Evaluation of the First Three Years of Treatment of Children with Congenital Hypothyroidism Identified through the Alberta Newborn Screening Program.

The effectiveness of newborn screening (NBS) for congenital hypothyroidism (CH) relies on timely screening, confirmation of diagnosis, and initiation and ongoing monitoring of treatment. The objective of this study was to ascertain the extent to which infants with CH have received timely and appropriate management within the first 3 years of life, following diagnosis through NBS in Alberta, Canada. Deidentified laboratory data were extracted between 1 April 2014 and 31 March 2019 from Alberta Health administrative databases for infants born in this time frame. Time to lab collection was anchored from date of birth. Timeliness was assessed as the frequency of monitoring of Thyroid Stimulating Hormone (TSH) and appropriateness as the frequency of children maintaining biochemical euthyroidism. Among 160 term infants, 95% had confirmation of diagnosis by 16 days of age. The cohort had a median of 2 (range 0-5) TSH measurements performed in the time interval from 0 to 1 month, 4 (0-12) from 1 to 6 months, 2 (0-10) from 6 to 12 months, and 7 (0-21) from 12 to 36 months. Approximately half were still biochemically hypothyroid (TSH > 7 mU/L) at 1 month of age. After becoming euthyroid, at least some period of hypo- (60%) or hyperthyroidism (TSH < 0.2 mU/L) (39%) was experienced. More work needs to be performed to discern factors contributing to prolonged periods of hypothyroidism or infrequent lab monitoring.

Utilizing Quality of Life Adjusted Days Alive and Out of Hospital in Heart Failure Clinical Trials.

BACKGROUND: In heart failure (HF) trials, there has been an emphasis on utilizing more patient-centered outcomes, including quality of life (QoL) and days alive and out of hospital. We aimed to explore the impact of QoL adjusted days alive and out of hospital as an outcome in 2 HF clinical trials. METHODS: Using data from 2 trials in HF (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT] and Study of Dietary Intervention under 100 mmol in Heart Failure [SODIUM-HF]), we determined treatment differences using percentage days alive and out of hospital (%DAOH) adjusted for QoL at 18 months as the primary outcome. For each participant, %DAOH was calculated as a ratio between days alive and out of hospital/total follow-up. Using a regression model, %DAOH was subsequently adjusted for QoL measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score. RESULTS: In the GUIDE-IT trial, 847 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 59.0 (interquartile range, 40.8-74.3), which did not change over 18 months. %DAOH was 90.76%±22.09% in the biomarker-guided arm and 88.56%±25.27% in the usual care arm. No significant difference in QoL adjusted %DAOH was observed (1.09% [95% CI, -1.57% to 3.97%]). In the SODIUM-HF trial, 796 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 69.8 (interquartile range, 49.3-84.3), which did not change over 18 months. %DAOH was 95.69%±16.31% in the low-sodium arm and 95.95%±14.76% in the usual care arm. No significant difference was observed (1.91% [95% CI, -0.85% to 4.77%]). CONCLUSIONS: In 2 large HF clinical trials, adjusting %DAOH for QoL was feasible and may provide complementary information on treatment effects in clinical trials.

Patient-Reported Frailty and Functional Status in Heart Failure With Preserved Ejection Fraction: Insights From VITALITY-HFpEF.

