Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia.

INTRODUCTION: A significant proportion of individuals suffering from post COVID-19 condition (PCC, also known as long COVID) can present with persistent, disabling fatigue similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-viral fatigue syndromes. There remains no clear pharmacological therapy for patients with this subtype of PCC, which can be referred to as post-COVID fatigue syndrome (PCFS). A low dose of the opioid antagonist naltrexone (ie, low-dose naltrexone (LDN)) has emerged as an off-label treatment for treating fatigue and other symptoms in PCC. However, only small, non-controlled studies have assessed LDN in PCC, so randomised trials are urgently required. METHODS AND ANALYSIS: A prospective, randomised, double-blind, parallel arm, placebo-controlled phase II trial will be performed to assess the efficacy of LDN for improving fatigue in PCFS. The trial will be decentralised and open to eligible individuals throughout the Canadian province of British Columbia (BC). Participants will be recruited through the province-wide Post-COVID-19 Interdisciplinary Clinical Care Network (PC-ICCN) and research volunteer platform (REACH BC). Eligible participants will be 19-69 years old, have had a confirmed or physician-suspected SARS-CoV-2 infection at least 3 months prior and meet clinical criteria for PCFS adapted from the Institute of Medicine ME/CFS criteria. Individuals who are taking opioid medications, have a history of ME/CFS prior to COVID-19 or history of significant liver disease will be excluded. Participants will be randomised to an LDN intervention arm (n=80) or placebo arm (n=80). Participants in each arm will be prescribed identical capsules starting at 1 mg daily and follow a prespecified schedule for up-titration to 4.5 mg daily or the maximum tolerated dose. The trial will be conducted over 16 weeks, with assessments at baseline, 6, 12 and 16 weeks. The primary outcome will be fatigue severity at 16 weeks evaluated by the Fatigue Severity Scale. Secondary outcomes will include pain Visual Analogue Scale score, overall symptom severity as measured by the Patient Phenotyping Questionnaire Short Form, 7-day step count and health-related quality of life measured by the EuroQol 5-Dimension questionnaire. ETHICS AND DISSEMINATION: The trial has been authorised by Health Canada and approved by The University of British Columbia/Children's and Women's Health Centre of British Columbia Research Ethics Board. On completion, findings will be disseminated to patients, caregivers and clinicians through engagement activities within existing PCC and ME/CFS networks. Results will be published in academic journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05430152.

Advanced cutaneous squamous cell carcinoma: Impact of age on the safety and efficacy of cemiplimab and the prognostic significance of blood biomarkers.

INTRODUCTION: Age-related differences in the safety profile of cemiplimab for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) have not been well described. We investigated the association of increasing age with immune related adverse events (irAE) from cemiplimab, efficacy outcomes, and the prognostic significance of pre-treatment blood biomarkers in contemporary practice. MATERIALS AND METHODS: Patients starting first-line cemiplimab for locally advanced or metastatic cSCC at British Columbia Cancer between April 2019 and January 2023 were identified. Landmark four-month logistic regression analysis compared the odds of developing irAE or sequelae amongst patients aged <75 years to those aged 75-84 or ≥ 85. Objective responses were determined using Response Evaluation Criteria in Solid Tumors version 1.1. Univariable Cox proportional hazard (PH) regression modelling of factors associated with overall survival (OS) was performed. RESULTS: Of 106 patients, the proportions aged <75, 75-84, and ≥ 85 years were 34%, 45%, and 21%, respectively. Overall, the proportion of patients with irAE ≥ grade 3, cemiplimab discontinuation, and hospitalization for immune toxicity was 27.4%, 31.1%, and 11.3%, respectively. There was no clear association between age and the odds of high grade irAE. However, increased odds of cemiplimab discontinuation was observed in patients aged 75-84 years (p = 0.05). Patients ≥85 years had increased hospitalizations due to irAE (OR = 5.00, 95% CI = 0.97-37.52) with two treatment-related deaths. Objective responses were similar across age cohorts (50.0%, 60.4%, and 54.5%) but progressive disease was higher in the age ≥ 85 group (22.2%, 18.8%, and 31.8%). On Cox PH regression analysis, age ≥ 85 years (vs. <75), Eastern Cooperative Oncology Group performance status 2-3 (vs. 0-1), and neutrophil to lymphocyte ratio (NLR) ≥7.80 (vs. <7.80) were associated with shorter survival. DISCUSSION: While the odds of high grade irAE were similar across age groups, significant age-related differences in treatment discontinuation and hospitalization due to immune toxicity were observed. Despite a higher incidence of primary progression and shorter OS in the oldest cohort, cemiplimab yielded robust objective responses regardless of age. Higher pre-treatment NLR was associated with shorter survival and the cut-point identified requires further study.

