included traditional food and nutrition programs, gardening programs, Elder knowledge sharing, story telling, talking circles, feasting, prayer, traditional dancing, hunting, and school-based wellness curricula. Many were wholistic, co-created with community, Indigenous-led and held in accessible community spaces. The heterogeneity in approaches reflects the diversity of Indigenous nations and communities. This review identifies important elements to include in culturally relevant programs to address diabetes-related wellness.

Evaluation of parent and youth experiences in advisory groups as part of a mental healthcare clinical trial: protocol for a mixed-method study.

INTRODUCTION: Patient engagement in healthcare research is a necessity to ensure that research objectives align with priorities, outcomes and needs of the population under study, and to facilitate ease of implementation and adoption of findings. In clinical trials, there is an increasing focus on patient engagement during the planning and conduct of clinical trials due to the potential for ethical and methodological benefits. As patient engagement in clinical trials increases, there is a need to evaluate the approaches of these activities to contribute evidence on what is most appropriate and successful. The purpose of this study is to evaluate patient engagement processes and the activities of patient partners during and after a paediatric mental healthcare trial. METHODS AND ANALYSIS: Using a mixed-methods study design, we will evaluate patient partners' engagement activities across set time-points during the trial and after trial completion. In this study, the term 'patient partner' is inclusive of two groups of people with lived experience: (1) caregivers (parents, formal/informal caregivers and family), and (2) youth (aged 15-24 years). Engagement will be evaluated using the participant and project questionnaires of the Public and Patient Engagement Evaluation Tool (PPEET), followed sequentially by semi-structured interviews. Quantitative data from the PPEET questionnaire will be analysed and reported using descriptive statistics. Data from open-ended questions from the PPEET questionnaires and semi-structured interviews will be analysed using thematic analysis. ETHICS AND DISSEMINATION: Approval from Athabasca University Research Ethics Board will be obtained for this project. Findings will be disseminated at both academic and public venues whether in-person or online, and using platforms that are caregiver and youth friendly. TRIAL REGISTRATION NUMBER: NCT04902391.

An Innovative Model of Pediatric Emergency Department Mental Health Care: Protocol for a Multicenter Type 1 Effectiveness-Implementation Cluster Randomized Trial.

Over the past decade, visits to American and Canadian emergency departments (EDs) for child and youth mental health care have increased substantially.1,2 Acute mental health crises can occur as a result of a variety of concerns, including those that are life threatening (eg, suicide attempts), pose safety concerns (eg, suicidal intentions, aggressive behaviors, alcohol and other drug use), and are physically distressing to the child or youth (eg, panic attacks). ED health care providers play a vital role in assessing the safety and well-being of the child or youth and referring them to services for ongoing care.3,4 During the ED visit, assessment and care should pinpoint risks, inform treatment, and consider family needs and preferences as part of a patient-centered approach. Yet, this approach to care is not widely adopted in EDs. Most EDs do not require the use of pediatric-specific mental health tools to guide assessments or have patient-centered procedures in place to guide the care of patients with mental health emergencies.5-7 Our team believes these limitations have led to the provision of acute mental health care that can lack sufficient quality and efficiency. This study protocol describes a trial designed to evaluate if a novel mental health care bundle that was co-designed with parents and youth results in greater improvements in the well-being of children and youth 30 days after seeking ED care for mental health and/or substance misuse concerns compared with existing care protocols. We hypothesize that the bundle will positively impact child and youth well-being, while also providing cost-effective health care system benefits.

Incidence and Predictors of Suicide Attempts and Suicide Deaths Among Individuals Recently Hospitalized for a Mental Disorder: A Population-Based Study.