BACKGROUND: The association between frailty and health status in patients with heart failure with preserved ejection fraction (HFpEF) is not well known. OBJECTIVES: The authors examined the association between: 1) patient-reported frailty, measured by the Fried frailty phenotype, Kansas City Cardiomyopathy Questionnaire Physical Limitation Score (KCCQ-PLS), 6-minute walking distance (6MWD), and other baseline characteristics; 2) baseline frailty compared with KCCQ-PLS and 24-week 6MWD; 3) frailty and changes in KCCQ-PLS and 6MWD; and 4) vericiguat and frailty at 24 weeks. METHODS: In a post hoc analysis, patients in the VITALITY-HFpEF (Patient-reported Outcomes in Vericiguat-treated Patients With HFpEF) trial were categorized as not frail (0 symptoms), prefrail (1-2 symptoms), and frail (≥3 symptoms) according to patient-reported number of frailty symptoms. Correlations and linear regression models were used to examine the association between frailty and other measures, and between frailty and KCCQ-PLS at baseline with 24-week 6MWD. RESULTS: Among 739 patients, 27.3% were not frail, 37.6% were prefrail, and 35.0% were frail at baseline. Frail patients were older, more likely to be women, and less likely to be from Asia. Baseline KCCQ-PLS and 6MWD (mean ± SD) among not frail, prefrail, and frail patients was 68.2 ± 23.2, 61.7 ± 22.6, and 48.4 ± 23.8 and 328.5 ± 117.1 m, 310.8 ± 98.9 m, and 250.7 ± 104.3 m (P < 0.01 for both). After accounting for baseline 6MWD, frailty status at baseline, but not KCCQ-PLS, was significantly associated with 6MWD at 24 weeks. By 24 weeks, 47.5% of patients had no change in frailty, 45.5% had become less frail, and 7.0% had become more frail. Treatment with vericiguat did not alter frailty status at 24 weeks. CONCLUSIONS: Patient-reported frailty is modestly correlated with both the KCCQ-PLS and 6MWD but offers prognostic insight into 6MWD at 24 weeks. (Patient-reported Outcomes in Vericiguat-treated Patients With HFpEF [VITALITY-HFpEF]; NCT03547583).

Leuprolide Acetate and QTc Interval in Gender-Diverse Youth.

Background: Puberty suppression is a standard of care for gender-affirming therapy in gender-diverse youth. Leuprolide acetate is a gonadotropin-releasing hormone agonist (GnRHa) commonly used for pubertal suppression. There are concerns that GnRHa agents prolong the rate-corrected QT interval (QTc) when used as androgen deprivation therapy in management of prostate cancer; however, there is a paucity of literature regarding the effect of leuprolide acetate on QTc intervals in gender-diverse youth. Aim: To determine the proportion of gender-diverse youth with QTc prolongation on leuprolide acetate therapy. Methods: A retrospective chart review of gender-diverse youth initiated on leuprolide acetate between July 1, 2018 and December 31, 2019 was conducted at a tertiary care pediatric hospital in Alberta, Canada. Youth aged 9-18 years were included if a 12-lead electrocardiogram was completed after initiating leuprolide acetate. The proportion of adolescents with clinically significant QTc prolongation was assessed, defined as QTc >460 milliseconds (ms). Results: Thirty-three pubertal youth were included. The cohort had a mean age of 13.7 years (standard deviation [SD] 2.1) and 69.7% identified as male (assigned female at birth). The mean post-leuprolide acetate QTc was 415 ms (SD 27, range 372-455). Twenty-two (66.7%) of youth were prescribed concomitant medications, including QTc-prolonging medications in 15.2%. None of the 33 youth on leuprolide acetate had QTc prolongation. Only 24.2% patients had a borderline QTc (QTc 440-460 ms). Conclusion: No gender-diverse youth on leuprolide acetate demonstrated clinically significant QTc prolongation.

The empirical estimate of the survival and variance using a weighted composite endpoint.