Adrenal insufficiency in pediatric kidney transplantation recipients.

BACKGROUND: Immunosuppression of pediatric kidney transplant (PKT) recipients often includes corticosteroids. Prolonged corticosteroid exposure has been associated with secondary adrenal insufficiency (AI); however, little is known about its impact on PKT recipients. METHODS: This was a retrospective cohort review of PKT recipients to evaluate AI prevalence, risk factors, and adverse effects. AI risk was assessed using morning cortisol (MC) and diagnosis confirmed by an ACTH stimulation test. Potential risk factors and adverse effects were tested for associations with MC levels and AI diagnosis. RESULTS: Fifty-one patients (60.8% male, age 7.4 (IQR 3.8, 13.1) years; 1 patient counted twice for repeat transplant) were included. Patients at risk for AI (MC < 240 nmol/L) underwent definitive ACTH stimulation testing, confirming AI in 13/51 (25.5%) patients. Identified risk factors for AI included current prednisone dosage (p = .001), 6-month prednisone exposure (p = .02), daily prednisone administration (p = .002), and rejection episodes since transplant (p = .001). MC level (2.5 years (IQR 1.1, 5.1) post-transplant) was associated with current prednisone dosage (p < .001), 6-month prednisone exposure (p = .001), daily prednisone administration (p = .006), rejection episodes since transplant (p = .003), greater number of medications (ß = -16.3, p < .001), 6-month hospitalization days (ß = -3.3, p = .013), creatinine variability (ß = -2.4, p = .025), and occurrence of acute kidney injury (ß = -70.6, p = .01). CONCLUSION: Greater corticosteroid exposure was associated with a lower MC level and confirmatory diagnosis of AI noted with an ACTH stimulation test. Adverse clinical findings with AI included greater medical complexity and kidney function lability. These data support systematic clinical surveillance for AI in PKT recipients treated with corticosteroids.

Risk Factor Analysis for Growth Arrest in Paediatric Physeal Fractures-A Prospective Study.

Background: Fractures through the physis account for 18-30% of all paediatric fractures, leading to growth arrest in up to 5.5% of cases. We have limited knowledge to predict which physeal fractures result in growth arrest and subsequent deformity or limb length discrepancy. The purpose of this study is to identify factors associated with physeal growth arrest to improve patient outcomes. Methods: This prospective cohort study was designed to develop a clinical prediction model for growth arrest after physeal injury. Patients ≤ 18 years old presenting within four weeks of injury were enrolled if they had open physes and sustained a physeal fracture of the humerus, radius, ulna, femur, tibia or fibula. Patients with prior history of same-site fracture or a condition known to alter bone growth or healing were excluded. Demographic data, potential prognostic indicators, and radiographic data were collected at baseline, during healing, and at one- and two-years post-injury. Results: A total of 332 patients had at least six months of follow-up or a diagnosis of growth arrest within six months of injury. In a comparison analysis, patients who developed growth arrest were more likely to be older (12.8 years vs. 9.4 years) and injured on the right side (53.0% vs. 45.7%). Initial displacement and angulation rates were higher in the growth arrest group (59.0% vs. 47.8% and 47.0% vs. 38.8%, respectively), but the amount of angulation was similar (27.0° vs. 28.4°). Rates of growth arrest were highest in distal femoral fractures (86%). Conclusions: The incidence of growth arrest in this patient population appears higher than the past literature reports at 30.1%. However, there may be variances in diagnostic criteria for growth arrest, and the true incidence may be lower. A number of patients were approaching skeletal maturity, and any growth arrest is likely to have less clinical significance in these cases. Further prospective long-term follow-up is required to determine risk factors, incidence, and true clinical impact of growth arrest when it does occur.

The acute care burden of asthma in children was profoundly reduced during the COVID-19 pandemic: A multi-centre Canadian retrospective study.

