Diagnosis of manganism and manganese neurotoxicity: A workshop report.

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.

Systematic review of epidemiological and toxicological evidence on health effects of fluoride in drinking water.

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.

Potentially Inappropriate Prescribing in Long-Term Care and its Relationship With Probable Delirium.

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.

Should we screen aging physicians for cognitive decline?

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.

Long-term cognitive impairment after probable delirium in long-term care residents: A population-based retrospective cohort study.

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.

Community-based screening and triage connecting First Nations children and youth to local supports: a cross-sectional study.

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.

Paediatric reference intervals and curves for haemoglobin and ferritin: protocol for a systematic review and meta-analysis.

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.

Concomitant use of statins and sodium-glucose co-transporter 2 inhibitors and the risk of myotoxicity reporting: A disproportionality analysis.

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.

Physical activity levels, pulmonary function, and MRI in children born extremely preterm: A comparison between children with and without bronchopulmonary dysplasia.

INTRODUCTION: Children with a history of bronchopulmonary dysplasia (BPD) may have lower physical activity levels, but evidence to date is mixed. This study compared physical activity levels between children born extremely preterm with and without history of BPD, and examined their associations with pulmonary magnetic resonance imaging (MRI) and pulmonary function test (PFT) indices. METHODS: This multicentre cross-sectional study included children aged 7-9 years born extremely preterm, with and without BPD. Children wore a pedometer for 1 week, then completed the Physical Activity Questionnaire (PAQ), pulmonary MRI, and PFT. Spearman correlations and multivariable linear regression modeling were performed. RESULTS: Of 45 children, 28 had a history of moderate-severe BPD. There were no differences in any physical activity outcomes by BPD status. Higher average daily step count and higher average daily moderate-to-vigorous physical activity (MVPA) were each correlated with greater forced vital capacity (r = 0.41 and 0.58), greater MRI lung proton density at full expiration (r = 0.42 and 0.49), and lower lung clearance index (r = -0.50 and -0.41). After adjusting for MRI total proton density and BPD status, a 5% increase in forced expiratory volume at 1 s was associated with 738 (95% CI: 208, 1268) more steps per day and 0.1 (0.0, 0.2) more hours of MVPA, respectively. CONCLUSION: School-aged children born extremely preterm have similar physical activity levels to their peers, regardless of history of BPD. MRI and PFT measures suggestive of gas trapping and/or airflow obstruction are associated with lower physical activity levels.

Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank.

BACKGROUND: Although a number of health outcomes such as CVDs, metabolic-related outcomes, neurological disorders, pregnancy outcomes, and cancers have been identified in relation to B vitamins, evidence is of uneven quality and volume, and there is uncertainty about putative causal relationships. OBJECTIVES: To explore the effects of B vitamins and homocysteine on a wide range of health outcomes based on a large biorepository linking biological samples and electronic medical records. METHODS: First, we performed a phenome-wide association study (PheWAS) to investigate the associations of genetically predicted plasma concentrations (genetic component of the circulating concentrations) of folate, vitamin B6, vitamin B12, and their metabolite homocysteine with a wide range of disease outcomes (including both prevalent and incident events) among 385,917 individuals in the UK Biobank. Second, 2-sample Mendelian randomization (MR) analysis was used to replicate any observed associations and detect causality. We considered MR P <0.05 as significant for replication. Third, dose-response, mediation, and bioinformatics analyses were carried out to examine any nonlinear trends and to disentangle the underlying mediating biological mechanisms for the identified associations. RESULTS: In total, 1117 phenotypes were tested in each PheWAS analysis. After multiple corrections, 32 phenotypic associations of B vitamins and homocysteine were identified. Two-sample MR analysis supported that 3 of them were causal, including associations of higher plasma vitamin B6 with lower risk of calculus of kidney (OR: 0.64; 95% CI: 0.42, 0.97; P = 0.033), higher homocysteine concentration with higher risk of hypercholesterolemia (OR: 1.28, 95% CI: 1.04, 1.56; P = 0.018), and chronic kidney disease (OR: 1.32, 95% CI: 1.06, 1.63; P = 0.012). Significant nonlinear dose-response relationships were observed for the associations of folate with anemia, vitamin B12 with vitamin B-complex deficiencies, anemia and cholelithiasis, and homocysteine with cerebrovascular disease. CONCLUSIONS: This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.