BACKGROUND: Composite endpoints for estimating treatment efficacy are routinely used in several therapeutic areas and have become complex in the number and types of component outcomes included. It is assumed that its components are of similar asperity and chronology between both treatment arms as well as uniform in magnitude of the treatment effect. However, these assumptions are rarely satisfied. Understanding this heterogeneity is important in developing a meaningful assessment of the treatment effect. METHODS: We developed the Weighted Composite Endpoint (WCE) method which uses weights derived from stakeholder values for each event type in the composite endpoint. The derivation for the product limit estimator and the variance of the estimate are presented. The method was then tested using data simulated from parameters based on a large cardiovascular trial. Variances from the estimated and traditional approach are compared through increasing sample size. RESULTS: The WCE method used all of the events through follow-up and generated a multiple recurrent event survival. The treatment effect was measured as the difference in mean survivals between two treatment arms and corresponding 95% confidence interval, providing a less conservative estimate of survival and variance, giving a higher survival with a narrower confidence interval compared to the traditional time-to-first-event analysis. CONCLUSIONS: The WCE method embraces the clinical texture of events types by incorporating stakeholder values as well as all events during follow-up. While the effective number of events is lower in the WCE analysis, the reduction in variance enhances the ability to detect a treatment effect in clinical trials.

Short-term and long-term survival in patients with prevalent haemodialysis-an integrated prognostic model: external validation.

OBJECTIVES: Prognostic tools with evidence for external validity in routine clinical practice are needed to align care with patients' preferences and deliver timely supportive services. Current models have limited, if any, evidence for external validity and none have been implemented and evaluated in clinical practice on a large scale. This study sought to provide evidence for external validity in a real life setting of the Cohen prognostic model that integrates actuarial factors with the 'Surprise Question' to assess 6-month, 12-month and 18-month survival of prevalent haemodialysis patients. METHODS: Cross-sectional study of 1372 patients in a Canadian university-based programme between 2010 and 2019. Survival probabilities were compared with observed survival. Discrimination and calibration were assessed through predicted risk-stratified observed survival, cumulative AUC, Somer's Dxy and a calibration slope estimate. RESULTS: Discrimination performance was moderate with a C statistic of 0.71-0.72 for all three time points. The model overpredicted mortality risk with the best predictive accuracy for 6- month survival. The differences between observed and mean predicted survival at 6 months, 12 months and 18 months were 3.2%, 8.8% and 12.9%, respectively. Kaplan-Meier curves stratified by Cox-based risk group showed good discrimination between high-risk and low-risk patients with HR estimates (95% CI): C2 vs C1 3.07 (1.57-5.99), C3 vs C1 5.85 (3.06-11.17), C4 vs C1 13.24 (6.91-25.34)). CONCLUSIONS: The Cohen prognostic model can be incorporated easily into routine dialysis care to identify patients at high risk for death over 6 months, 12 months and 18 months and help target vulnerable patients for timely supportive care interventions.

Sodium Restriction in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Sodium restriction is a nonpharmacologic treatment suggested by practice guidelines for the management of patients with heart failure (HF). In this study, we synthesized the data from randomized controlled trials (RCTs) evaluating the effects of sodium restriction on clinical outcomes in patients with HF. METHODS: In this aggregate data meta-analysis, Cochrane Central, MEDLINE (Medical Literature Analysis and Retrieval System Online), Embase Ovid, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) Plus databases were searched up to April 2, 2022. RCTs were included if they investigated the effects of sodium/salt restriction as compared to no restriction on clinical outcomes in patients with HF. Outcomes of interest included mortality, hospitalization, change in New York Heart Association functional class, and quality of life (QoL). RESULTS: Seventeen RCTs were identified (834 and 871 patients in intervention and control groups, respectively). Sodium restriction did not reduce the risk of all-cause death (odds ratio, 0.95 [95% CI, 0.58-1.58]), hospitalization (odds ratio, 0.84 [95% CI, 0.62-1.13]), or the composite of death/hospitalization (odds ratio, 0.88 [95% CI, 0.63-1.23]). The results were similar in different subgroups, except for the numerically lower risk of death with reduced sodium intake reported in RCTs with dietary sodium at the 2000 to 3000 mg/d range as opposed to <2000 mg/d (and in RCTs with versus without fluid restriction as a co-intervention). Among RCTs reporting New York Heart Association change, 2 RCTs (which accounted for two-thirds of the data) showed improvement in New York Heart Association class with sodium restriction. Substantial heterogeneity existed for QoL: 6 RCTs showed improvement of QoL and 4 RCTs showed no improvement of sodium restriction on QoL. CONCLUSIONS: In a meta-analysis of RCTs, sodium restriction was not associated with fewer deaths or hospitalizations in patients with HF. Dietary sodium restriction may be associated with improvements in symptoms and QoL.