Objectives: Asthma is a chronic lung condition that can be exacerbated when triggered by viruses. Pandemic public health restrictions aimed to reduce COVID-19 transmission indirectly effected other circulating viruses. This study assessed the impact of the pandemic and associated public health measures on acute paediatric asthma across four tertiary sites in three Canadian provinces. We queried whether pandemic-related changes would impair preventive care and delay presentation to care, increasing asthma exacerbation severity. Methods: This retrospective study compared the frequency of acute care access and severity of presentation to emergency departments (ED) for acute asthma to four tertiary care children's hospitals during the COVID-19 pandemic (from March 17, 2020 to June 30, 2021) to a pre-lockdown control period (July 1, 2018 to March 16, 2020). Data was subjected to interrupted time series and Chi-square analysis. Results: Our study included 26,316 acute asthma visits to ED. Sites experienced a 63% to 89% reduction in acute asthma visits during the pandemic, compared with pre-lockdown controls, and a 17% to 85% reduction in asthma, that is out of proportion as a fraction of all-cause ED visits. For asthma, there was no difference in severity measured by rate of ward admission or rate of Paediatric Intensive Care Unit (PICU) admission. Conclusions: Public health measures appear to have resulted in a specific protective association on acute asthma with reduced acute care utilization over and above the reduction in all-cause presentations, without an increase in severity upon presentation. Our study indicates an importance to antiviral public health and engineering strategies to reduce viral transmission and thereby asthma morbidity.

What Technique Results in the Lowest Rate of Velopharyngeal Insufficiency in Patients With Submucous Cleft Palate? A Systematic Review and Meta-Analysis.

Objective: To determine which surgical technique offers the lowest rate of velopharyngeal insufficiency (VPI) without the need for further operative intervention, in pediatric patients with nonsyndromic submucous cleft palate (SMCP). Methods: This systematic review and meta-analysis included articles reporting on nonsyndromic pediatric patients treated surgically during childhood for SMCP, with data on postoperative speech outcomes and/or recommendations for secondary surgery. Main outcome measures included rates of unfavorable speech outcomes defined as persistent VPI requiring secondary surgery and speech outcome data. Results: 15 articles met our inclusion criteria, reporting on 383 children who underwent surgical treatment; 343 patients were included in studies reporting recommendations for secondary surgery. There was 1 randomized comparative trial, 4 comparative studies, and 10 single cohort studies. Eight articles used validated speech assessment tools. Our model showed the proportion of patients recommended for secondary surgery varied between techniques, ranging from 0.0% (CI 0.0, 1000) in pharyngeal flap to 17.8% (CI 8.9, 32.5) in straight line repair techniques, but there was no statistically significant difference between treatments (P = .33). Speech improvement ranged from 44.4% to 100%, with 9 studies recommending secondary surgery for some of their patient series. Conclusions: Although not of statistical significance, pharyngeal flap yields the lowest rate of reoperation as a primary technique for pediatric patients with nonsyndromic SMCP. Delayed repair age inherent to SMCP may render operations that rely on a functional levator muscle with less favorable outcomes. The absence of standardized surgical techniques, speech outcomes, speech therapy, and assessment make comparative analysis and recommendation difficult. We advocate for standardized speech assessment tools to improve future quantitative assessment of cleft surgery outcomes and a randomized controlled trial to better elucidate the preferred first-line technique.