Aetiology of extracranial carotid free-floating thrombus in a prospective multicentre cohort.

BACKGROUND: Carotid free-floating thrombi (FFT) in patients with acute transient ischaemic attack (TIA)/stroke have a high risk of early recurrent stroke. Management depends on aetiology, which can include local plaque rupture, dissection, coagulopathy, malignancy and cardioembolism. Our objectives were to classify the underlying aetiology of FFT and to estimate the proportion of patients with underlying stenosis requiring revascularisation. METHODS: We prospectively enrolled consecutive patients presenting to three comprehensive stroke centres with acute TIA/stroke and ipsilateral internal carotid artery FFT. The aetiology of FFT was classified as: carotid atherosclerotic disease, carotid dissection, cardioembolism, both carotid atherosclerosis and cardioembolism, or embolic stroke of uncertain source (ESUS). Patients with carotid atherosclerosis were further subclassified as having ≥50% or <50% stenosis. RESULTS: We enrolled 83 patients with confirmed FFT. Aetiological assessments revealed 66/83 (79.5%) had carotid atherosclerotic plaque, 4/83 (4.8%) had a carotid dissection, 10/83 (12%) had both atrial fibrillation and carotid atherosclerotic plaque and 3/83 (3.6%) were classified as ESUS. Of the 76 patients with atherosclerotic plaque (including those with atrial fibrillation), 40 (52.6%) had ≥50% ipsilateral stenosis. CONCLUSIONS: The majority of symptomatic carotid artery FFT are likely caused by local plaque rupture, more than half of which are associated with moderate to severe carotid stenosis requiring revascularisation. However, a significant number of FFTs are caused by non-atherosclerotic mechanisms warranting additional investigations.

A longitudinal analysis of early lung function trajectory in survivors of childhood Hodgkin lymphoma.

BACKGROUND: Childhood Hodgkin lymphoma survivors suffer from long-term effects decades after treatment completion with a prevalence of pulmonary dysfunction of up to 65.2%. AIMS: This study explored the early trajectory of pulmonary function in pediatric cancer patients with Hodgkin lymphoma who received pulmonary toxic therapy. METHODS AND RESULTS: In this single-center, 20-year retrospective cohort study, we included patients who were <18 years old at diagnosis of Hodgkin lymphoma between January 1994 and December 2014, and received bleomycin or thoracic radiation. We measured pulmonary function and reported on percent predicted values for forced expiratory volume in 1 s, total lung capacity, and diffusing capacity of the lungs. We used linear mixed models to identify the association of clinical factors with longitudinal changes in lung function at time points before and after treatment completion. Of 80 children who met inclusion criteria, all were treated with bleomycin, and 83.8% received thoracic radiation. More than half (51.2%) of patients had any abnormalities in lung function measures during the study observation period which averaged 24.2 months (±31.1SD). Females, younger age at diagnosis and treatment with radiation were associated with lower lung function measurements at various time points. While the majority of children experienced a recovery of their lung function within 1-2 years after treatment completion, some children with these risk factors did not. CONCLUSION: Pulmonary function abnormalities begin early in children treated for Hodgkin lymphoma. While the majority of children demonstrate a slow and continuous improvement in lung function back to baseline over time, we recommend routine asymptomatic screening of pulmonary function in certain childhood cancer survivors, particularly females, those diagnosed young and patients who received radiation therapy.

Understanding the experiences of lung volume recruitment among boys with Duchenne muscular dystrophy: A multicenter qualitative study.