Prenatal Genetic Testing in the Era of Next Generation Sequencing: A One-Center Canadian Experience.

The introduction of next generation sequencing (NGS) technologies has revolutionized the practice of Medical Genetics, and despite initial reticence in its application to prenatal genetics (PG), it is becoming gradually routine, subject to availability. Guidance for the clinical implementation of NGS in PG, in particular whole exome sequencing (ES), has been provided by several professional societies with multiple clinical studies quoting a wide range of testing yields. ES was introduced in our tertiary care center in 2017; however, its use in relation to prenatally assessed cases has been limited to the postnatal period. In this study, we review our approach to prenatal testing including the use of microarray (CMA), and NGS technology (gene panels, ES) over a period of three years. The overall diagnostic yield was 30.4%, with 43.2% of those diagnoses being obtained through CMA, and the majority by using NGS technology (42% through gene panels and 16.6% by ES testing, respectively). Of these, 43.4% of the diagnoses were obtained during ongoing pregnancies. Seventy percent of the abnormal pregnancies tested went undiagnosed. We are providing a contemporary, one tertiary care center retrospective view of a real-life PG practice in the context of an evolving use of NGS within a Canadian public health care system that may apply to many similar jurisdictions around the world.

Clinical Phenotypes of Heart Failure across the spectrum of Ejection Fraction: A Cluster Analysis.

INTRODUCTION: Heart failure (HF), and especially HF with preserved ejection fraction (HFpEF), remains a challenging condition to define. The heterogenous nature of this population may be related to a variety of underlying etiologies interacting myocardial dysfunction. METHOD: Alberta HEART study was a prospective, observational cohort that enrolled participants along the spectrum of heart failure including: healthy controls, people at risk of HF, and patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF). We aimed to explore phenotypes of patients with HF and at-risk of developing HF. Utilising 27 detailed clinical, echocardiographic and biomarker variables, latent class analysis with and without multiple imputation was undertaken to identify distinct clinical phenotypes. RESULTS: Of 621 participants, 191 (30.8%) and 169 (27.2%) were adjudicated by cardiologists to have HFpEF and HFrEF respectively. In the overall cohort, latent class analysis identified four distinct phenotypes. Phenotype A (n=152, 24.5%) was a healthy and low risk group. Phenotype B (n=129, 20.8%) demonstrated increased left ventricular mass and end-diastolic volumes, with elevated natriuretic peptides and clinical features of congestion. Phenotype C (n=128, 20.6%) was primarily characterised by obesity (80%) and normal indexed cardiac chamber sizes, low natriuretic peptide levels and minimal features of congestion.  Phenotype D (n=212, 34.1%) consisted of elderly patients with clinical features of congestions. Phenotypes B and D demonstrated the highest risk of mortality and hospitalization over a median follow-up of 3.7 years. CONCLUSION: Phenotypes with congestive features demonstrated increased risk profiles. Heart failure is a heterogenous classification which requires further work to appropriately categorise patients based on the underlying etiology or mechanism of impairment.

Associated factors and clinical outcomes in mechanical circulatory support use in patients undergoing high risk on-pump cardiac surgery: Insights from the LEVO-CTS trial.