Objectif: Déterminer les techniques chirurgicales qui offrent le plus bas taux d'insuffisance vélopharyngée (IVP) sans autre intervention opératoire chez les patients pédiatriques présentant une fissure palatine sous-muqueuse (FPSM) non syndromique. Méthodologie: La présente analyse systématique et méta-analyse incluait des articles rendant compte de patients pédiatriques non syndromiques ayant reçu un traitement chirurgical pendant l'enfance à cause d'une FPSM, y compris des données sur l'élocution postopératoire ou les recommandations en vue d'une opération secondaire. Les principales mesures de résultats incluaient les taux d'élocution défavorables définis comme une IVP persistante exigeant une opération secondaire et les données sur les résultats de l'élocution. Résultats: Au total, 15 articles respectaient les critères d'inclusion et rendaient compte de 383 enfants qui ont subi un traitement chirurgical; 343 patients ont participé à des études qui recommandaient une opération secondaire. Ces articles incluaient une étude comparative randomisée, quatre études comparatives et dix études de cohortes uniques. Huit faisaient appel à des outils d'évaluation de l'élocution validés. Le modèle des auteurs démontrait que la proportion de patients chez qui on recommandait une opération secondaire variait selon les techniques, soit de 0,0 % (IC, 0,0, 100,0) pour la technique de lambeau pharyngien à 17,8 % (IC, 8,9, 32,5) pour la technique de réparation linéaire, mais il n'y avait pas de différence significative entre les traitements (p=0,33). L'amélioration de l'élocution oscillait entre 44,4 % et 100 %, neuf études recommandant une opération secondaire pour certains patients de leur série. Conclusions: Même si ce résultat n'avait pas de signification statistique, le lambeau pharyngé est associé au taux de réopération le plus faible lorsqu'il est utilisé comme technique primaire chez les patients pédiatriques ayant une FPSM non syndromique. En raison de l'âge tardif de réparation inhérent à la FPSM, les opérations qui reposent sur le muscle élévateur fonctionnel peuvent donner des résultats moins favorables. Il peut être difficile de procéder à une analyse comparative et de formuler des recommandations à cause de l'absence de techniques chirurgicales standardisées, de résultats sur l'élocution, d'orthophonie et d'évaluation. Les auteurs préconisent des outils d'évaluation de l'élocution standardisés pour améliorer la future évaluation quantitative des résultats de l'opération de la fissure palatine et la tenue d'une étude contrôlée randomisée pour mieux déterminer la technique de première ligne à favoriser.

Prediction models for post-discharge mortality among under-five children with suspected sepsis in Uganda: A multicohort analysis.

In many low-income countries, over five percent of hospitalized children die following hospital discharge. The lack of available tools to identify those at risk of post-discharge mortality has limited the ability to make progress towards improving outcomes. We aimed to develop algorithms designed to predict post-discharge mortality among children admitted with suspected sepsis. Four prospective cohort studies of children in two age groups (0-6 and 6-60 months) were conducted between 2012-2021 in six Ugandan hospitals. Prediction models were derived for six-months post-discharge mortality, based on candidate predictors collected at admission, each with a maximum of eight variables, and internally validated using 10-fold cross-validation. 8,810 children were enrolled: 470 (5.3%) died in hospital; 257 (7.7%) and 233 (4.8%) post-discharge deaths occurred in the 0-6-month and 6-60-month age groups, respectively. The primary models had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95%CI 0.74-0.80) for 0-6-month-olds and 0.75 (95%CI 0.72-0.79) for 6-60-month-olds; mean AUROCs among the 10 cross-validation folds were 0.75 and 0.73, respectively. Calibration across risk strata was good: Brier scores were 0.07 and 0.04, respectively. The most important variables included anthropometry and oxygen saturation. Additional variables included: illness duration, jaundice-age interaction, and a bulging fontanelle among 0-6-month-olds; and prior admissions, coma score, temperature, age-respiratory rate interaction, and HIV status among 6-60-month-olds. Simple prediction models at admission with suspected sepsis can identify children at risk of post-discharge mortality. Further external validation is recommended for different contexts. Models can be digitally integrated into existing processes to improve peri-discharge care as children transition from the hospital to the community.

Optimizing the approach to monitoring allograft inflammation using serial urinary CXCL10/creatinine testing in pediatric kidney transplant recipients.

BACKGROUND: Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting. METHODS: Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery. RESULTS: Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection. CONCLUSIONS: Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.

Prepregnancy body mass index and other risk factors for early-onset and late-onset haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome: a population-based retrospective cohort study in British Columbia, Canada.