BACKGROUND: Despite recommendations for regular lung volume recruitment (LVR) use in clinical practice guidelines for children with neuromuscular disease, adherence to LVR is poor. We aimed to describe the experience of LVR by boys with Duchenne muscular dystrophy (DMD), their families, and healthcare providers (HCPs), as well as to identify the barriers and facilitators to LVR use. METHODS: This multicenter, qualitative study evaluated boys with DMD (n = 11) who used twice-daily LVR as part of a randomized controlled trial, as well as their parents (n = 11), and HCPs involved in the clinical use of LVR (n = 9). Semistructured interviews were conducted to identify participants' understanding of LVR therapy and their beliefs, barriers and facilitators to its use. Thematic analysis was conducted using an inductive approach. A subanalysis compared adherent and nonadherent children. RESULTS: Seven themes were identified related to participants' beliefs and experiences with LVR: emotional impact, adaptation to LVR, perceived benefits of LVR, routine, family engagement, clinical resources, and equipment-related factors. Strategies to improve adherence were also identified, including education, reinforcement and demonstration of LVR benefit, as well as clinician support. There were no thematic differences between adherent and nonadherent children. DISCUSSION: Despite the benefits of LVR and positive experiences with it by many families, there remain barriers to adherence to treatment. HCPs need to balance the need for early introduction to give families time to adapt to LVR while ensuring that the benefit of LVR outweighs the burden. Clinician support is important for family engagement.

Biomarkers of environmental manganese exposure.

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.

Systemic quinolones and risk of retinal detachment III: a nested case-control study using a US electronic health records database.

BACKGROUND: Quinolones are popular antibiotics that are known for their potency, broad coverage, and reasonable safety. Concerns have been raised about a possible association between quinolones and retinal detachment (RD). METHODS: We conducted a nested case-control study using electronic health records (EHR) from the Health Facts® Database. The initial cohort included all patients who were admitted between 2000 and 2016, with no history of eye disease, and had a minimum medical history of one year. Eligible cases comprised inpatients who were first admitted with a primary diagnosis of RD between 2010 and 2015. Each eligible case was matched without replacement to five unique controls by sex, race, age, and period-at-risk. We used conditional logistic regression to calculate RD risk, adjusting for exposure to other medications, and major risk factors. RESULTS: We identified 772 cases and 3860 controls. Whereas our primary analysis of all subjects revealed no quinolone-associated RD risk, elevated but non-significant risks were noted in African Americans (ciprofloxacin and levofloxacin), those aged 56-70 years old (moxifloxacin), and women (ciprofloxacin). CONCLUSION: Our study did not identify an elevated RD risk within 30 days following systemic administration of quinolone antibiotics. Suggestions of increased risk observed in some population subgroups warrant further investigation.

Risk factors for respiratory adverse events after adenoidectomy and tonsillectomy in children with down syndrome: a retrospective cohort study.

Obstructive sleep apnea syndrome is a major cause of morbidity in the Down syndrome population and is commonly treated with adenoidectomy and/or tonsillectomy (AT). However, these children are at increased risk for perioperative respiratory adverse events (PRAEs). The objective of this study was to examine risk factors for major PRAEs requiring intervention in children with Down syndrome undergoing AT and to describe their postoperative monitoring environment. This retrospective study included all children with Down syndrome aged 0-18 years who underwent a preoperative polysomnogram followed by AT at a tertiary pediatric institution. Descriptive statistics were used to summarize baseline demographic and clinical characteristics. A multivariable model for prediction of PRAEs was constructed. A priori, it was decided that minimum oxygen saturation, apnea-hypopnea index, and average oxygen saturation asleep would be included, along with medical comorbidities associated with PRAEs at p < 0.2 in univariable analyses. Fifty-eight children were included in this study; twelve had a PRAE. Cardiac disease was associated with PRAEs on univariable analysis (p = 0.03). In multivariable analysis, average oxygen saturation asleep was associated with PRAEs (OR 1.50; 95% confidence interval 1.00, 2.41; p = 0.05). For all of the remaining variables, p > 0.15. Fifty-six children were admitted for monitoring overnight; four were admitted to the intensive care unit and fifty-two were admitted to the ward. CONCLUSIONS: A multivariable model found evidence that lower average oxygen saturation while asleep was associated with PRAEs requiring intervention in children with Down syndrome. This study highlights the difficulty in predicting complications in this population. WHAT IS KNOWN: • Obstructive sleep apnea syndrome is a major cause of morbidity in the Down syndrome population and is commonly treated with adenoidectomy and/or tonsillectomy. • However, children with Down syndrome are at increased risk for perioperative respiratory adverse events (PRAEs) following adenoidectomy and/or tonsillectomy. WHAT IS NEW: • We found that a lower average oxygen saturation asleep is associated with increased odds of PRAEs, adjusting for age, total apnea-hypopnea index, cardiac comorbidity, and minimum oxygen saturation. • This study highlights the difficulty in predicting complications in this population.