BACKGROUND: We describe variables and outcomes associated with peri-operative mechanical circulatory support (MCS) utilization among patients enrolled in the Levosimendan in patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial. METHODS: In the LEVO-CTS trial, MCS utilization (defined as intra-aortic balloon pump, extracorporeal membrane oxygenation, or surgical ventricular assist device) within 5 days of surgery was examined. The association between MCS use and outcomes including 90-day mortality, 30-day renal-replacement therapy, and hospital and critical stay length of stay were determined. RESULTS: Among the 849 patients from 70 centers randomized to levosimendan or placebo, 85 (10.0%) patients were treated with MCS (71 intra-aortic balloon pump, 7 extracorporeal membrane oxygenation, 7 ventricular assist device); with 89.4% started on post-operative day 0. Inter-institutional use ranged from 0% to 100%. Variables independently associated with MCS utilization included combined coronary artery bypass grafting and valve surgery (adjusted odds ratio [OR] 2.73, 95% confidence interval [CI] 1.70-4.37, P < .001), history of lung disease (OR 1.70, 95% CI 1.06-2.70, P = .029), and history of heart failure (OR 2.44, 95% CI 1.10-5.45, P = .027). Adjusted 90-day mortality (22.4% vs 4.1%, hazard ratio 6.11, 95% CI 3.95-9.44, P < .001) was higher, and median critical care length of stay (8.0 vs 4.0 days, P < .001) was longer in patients managed with MCS. CONCLUSIONS: In a randomized controlled trial of high-risk cardiac surgical patients in North America, we observed patient, and surgical variables associated with MCS utilization. MCS use was associated with a higher risk of post-operative mortality.

Re-referring Children for Multidisciplinary Obesity Management.

OBJECTIVES: To examine characteristics of children referred for obesity management based on referral frequency, child- and referrer-related variables associated with re-referral, and determine whether re-referral increased treatment initiation. STUDY DESIGN: This population-level, retrospective analysis included all 2- to 17-year-olds referred for obesity management to 1 of 3 multidisciplinary clinics in Alberta, Canada between April 2013 and December 2017. Children were dichotomized based on referral frequency, specifically once only or more than once (re-referred). Data were retrieved from standardized referral forms and patient registries. Analyses included logistic regression and generalized estimating equations models. RESULT: We analyzed data from 2745 children (47.2% female; mean age: 11.4 years; mean body mass index z score: 3.03) and 2705 physicians (60.2% female; 65.6% pediatricians). Overall, 300 (10.2%) children were re-referred with most (n = 276; 92.0%) being referred twice. Children were less likely to be re-referred if they were referred by a family physician (vs pediatrician) (aOR 0.62; 95% CI 0.46-0.84; P = .0018) or scheduled a clinic appointment following their index referral (aOR: 0.29; 95% CI 0.21-0.4; P < .001). Treatment initiation was higher in children who were referred once only (42.1%) vs their re-referred peers (18.0%; P < .0001); however, for children who were re-referred, they were more likely to initiate treatment following their second referral (aOR 2.3; 95% CI 1.22-4.31; P = .01). This improvement was not sustained on subsequent referrals (aOR 0.44; 95% CI 0.17-1.12; P = .08). CONCLUSIONS: Few children were re-referred for pediatric obesity management; however, for those children who were re-referred, being re-referred once only increased the likelihood of treatment initiation.

The influence of comorbidities on achieving an N-terminal pro-b-type natriuretic peptide target: a secondary analysis of the GUIDE-IT trial.

AIMS: N-terminal pro-b-type natriuretic peptide (NT-proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT-proBNP targets and clinical outcomes. METHODS: A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment trial. NT-proBNP was analysed every 3 months. RESULTS: Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43-76], and median BMI was 29 kg/m2 (IQR 25-34). Patients with AF, eGFR < 60 mL/min/1.73 m2 , or a BMI < 29 kg/m2 had a higher level of NT-proBNP at randomization and over all study visits (all P values < 0.001). Over 18 months, the rate of change of NT-proBNP was less for patients with AF (compared with those without AF, P = 0.037) and patients with an eGFR < 60 mL/min/1.73 m2 (compared with eGFR > 60 mL/min/1.73 m2 , P < 0.001). The rate of change of NT-proBNP was similar for patients with a BMI above or below the median value. Using the 90 day NT-proBNP, patients with AF, lower eGFR, or lower BMI were less likely to achieve the target NT-proBNP < 1000 pg/mL than patients without AF, higher eGFR, or higher BMI, respectively. None of these differed between the Usual Care or Guided Care arm for AF, eGFR, or BMI (Pinteractions all NS). CONCLUSIONS: Patients with AF, a lower BMI, or worse renal function are less likely to achieve a lower or target NT-proBNP. Clinicians should be aware of these factors both when interpreting NT-proBNP levels and making therapeutic decisions about heart failure therapies.

Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial.

BACKGROUND: Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death. METHODS: This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data. RESULTS: Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety. INTERPRETATION: There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04329611.

Is There Any Interaction Between Sex and Renal Function Change During Hospital Stay in Patients Hospitalized With Acute Heart Failure?

BACKGROUND: Renal dysfunction is a strong predictor of outcomes in patients with acute heart failure (AHF). However, less is known about how sex may influence the prognostic import of renal function in AHF. METHODS AND RESULTS: In a post hoc analysis of the ASCEND-HF trial including 5377 patients with AHF (33% female), patients were categorized into 3 groups based on the changes in renal function during their hospital stay. Worsening, stable, and improving renal functions were defined as a ≥20% decrease, a <20% change, and a ≥20% increase in the estimated glomerular filtration rate, respectively. The primary outcome was the composite of 30-day all-cause mortality or HF rehospitalization. The median baseline and discharge estimated glomerular filtration rate were 58.4 and 56.9 mL/min/1.73 m2, respectively. Worsening, stable, and improving renal function was observed in 31.9%, 63.2, and 4.9% of patients, respectively. Worsening renal function was associated with adverse outcomes at 30 days (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.22-1.76). This association existed in both males and females (aHR 1.42 and aHR 1.56, respectively, both P < .01). There was an interaction between renal function changes and sex (P = .025), because improving renal function was associated with better outcomes in men (aHR 0.29, 95% CI 0.13-0.66) as compared with women (aHR 1.18, 95% CI 0.59-2.35). There was no interaction between the ejection fraction and renal function in association with subsequent outcomes. CONCLUSIONS: Irrespective of sex, worsening renal function was associated with poorer outcomes at 30 days in patients with AHF. More studies are warranted to further delineate the possible sex differences in this setting.

Physician-related predictors of referral for multidisciplinary paediatric obesity management: a population-based study.

BACKGROUND: It is recommended that primary care-based physicians refer children with overweight and obesity to multidisciplinary paediatric obesity management, which can help to improve weight and health. OBJECTIVE: To determine predictors of referral to multidisciplinary paediatric obesity management. METHODS: This retrospective, population-level study included physicians who could refer 2-17 years old with a body mass index ≥85th percentile to one of three multidisciplinary paediatric obesity management clinics in Alberta, Canada. Physician demographic and procedural data were obtained from Practitioner Claims and Provider Registry maintained by Alberta Health from January 2014 to December 2017. Physician characteristics were compared based on whether they did or did not refer children for obesity management. Univariable and multivariable logistic regression models analysed associations between physician characteristics and referral making. RESULTS: Of the 3863 physicians (3468 family physicians, 395 paediatricians; 56% male; 49.3 ± 12.2 years old; 22.3 ± 12.6 years since graduation) practicing during the study period, 1358 (35.2%) referred at least one child for multidisciplinary paediatric obesity management. Multivariable regression revealed that female physicians (versus males) [odds ratio (OR): 1.68, 95% confidence interval (CI): 1.46-1.93; P < 0.0001], paediatricians (versus family physicians) (OR: 4.89, 95% CI: 3.85-6.21; P < 0.0001) and urban-based physicians (versus non-urban-based physicians) (OR: 2.17, 95% CI: 1.79-2.65; P < 0.0001) were more likely to refer children for multidisciplinary paediatric obesity management. CONCLUSIONS: Approximately one-third of family physicians and paediatricians referred children for multidisciplinary paediatric obesity management. Strategies are needed to improve referral practices for managing paediatric obesity, especially among male physicians, family physicians and non-urban-based physicians as they were less likely to refer children.