BACKGROUND: Obesity increases risk of pre-eclampsia, but the association with haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is understudied. OBJECTIVE: To examine the association between prepregnancy body mass index (BMI) and HELLP syndrome, including early-onset versus late-onset disease. STUDY DESIGN: A retrospective cohort study using population-based data. SETTING: British Columbia, Canada, 2008/2009-2019/2020. POPULATION: All pregnancies resulting in live births or stillbirths at ≥20 weeks' gestation. METHODS: BMI categories (kg/m2) included underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9) and obese (≥30.0). Rates of early-onset and late-onset HELLP syndrome (<34 vs ≥34 weeks, respectively) were calculated per 1000 ongoing pregnancies at 20 and 34 weeks' gestation, respectively. Cox regression was used to assess the associations between risk factors (eg, BMI, maternal age and parity) and early-onset versus late-onset HELLP syndrome. MAIN OUTCOME MEASURES: Early-onset and late-onset HELLP syndrome. RESULTS: The rates of HELLP syndrome per 1000 women were 2.8 overall (1116 cases among 391 941 women), and 1.9, 2.5, 3.2 and 4.0 in underweight, normal BMI, overweight and obese categories, respectively. Overall, gestational age-specific rates of HELLP syndrome increased with prepregnancy BMI. Obesity (compared with normal BMI) was more strongly associated with early-onset HELLP syndrome (adjusted HR (AHR) 2.24 (95% CI 1.65 to 3.04) than with late-onset HELLP syndrome (AHR 1.48, 95% CI 1.23 to 1.80) (p value for interaction 0.025). Chronic hypertension, multiple gestation, bleeding (<20 weeks' gestation and antepartum) also showed differing AHRs between early-onset versus late-onset HELLP syndrome. CONCLUSIONS: Prepregnancy BMI is positively associated with HELLP syndrome and the association is stronger with early-onset HELLP syndrome. Associations with early-onset and late-onset HELLP syndrome differed for some risk factors, suggesting possible differences in aetiological mechanisms.

COVID-19 Pandemic-Related Changes in Rates of Neonatal Abstinence Syndrome.

This cross-sectional study examines COVID-19 pandemic­related changes in rates of neonatal abstinence syndrome (NAS) and whether infants in urban or rural areas and those with low socioeconomic status were disproportionately affected.

Coaching for parents of children with type 1 diabetes: A randomized controlled trial.

OBJECTIVE: To assess the effectiveness of a standardized bi-weekly six-month telephone coaching intervention for parents of children with type 1 diabetes. METHODS: This single-blind randomized controlled trial followed participants for 12 months. The primary outcome was children's health-related quality of life. Secondary outcomes included treatment adherence, diabetes-related family conflict, and hemoglobin A1c. Data was collected using validated questionnaires and health records. We compared groups using a linear mixed effects model. RESULTS: 102 families were randomized (control: n = 49; intervention: n = 53). Coaching had no impact on children's overall health-related quality of life or overall secondary outcomes; however, there were patterns in subsections that suggest the possible impact of coaching. Coaching was perceived as a positive addition to routine care by 80% of families and 82% would recommend working with a coach to another family. 58% of participants would continue coaching beyond the study. CONCLUSION: Coaching did not impact overall quality of life or secondary outcomes; however, coaching was well received by families who perceived significant benefits. Patterns in subsections warrant further study. PRACTICE IMPLICATIONS: Adding a health coach into diabetes multidisciplinary care supports families in a way that is unique from their routine clinical care.

Blood Pressure and Heart Rate Variability and the Impact on Pregnancy Outcomes: A Systematic Review.

BACKGROUND: Long-term (visit-to-visit) blood pressure variability (BPV) and heart rate variability (HRV) outside pregnancy are associated with adverse cardiovascular outcomes. Given the limitations of relying solely on blood pressure level to identify pregnancies at risk, long-term (visit-to-visit) BPV or HRV may provide additional diagnostic/prognostic counsel. To address this, we conducted a systematic review to examine the association between long-term BPV and HRV in pregnancy and adverse maternal and perinatal outcomes. METHODS AND RESULTS: Databases were searched from inception to May 2023 for studies including pregnant women, with sufficient blood pressure or heart rate measurements to calculate any chosen measure of BPV or HRV. Studies were excluded that reported short-term, not long-term, variability. Adjusted odds ratios were extracted. Eight studies (138 949 pregnancies) reporting BPV met our inclusion criteria; no study reported HRV and its association with pregnancy outcomes. BPV appeared to be higher in women with hypertension and preeclampsia specifically, compared with unselected pregnancy cohorts. Greater BPV was associated with significantly more adverse pregnancy outcomes, particularly maternal (gestational hypertension [odds ratio range, 1.40-2.15], severe hypertension [1.40-2.20]), and fetal growth (small-for-gestational-age infants [1.12-1.32] or low birth weight [1.18-1.39]). These associations were independent of mean blood pressure level. In women with hypertension, there were stronger associations with maternal outcomes but no consistent pattern for perinatal outcomes. CONCLUSIONS: Future work should aim to confirm whether BPV could be useful for risk stratification prospectively in pregnancy, and should determine the optimal management path for those women identified at increased risk of adverse outcomes.