Objective: To examine the incidence and predictors of suicide attempts and deaths in the year after psychiatric hospitalization.Methods: A population-based dataset was used to develop a cohort of individuals 18 years or older admitted with a mental disorder (defined by ICD-10 codes) from 2005 to 2016 (n = 26,975) in Manitoba, Canada. Using Cox regression, hazard ratios were calculated for each covariate among those who attempted and died by suicide in the year following hospitalization, while adjusting for confounders.Results: In the year following hospitalization for a mental disorder, 0.7% of the individuals died by suicide and 3.5% attempted suicide. Statistically significant risk factors for suicide in the year after discharge from psychiatric hospitalization included male sex (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.10-1.97) and urban location (HR, 1.37; 95% CI, 1.02-1.85) and for attempting suicide included female sex (HR, 0.63; 95% CI, 0.55-0.72), living rurally (HR, 0.66; 95% CI, 0.58-0.75), a previous mental disorder (HR, 1.63; 95% CI, 1.38-1.92), justice involvement (HR, 1.48; 95% CI, 1.28-1.70), and being on income assistance (HR, 1.17; 95% CI, 1.01-1.35) (P < .05 for all). Age (HR, 0.99; 95% CI, 0.99-0.99) (P < .05) was associated with a reduced rate of suicide attempts.Conclusions: Further research into interventions to address the identified risk factors for suicide in the recently discharged population is critical to improve management.

Use of a Meter With Color-Range Indicators and a Mobile Diabetes Management App Improved Glycemic Control and Patient Satisfaction in an Underserved Hispanic Population: "Tu Salud"-A Randomized Controlled Partial Cross-Over Clinical Study.

Objective: To demonstrate the clinical value of OneTouch (OT) Verio Flex glucose meter used in combination with a Spanish-language version of the OT Reveal mobile application (app) to support diabetes care and improve glycemic control in an underserved Hispanic population with type 2 diabetes. Research Design and Methods: Test subjects (n = 81) used the meter and app for 12 weeks, while a randomized control group (n = 39) used their own glucose meters without connection to an app. Thereafter, test subjects continued the same regimen for an additional 12 weeks to determine the durability of effect, and control subjects crossed over to use the new meter and app. Results: Test subjects experienced a mean reduction in A1C of 1.0% after 12 weeks (P <0.001), a statistically significant greater reduction than in control subjects (P = 0.045). The improvement in A1C in test subjects was sustained over the next 12 weeks. Crossed-over subjects also demonstrated significant improvements in A1C (P <0.001). Mean blood glucose was reduced significantly without an increase in hypoglycemia, and results in range increased over 12 weeks of meter and mobile app use. Results were independent of subjects' numeracy skills. Subjects using the new meter and app reacted favorably to the tools and expressed improvements in their diabetes treatment satisfaction based on Diabetes Treatment Satisfaction Questionnaire-Change scores. Conclusion: Use of the OT meter and a Spanish-language version of its diabetes management app in an underserved population helped participants achieve a sustained improvement in glycemic control. The tools were well received by the subjects and may have important utility in other low-numeracy, low-literacy populations.

Risky Gambling Behaviors: Associations with Mental Health and a History of Adverse Childhood Experiences (ACEs).

Problem gambling and adverse childhood experiences (ACEs) are highly co-morbid and lead to numerous adverse health outcomes. Research demonstrates that greater levels of well-being protect individuals from experiencing ACE-related harms after a history of childhood adversity; however, this relationship has not been examined in the gambling literature. We hypothesized that individuals who experienced ACEs would engage in more problem gambling behaviors. We also hypothesized that individuals who experienced ACEs and reported flourishing mental health would have lower rates of problem gambling than individuals who experienced ACEs but did not report flourishing mental health. We conducted a secondary data analysis of the adult sample in the Well-Being and Experiences (WE) Study. Examining a parent population, parents and caregivers (N = 1000; Mage = 45.2 years; 86.5% female) of adolescents were interviewed on a variety of measures, including their history of ACEs, their gambling behaviors within the past year, and their mental health and well-being. We used multinomial logistic regression analysis to examine the relationship between 15 ACEs and gambling type (i.e., non-gambler, non-problem gambler, at-risk/problem gambler). We used interaction terms between each ACE and mental health to examine the moderating role of flourishing mental health and well-being. ACEs were associated with at-risk/problem gambling supporting hypothesis 1. Contrary to hypothesis 2, overall, flourishing mental health did not moderate the relationship between ACEs and gambling severity except for one ACE. In this study, we were able to gain a better understanding of how different ACEs each contribute to varying levels of gambling severity.

A Longitudinal Study of Correlates, Discharge Disposition, and Rate of Re-presentation to Emergency Services of Adults who Engage in Non-suicidal Self-injury.