Paediatric overweight and obesity impact one-third of children in Canada and the USA. It is recommended that physicians refer children with overweight and obesity to paediatric obesity management, which can help to improve their weight and health. While referral practices of US physicians have been well characterized, Canadian evidence remains limited. To address this gap, we examined predictors of referral making for paediatric obesity management. Our study included physicians (family physicians and paediatricians) who could refer 2­17 years old with overweight and obesity to three paediatric weight management clinics in Alberta, Canada between January 2014 and December 2017. Descriptive analyses and regression models were performed. Of the 3863 physicians practicing during the study period, 1358 (35.2%) referred at least one child for paediatric obesity management. Referring physicians were more likely to be female, paediatricians and practicing in urban-based clinics. Additional research is needed to explore physicians' decisions to refer children for obesity management, which can inform interventions to enhance referral, and ultimately, improve the health and well-being of children with obesity.

The Prevalence and Severity of Chronic Pain in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic pain is a common and distressing symptom reported by patients with chronic kidney disease (CKD). Clinical practice and research in this area do not appear to be advancing sufficiently to address the issue of chronic pain management in patients with CKD. OBJECTIVES: To determine the prevalence and severity of chronic pain in patients with CKD. DESIGN: Systematic review and meta-analysis. SETTING: Interventional and observational studies presenting data from 2000 or later. Exclusion criteria included acute kidney injury or studies that limited the study population to a specific cause, symptom, and/or comorbidity. PATIENTS: Adults with glomerular filtration rate (GFR) category 3 to 5 CKD including dialysis patients and those managed conservatively without dialysis. MEASUREMENTS: Data extracted included title, first author, design, country, year of data collection, publication year, mean age, stage of CKD, prevalence of pain, and severity of pain. METHODS: Databases searched included MEDLINE, CINAHL, EMBASE, and Cochrane Library, last searched on February 3, 2020. Two reviewers independently screened all titles and abstracts, assessed potentially relevant articles, and extracted data. We estimated pooled prevalence of overall chronic pain, musculoskeletal pain, bone/joint pain, muscle pain/soreness, and neuropathic pain and the I 2 statistic was computed to measure heterogeneity. Random effects models were used to account for variations in study design and sample populations and a double arcsine transformation was used in the model calculations to account for potential overweighting of studies reporting either very high or very low prevalence measurements. Pain severity scores were calibrated to a score out of 10, to compare across studies. Weighted mean severity scores and 95% confidence intervals were reported. RESULTS: Sixty-eight studies representing 16 558 patients from 26 countries were included. The mean prevalence of chronic pain in hemodialysis patients was 60.5%, and the mean prevalence of moderate or severe pain was 43.6%. Although limited, pain prevalence data for peritoneal dialysis patients (35.9%), those managed conservatively without dialysis (59.8%), those following withdrawal of dialysis (39.2%), and patients with earlier GFR category of CKD (61.2%) suggest similarly high prevalence rates. LIMITATIONS: Studies lacked a consistent approach to defining the chronicity and nature of pain. There was also variability in the measures used to determine pain severity, limiting the ability to compare findings across populations. Furthermore, most studies reported mean severity scores for the entire cohort, rather than reporting the prevalence (numerator and denominator) for each of the pain severity categories (mild, moderate, and severe). Mean severity scores for a population do not allow for "responder analyses" nor allow for an understanding of clinically relevant pain. CONCLUSIONS: Chronic pain is common and often severe across diverse CKD populations providing a strong imperative to establish chronic pain management as a clinical and research priority. Future research needs to move toward a better understanding of the determinants of chronic pain and to evaluating the effectiveness of pain management strategies with particular attention to the patient outcomes such as overall symptom burden, physical function, and quality of life. The current variability in the outcome measures used to assess pain limits the ability to pool data or make comparisons among studies, which will hinder future evaluations of the efficacy and effectiveness of treatments. Recommendations for measuring and reporting pain in future CKD studies are provided. TRIAL REGISTRATION: PROSPERO Registration number CRD42020166965.