Obesity, Twin Pregnancy, and the Role of Assisted Reproductive Technology.

Importance: The prevalence of overweight and obesity (body mass index [BMI] ≥25) has increased globally, and high BMI has been linked to higher rates of twin birth. However, evidence from large population-based studies is lacking; the issue needs careful study, as women with obesity are also more likely to use assisted reproductive technology (ART), which frequently results in twin pregnancy. Objective: To examine the association between BMI and twin birth and the role of ART as a potential mediator in this association. Design, Setting, and Participants: This retrospective cohort study included all live births and stillbirths with gestational age of 20 weeks or longer in British Columbia, Canada, from 2008 to 2020, using data from the British Columbia Perinatal Database Registry. Data analysis was conducted from November 2022 to June 2023. Exposures: Prepregnancy BMI, calculated as weight in kilograms divided by height in meters squared, and use of ART. Main Outcomes and Measures: The study assessed whether prepregnancy BMI is associated with the rate of twin vs singleton delivery and whether this association is explained by the differential use of ART in women with obesity. Results: A total of 524 845 deliveries at 20 weeks' or longer gestation occurred in British Columbia during the study period, and 392 046 women had complete data on prepregnancy BMI. The median (IQR) age was 31.4 (27.7-35.0) years, approximately half were nulliparous (243 443 [46.4%]) and less than 10% smoked during pregnancy (36 894 [7.1%]). Overall, 8295 women had a twin delivery (15.8 per 1000 deliveries), and rates per 1000 deliveries by prepregnancy BMI categories were 11.9 (underweight), 15.1 (normal), 16.0 (overweight), 16.0 (obesity class I), 16.7 (obesity class II), and 18.9 (obesity class III). After adjustment for other covariates, women with underweight had relatively 16% fewer twins compared with women with normal BMI (adjusted risk ratio [aRR], 0.84; 95% CI, 0.74-0.95), while women with overweight, class I obesity, class II obesity, and class III obesity had 14% (aRR, 1.14; 95% CI, 1.07-1.21), 16% (aRR, 1.16; 95% CI, 1.06-1.27), 17% (aRR, 1.17; 95% CI, 1.02-1.34), and 41% higher rates (aRR, 1.41; 95% CI, 1.19-1.66), respectively. The proportion of women who conceived by ART increased with increasing BMI, and ART was associated with nearly a 12-fold higher rate of twin delivery (aRR, 11.80; 95% CI 11.10-12.54). ART explained about a quarter of the association between obesity class I and II and twin delivery (eg, obesity class I, 23% mediated; 95% CI, 7%-39% mediated), but none of this association was mediated by ART in women with class III obesity. Conclusions and relevance: In this cohort study of 524 845 births, the rate of twin birth increased with increasing prepregnancy BMI. In women with a BMI between 30 and 40, approximately one-quarter of this association was explained by higher use of ART; however, there was no evidence of such mediation in women with BMI of 40 or greater.

Defining a Childhood Type 1 Diabetes Cohort, Clinical Practice Measures, and Outcomes Within Administrative Data in British Columbia.

OBJECTIVE: We used administrative data to 1) establish a cohort of individuals with childhood-onset type 1 diabetes (T1D) in British Columbia (BC), and 2) define T1D-related clinical practice measures. METHODS: We applied a validated diabetes case-finding definition and differentiating algorithm to linked administrative data (1992-1993 to 2019-2020). Cases were removed when they did not meet inclusion criteria for childhood-onset T1D. Clinical practice measures were defined based on clinical practice guidelines. RESULTS: We developed an administrative cohort that included 5,901 individuals with childhood-diagnosed T1D between April 1, 1996, and March 31, 2020. The mean age was 22.31 (standard deviation 8.21) years. Clinical practice measures derived included diabetes outpatient visits (N=4,935) and glycated hemoglobin tests (N=4,935), and screening for thyroid function (N=4,457), retinopathy (N=1,602), and nephropathy (N=2,369). CONCLUSIONS: We established an administrative cohort of ∼6,000 individuals with childhood-onset T1D with 20+ years of follow-up data that can be used to describe the association between clinical practice measures and clinical outcomes.