OBJECTIVE: In DSM-5, non-suicidal self-injury (NSSI) and suicide attempts (SA) are classified as distinct disorders in the section of conditions for further study. However, some have questioned the validity of distinguishing NSSI from SA. The objective of this study was to longitudinally examine the correlates, discharge disposition, and rate of re-presentation to emergency services of adults who engaged in NSSI and compare them to (a) adults who engage in SA and (b) adults with no self-harm or suicidal ideation (SI). METHOD: Data came from 4,772 presentations to adult psychiatric services in the emergency departments of tertiary care hospitals in Winnipeg, Canada between January 2009 and June 2012. Chart reviews were conducted for all presentations with NSSI (n = 158), and a sample of those with SA (n = 172) and no SH or SI (n = 173). RESULTS: Among the adults who returned to emergency services, those who originally presented with SA re-presented significantly sooner than those who presented with NSSI. (χ2(1) = 7.457, p = 0.006). Those who originally presented with NSSI that returned to hospital did not return with repeat NSSI, but instead the majority re-presented with suicidal thoughts and SA. Further, those who re-presented with NSSI and SA were less likely to be hospitalized or to receive a referral to mental health services, and more likely to be discharged to usual care at time of initial presentation. CONCLUSIONS: Overall, these findings indicate a trajectory of escalation of self-harm behavior for certain people who engage in NSSI, especially those who re-present to emergency services.HIGHLIGHTSA quarter of people with self-harm re-present to emergency services within four-and-a-half years.Those with suicide attempts re-presented significantly sooner than non-suicidal self-injury.There is a need for increased interventions in emergency services for those with self-harm.

Site-specific cancer risk following cobalt exposure via orthopedic implants or in occupational settings: A systematic review and meta-analysis.

In 2020, the European Commission up-classified metal cobalt as Class 1B Carcinogen (presumed to have carcinogenic potential) based primarily on data from rodent inhalation carcinogenicity studies. This up-classification requires an assessment under the Medical Device Regulations of cobalt cancer risk from medical devices. We performed a systematic review and meta-analysis to evaluate site-specific cancer risks with cobalt exposure from either total joint replacement (TJR) or occupational exposure (OC). Results were stratified by exposure type (OC or TJR), exposure level (metal-on-metal (MoM) or non-MoM), follow-up duration (latency period: <5, 5-10 or >10 years), and cancer incidence or mortality (detection bias assessment). From 30 studies (653,104 subjects, average 14.5 years follow-up), the association between TJR/OC and cancer risk was null for 22 of 27 cancer sites, negative for 3 sites, and positive for prostate cancer and myeloma. Significant heterogeneity and large estimate ranges were observed for many cancer sites. No significant increase in estimates was observed by exposure level or follow-up duration. The current evidence, including weak associations, heterogeneity across studies and no increased association with exposure level or follow-up duration, is insufficient to conclude that there exists an increased risk for people exposed to cobalt in TJR/OC of developing site-specific cancers.

The 5-year pre- and post-hospitalization treated prevalence of mental disorders and psychotropic medication use in critically ill patients: a Canadian population-based study.

PURPOSE: The interplay between critical illness and mental disorders is poorly understood. The purpose of this study is to measure both the treated prevalence of mental disorders and psychotropic medication use before and after hospitalization and the impact of intensive care unit (ICU) admission on these outcomes. METHODS: Using a population-based administrative database in Manitoba, Canada, 49,439 ICU patients admitted between 2000 and 2012 were compared to two matched comparison groups (hospitalized; n = 146,968 and general population; n = 141,937). Treated prevalence of mental disorders and psychotropic medication prescriptions were measured in the 5-year periods before and after the hospitalization. Multivariable models compared adjusted prevalence ratios (APRs) between populations. RESULTS: The 5-year treated mental disorder prevalence in the ICU population increased from 41.5% pre-hospitalization to 55.6% post-hospitalization. Compared to non-ICU hospitalized patients, the adjusted treated mental disorder prevalence in ICU patients was lower prior to hospitalization (1-year APR 0.94, 95% CI 0.92-0.97, p < 0.0001; 5-year APR 0.99, 95% CI 0.98-1.00, p = 0.1), but higher following discharge (1-year APR 1.08, 95% CI 1.05-1.11, p < 0.0001, 5-year APR 1.03, 95% CI 1.01-1.05, p < 0.0001). A high proportion of ICU patients received antidepressant, anxiolytic and sedative-hypnotic prescriptions before and after their hospitalization. In multivariable analyses, ICU exposure was associated with an increase in mood, anxiety and psychotic disorders, and sedative-hypnotics use (p < 0.0001 for all Time × Group interactions). CONCLUSIONS: During the 5 years after admission to ICU, there is a significant increase in treated prevalence of mental disorders and psychotropic medication use compared to the 5 years prior to ICU and compared to general population and hospital cohorts. Prevention and intervention programs that identify and treat mental disorders among survivors of critical illness warrant further study.