Routine lung volume recruitment in boys with Duchenne muscular dystrophy: a randomised clinical trial.

BACKGROUND: Impaired cough results in airway secretion retention, atelectasis and pneumonia in individuals with Duchenne muscular dystrophy (DMD). Lung volume recruitment (LVR) stacks breaths to inflate the lungs to greater volumes than spontaneous effort. LVR is recommended in DMD clinical care guidelines but is not well studied. We aimed to determine whether twice-daily LVR, compared with standard of care alone, attenuates the decline in FVC at 2 years in boys with DMD. METHODS: In this multicentre, assessor-blinded, randomised controlled trial, boys with DMD, aged 6-16 years with FVC >30% predicted, were randomised to receive conventional treatment or conventional treatment plus manual LVR twice daily for 2 years. The primary outcome was FVC % predicted at 2 years, adjusted for baseline FVC % predicted, age and ambulatory status. Secondary outcomes included change in chest wall distensibility (maximal insufflation capacity minus FVC) and peak cough flow. RESULTS: Sixty-six boys (36 in LVR group, 30 in control) were evaluated (median age (IQR): 11.5 years (9.5-13.5), median baseline FVC (IQR): 85% predicted (73-96)). Adjusted mean difference in FVC between groups at 2 years was 1.9% predicted (95% CI -6.9% to 10.7%; p=0.68) in the direction of treatment benefit. We found no differences in secondary outcomes. CONCLUSION: There was no difference in decline in FVC % predicted with use of twice-daily LVR for boys with DMD and relatively normal lung function. The burden associated with routine LVR may outweigh the benefit. Benefits of LVR to maintain lung health in boys with worse baseline lung function still need to be clarified. TRIAL REGISTRATION NUMBER: NCT01999075.

Pulmonary Magnetic Resonance Imaging of Ex-Preterm Children with and without Bronchopulmonary Dysplasia.

Rationale: Children born prematurely, particularly those with bronchopulmonary dysplasia, have persisting lung abnormalities requiring longitudinal monitoring. Pulmonary ultrashort echo time magnetic resonance imaging (MRI) measurements may provide sensitive markers of persisting lung abnormalities and have not been evaluated in school-aged children born prematurely. Objectives: To compare pulmonary MRI and pulmonary function test measurements in preterm-born school-aged children with and without bronchopulmonary dysplasia. Methods: Children aged 7-9 years, born extremely preterm, with and without bronchopulmonary dysplasia, were recruited from three centers. Participants underwent pulmonary ultrashort echo time MRI and pulmonary function tests. Primary outcomes included total proton density and proton density at full expiration, measured using MRI. Multiple linear regression analysis was performed, adjusting for gestational age and bronchopulmonary dysplasia. Associations between MRI and pulmonary function were tested. Results: Thirty-five children were included in the primary analysis (24 with bronchopulmonary dysplasia, 11 without); 29 completed pulmonary function tests, of whom 11 (38%) had airflow limitation. Children with bronchopulmonary dysplasia had 44% (95% confidence interval [CI], 10-66%) lower mean total proton density (mean ± standard deviation, 3.6 ± 2.6) than those without (6.1 ± 4.0). Those with bronchopulmonary dysplasia had 25% (95% CI, 3-42%) lower proton density at full expiration than those without. Lower total proton density and proton density at full expiration were moderately correlated with greater residual volume, residual volume/total lung capacity, and lung clearance index (Spearman correlations for total proton density: -0.42, -0.57, and -0.53, respectively. Spearman correlations for proton density at full expiration: -0.28, -0.57, and -0.45, respectively). Conclusions: School-aged preterm-born children with bronchopulmonary dysplasia have parenchymal tissue abnormalities measured using ultrashort MRI proton density, compared with those without. MRI proton density correlated with pulmonary function measures indicative of gas trapping. Clinical trial registered with www.clinicaltrials.gov (NCT02921308).