Human milk oligosaccharide composition following supplementation with folic acid vs (6S)-5-methyltetrahydrofolic acid during pregnancy and mediation by human milk folate forms.

Supplementation with folic acid versus (6S)-5-methyltetrahydrofolic acid (5-MTHF) results in different folate forms in human milk, with folic acid increasing unmetabolized folic acid (UMFA) at the expense of reduced folate forms. It is unknown whether folate forms present in human milk have further effects on human milk composition, such as human milk oligosaccharide (HMO) concentrations. We randomized 60 pregnant women in Canada to 0.6 mg/day folic acid or (6S)-5-MTHF. Human milk folate forms (LC-MS/MS) and nineteen HMOs (HPLC) were quantified at 1 week postpartum. Linear regression and causal mediation analysis were used to evaluate the effect of folate supplementation on HMO concentrations, and possible mediation by concentrations of UMFA and reduced folate forms in human milk (controlling for secretor status and parity). HMO concentrations were not different between groups, with no evidence of mediation by reduced folate forms; however, increased UMFA was associated with reduced concentrations of total HMOs and 3'-sialyllactose.

"The Cost in the Individual": Longitudinal Burnout Prevalence Among Pediatric Emergency Physicians Through 9 Months of the COVID-19 Pandemic.

OBJECTIVES: Emergency medicine (EM) confers a high risk of burnout that may be exacerbated by the COVID-19 pandemic. We aimed to determine the longitudinal prevalence of burnout in pediatric EM (PEM) physicians/fellows working in tertiary PEM departments across Canada and its fluctuation during the pandemic. METHODS: A national mixed-methods survey using a validated 2-question proxy for burnout was distributed monthly through 9 months. The primary outcome was the trajectory in probability of burnout, which was examined as both emotional exhaustion (EE) and depersonalization (DP), EE alone, and DP alone. Secondary outcomes investigated burnout and its association with demographic variables. Quantitative data were analyzed using logistic regression for primary outcomes and subanalyses for secondary outcomes. Conventional content analysis was used to analyze qualitative data and generate themes. RESULTS: From February to October 2021, 92 of 98 respondents completed at least 1 survey, 78% completed at least 3 consecutive surveys, and 48% completed at least 6 consecutive surveys. Predicted probability of EE was bimodal with peaks in May (25%) and October (22%) 2021. Rates of DP alone or having both EE and DP were approximately 1% and stable over the study period. Mid-career physicians were at lower risk of EE (odds ratio, 0.02; 95% confidence interval, 0-0.22) compared with early-career physicians. Underlying drivers of burnout were multifaceted. CONCLUSIONS: Our study suggests that increased COVID-19 case burden was correlated with EE levels during the third and fourth waves of the pandemic. Emotional exhaustion was worsened by systemic factors, and interventions must target common themes of unsustainable workloads and overwhelming lack of control.

Risk factors for pre-eclampsia in clinical practice guidelines: Comparison with the evidence.

OBJECTIVE: To compare pre-eclampsia risk factors identified by clinical practice guidelines (CPGs) with risk factors from hierarchical evidence review, to guide pre-eclampsia prevention. DESIGN: Our search strategy provided hierarchical evidence of relationships between risk factors and pre-eclampsia using Medline (Ovid), searched from January 2010 to January 2021. SETTING: Published studies and CPGs. POPULATION: Pregnant women. METHODS: We evaluated the strength of association and quality of evidence (GRADE). CPGs (n = 15) were taken from a previous systematic review. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Of 78 pre-eclampsia risk factors, 13 (16.5%) arise only during pregnancy. Strength of association was usually 'probable' (n = 40, 51.3%) and the quality of evidence was low (n = 35, 44.9%). The 'major' and 'moderate' risk factors proposed by 8/15 CPGs were not well aligned with the evidence; of the ten 'major' risk factors (alone warranting aspirin prophylaxis), associations with pre-eclampsia were definite (n = 4), probable (n = 5) or possible (n = 1), based on moderate (n = 4), low (n = 5) or very low (n = 1) quality evidence. Obesity ('moderate' risk factor) was definitely associated with pre-eclampsia (high-quality evidence). The other ten 'moderate' risk factors had probable (n = 8), possible (n = 1) or no (n = 1) association with pre-eclampsia, based on evidence of moderate (n = 1), low (n = 5) or very low (n = 4) quality. Three risk factors not identified by the CPGs had probable associations (high quality): being overweight; 'prehypertension' at booking; and blood pressure of 130-139/80-89 mmHg in early pregnancy. CONCLUSIONS: Pre-eclampsia risk factors in CPGs are poorly aligned with evidence, particularly for the strongest risk factor of obesity. There is a lack of distinction between risk factors identifiable in early pregnancy and those arising later. A refresh of the strategies advocated by CPGs is needed.