An integrated benefit-risk assessment of cobalt-containing alloys used in medical devices: Implications for regulatory requirements in the European Union.

In 2017, the European Union (EU) Committee for Risk Assessment (RAC) recommended the classification of metallic cobalt (Co) as Category 1B with respect to its carcinogenic and reproductive hazard potential and Category 2 for mutagenicity but did not evaluate the relevance of these classifications for patients exposed to Co-containing alloys (CoCA) used in medical devices. CoCA are inherently different materials from Co metal from a toxicological perspective and thus require a separate assessment. CoCA are biocompatible materials with a unique combination of properties including strength, durability, and a long history of safe use that make them uniquely suited for use in a wide-range of medical devices. Assessments were performed on relevant preclinical and clinical carcinogenicity and reproductive toxicity data for Co and CoCA to meet the requirements under the EU Medical Device Regulation triggered by the ECHA re-classification (adopted in October 2019 under the 14th Adaptation to Technical Progress to CLP) and to address their relevance to patient safety. The objective of this review is to present an integrated overview of these assessments, a benefit-risk assessment and an examination of potential alternative materials. The data support the conclusion that the exposure to CoCA in medical devices via clinically relevant routes does not represent a hazard for carcinogenicity or reproductive toxicity. Additionally, the risk for the adverse effects that are known to occur with elevated Co concentrations (e.g., cardiomyopathy) are very low for CoCA implant devices (infrequent reports often reflecting a unique catastrophic failure event out of millions of patients) and negligible for CoCA non-implant devices (not measurable/no case reports). In conclusion, the favorable benefit-risk profile also in relation to possible alternatives presented herein strongly support continued use of CoCA in medical devices.

Carcinogenic assessment of cobalt-containing alloys in medical devices or cobalt in occupational settings: A systematic review and meta-analysis of overall cancer risk from published epidemiologic studies.

In 2020, the European Commission up-classified pure cobalt metal to a Category 1B hazard, based primarily on data from rodent inhalation carcinogenicity studies of metallic cobalt. The European Commission review did not evaluate cobalt-containing alloys in medical devices, which have very different properties vs. pure cobalt metal and did not include a systematic epidemiologic review. We performed a systematic review and meta-analysis of published, peer-reviewed epidemiologic studies evaluating the association between overall cancer risk and exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings. Study-specific estimates were pooled using random-effects models. Analyses included 20 papers on orthopedic implants and 10 occupational cohort papers (~1 million individuals). The meta-analysis summary estimates (95% confidence intervals) for overall cancer risk were 1.00 (0.96-1.04) overall and 0.97 (0.94-1.00) among high-quality studies. Results were also similar in analyses stratified by type of exposure/data sources (occupational cohort, implant registry or database), comparators (general or implant population), cancer incidence or mortality, follow-up duration (latency period), and study precision. In conclusion, meta-analysis found no association between exposure to orthopedic implants containing cobalt alloys or cobalt particulates in occupational settings and overall cancer risk, including an analysis of studies directly comparing metal-on-metal vs. non-metal-on-metal implants.

A hazard evaluation of the reproductive/developmental toxicity of cobalt in medical devices.

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices. Reproductive responses to Co are limited to the male testes and sperm function following high systemic exposure in rodents, only at Co concentrations/doses that result in overt toxicity (i.e., above the maximum tolerable dose (MTD)). The potential mechanisms of Co reproductive/developmental toxicity, including its indirect mode of action in the testes and relevance to humans, are discussed. The available preclinical and clincial evidence suggests that it would be more appropriate to classify Co as a Reproductive Hazard Category 2 compound: suspected human reproductive toxicant and, in the case of Co-containing medical devices, it should not be considered a reproductive hazard.