Locus-of-care disparities in end-of-life care intensity among adolescents and young adults with cancer: A population-based study using the IMPACT cohort.

BACKGROUND: Adolescents and young adults (AYAs) with cancer may experience elevated rates of high-intensity end-of-life (HI-EOL) care. Locus-of-care (LOC) disparities (pediatric vs adult) in AYA end-of-life (EOL) care are unstudied. METHODS: A decedent population-based cohort of Ontario AYAs diagnosed between 1992 and 2012 at the ages of 15 to 21 years was linked to administrative data. The authors determined the prevalence and associations of a composite outcome of HI-EOL care that included any of the following: intravenous chemotherapy within 14 days of death, more than 1 emergency department visit, more than 1 hospitalization, or an intensive care unit (ICU) admission within 30 days of death. Secondary outcomes included measures of the most invasive EOL care (ventilation within 14 days of death and ICU death) and in-hospital death. RESULTS: There were 483 decedents: 60.5% experienced HI-EOL care, 20.3% were ventilated, and 22.8% died in the ICU. Compared with patients with solid tumors, patients with hematological malignancies had the greatest odds of HI-EOL care (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.5-3.4), ventilation (OR, 4.7; 95% CI, 2.7-8.3), and ICU death (OR, 4.4; 95% CI, 2.6-4.4). Subjects treated in pediatric centers versus adult centers near death (OR, 2.4; 95% CI, 1.2-4.8) and those living in rural areas (OR, 2.1; 95% CI, 1.1-3.9) were more likely to experience ICU death. CONCLUSIONS: AYAs with cancer experience high rates of HI-EOL care, with patients in pediatric centers and those living in rural areas having the highest odds of ICU death. This study is the first to identify LOC-based disparities in EOL care for AYAs, and it highlights the need to explore the mechanisms underlying these disparities.

Systemic quinolones and risk of retinal detachment I: analysis of data from the US FDA adverse event reporting system.

BACKGROUND: Quinolones comprise a class of antibiotics that are globally preferred for treating a wide range of bacterial infections due to their potency, broad coverage, favorable pharmacologic profile, and mostly mild to moderate adverse reactions. Spontaneous reports on adverse drug events (ADE) and data from some pharmacoepidemiologic studies have raised concerns regarding quinolones and risk of retinal detachment (RD). This study examined ADE reports submitted to FDA adverse event reporting system (FAERS) for evidence on quinolone-associated RD risk. RESEARCH DESIGN AND METHODS: We identified all RD reports in FAERS between 2010-2019. We compared ADE signals between quinolones and selected medications that were previously associated with RD, and with reference medications not known to cause RD. For signal detection, we used two techniques: the proportional reporting ratio (PRR) and multi-item gamma Poisson shrinker (MGPS), which are known for their higher sensitivity and specificity for ADE signal detection, respectively. RESULTS: Moxifloxacin showed a positive and significant PRR signal for RD [PRR: 2.54 (1.60, 4.04)], and a marginally significant EBGM signal [EBGM: 2.21 (1.41, 3.02)]. CONCLUSION: Moxifloxacin is the only quinolone showing a positive disproportionality signal for RD. Further epidemiologic research is needed to clarify the association between moxifloxacin and RD risk.