Blood pressure measurement and adverse pregnancy outcomes: A cohort study testing blood pressure variability and alternatives to 140/90 mmHg.

OBJECTIVE: To examine the association with adverse pregnancy outcomes of: (1) American College of Cardiology/American Heart Association blood pressure (BP) thresholds, and (2) visit-to-visit BP variability (BPV), adjusted for BP level. DESIGN: An observational study. SETTING: Analysis of data from the population-based UK Southampton Women's Survey (SWS). POPULATION OR SAMPLE: 3003 SWS participants. METHODS: Generalised estimating equations were used to estimate crude and adjusted relative risks (RRs) of adverse pregnancy outcomes by BP thresholds, and by BPV (as standard deviation [SD], average real variability [ARV] and variability independent of the mean [VIM]). Likelihood ratios (LRs) were calculated to evaluate diagnostic test properties, for BP at or above a threshold, compared with those below. MAIN OUTCOME MEASURES: Gestational hypertension, severe hypertension, pre-eclampsia, preterm birth (PTB), small-for-gestational-age (SGA) infants, neonatal intensive care unit (NICU) admission. RESULTS: A median of 11 BP measurements were included per participant. For BP at ≥20 weeks' gestation, higher BP was associated with more adverse pregnancy outcomes; however, only BP <140/90 mmHg was a good rule-out test (negative LR <0.20) for pre-eclampsia and BP ≥140/90 mmHg a good rule-in test (positive LR >8.00) for the condition. BP ≥160/110 mmHg could rule-in PTB, SGA infants and NICU admission (positive LR >5.0). Higher BPV (by SD, ARV, or VIM) was associated with gestational hypertension, severe hypertension, pre-eclampsia, PTB, SGA and NICU admission (adjusted RRs 1.05-1.39). CONCLUSIONS: While our findings do not support lowering the BP threshold for pregnancy hypertension, they suggest BPV could be useful to identify elevated risk of adverse outcomes.

National Survey on the Emergency Department Management of Febrile Infants 29 to 60 Days Old With an Abnormal Urinalysis.

OBJECTIVES: Recent clinical practice guidelines recommend that decisions regarding lumbar puncture (LP) for febrile infants older than 28 days should no longer be based on urinalysis results, but rather independently determined by inflammatory markers and sometimes guided by shared decision-making (SDM). This study sought to assess management decisions for febrile infants aged 29 to 60 days with an abnormal urinalysis. METHODS: A scenario-based survey was sent to emergency department physicians at all 15 Canadian tertiary pediatric centers. Participants were asked questions regarding management decisions when presented with a well-appearing febrile infant in the second month of life with either an abnormal or normal urinalysis. RESULTS: Response rate was 50.2% (n = 116/231). Overall, few respondents would perform an LP based on either an abnormal or normal urinalysis alone (10.3% and 6.0%, respectively). However, regression analysis demonstrated that decisions regarding LP were influenced by urinalysis results (P < 0.001), with respondents more likely to defer to inflammatory marker results for infants with a normal urinalysis result (57.8%) compared with those with an abnormal urinalysis (28.4%). Hospitalization (62.1%) and empiric antibiotic treatment by intravenous route (87.9%) were both frequent for low-risk infants with an abnormal urinalysis. Nearly half of respondents reported rarely (<25% of encounters) engaging families in SDM regarding LP decisions. CONCLUSIONS: Knowledge translation initiatives reflecting current evidence should target use of inflammatory markers rather than urinalysis results to guide decisions regarding LP. Efforts emphasizing outpatient management with oral antibiotics and SDM for low-risk infants with an abnormal urinalysis could also further align management with current evidence and guidelines.