CONTEXTE: La douleur chronique est un symptôme affligeant fréquemment rapporté par les patients atteints d'insuffisance rénale chronique (IRC). Pourtant, la recherche et la pratique clinique dans ce domaine ne semblent pas progresser suffisamment pour aborder sa gestion dans cette population. OBJECTIF: Déterminer la prévalence et l'intensité de la douleur chronique chez les patients atteints d'IRC. TYPE D'ÉTUDE: Revue systématique et méta-analyse. SOURCES: Les études observationnelles et interventionnelles présentant des données depuis l'an 2000. Ont été exclus les cas d'insuffisance rénale aigüe et les études portant sur une population ayant une cause, un symptôme ou une maladie concomitante en particulier. SUJETS: Des adultes atteints d'IRC de stade 3 à 5, y compris des patients dialysés et des patients non dialysés pris en charge de façon conservatrice. MESURES: Les données extraites comprenaient le titre de l'article, le nom de l'auteur principal, le type d'étude, le pays où s'est tenue l'étude, l'année de collection des données, l'année de publication, l'âge médian des sujets, le stade de l'IRC, la prévalence de la douleur et son intensité. MÉTHODOLOGIE: Les données ont été colligées dans MEDLINE, CINAHL, EMBASE et la bibliothèque Cochrane. La dernière consultation date du 3 février 2020. Deux examinateurs ont, de façon indépendante, trié les titres et les abrégés, évalué les articles potentiellement pertinents et extrait les données. La prévalence combinée de la douleur chronique globale, de la douleur musculo-squelettique, de la douleur osseuse/articulaire, de la douleur musculaire et de la douleur neuropathique a été évaluée, et le calcul de la statistique I 2 a servi à mesurer l'hétérogénéité. Des modèles à effets aléatoires ont été employés pour tenir compte des variations selon le type d'étude et les populations échantillonnées. Les calculs de ces modèles ont subi une double transformation arc-sinus pour tenir compte d'une potentielle surpondération des études comportant des mesures de prévalence très importantes ou très faibles. Pour fins de comparaison, les scores d'intensité de la douleur ont été étalonnés à un score sur 10. Des scores d'intensité moyenne pondérée et des intervalles de confiance à 95 % ont été mentionnés. RÉSULTATS: Soixante-huit études ont été incluses, lesquelles portaient sur un total de 16 558 patients dans 26 pays. La prévalence moyenne de la douleur chronique chez les patients hémodialysés était de 60,5 %; la prévalence moyenne de la douleur modérée ou sévère était de 43,6 %. Quoique limitées, les données portant sur des patients sous dialyse péritonéale (35,9 %), des patients suivant des traitements conservateurs sans dialyse (59,8 %), des patients ayant arrêté la dialyse (39,2 %) ou des patients atteints d'un stade inférieur d'IRC (61,2 %) suggèrent une prévalence tout aussi élevée. LIMITES: Les études incluses manquaient de cohérence dans leur approche pour définir la chronicité et la nature de la douleur. Les mesures utilisées pour déterminer l'intensité de la douleur étaient variables, ce qui a limité la comparaison des résultats entre les populations. La plupart des études indiquaient des scores moyens d'intensité pour l'ensemble de la cohorte plutôt que la prévalence (numérateur et dénominateur) de chacune des catégories d'intensité (légère, modérée et sévère). Les scores moyens d'intensité pour une population ne permettent pas « les analyses de répondants ¼ et la compréhension de la douleur cliniquement pertinente. CONCLUSION: La douleur chronique est fréquente et souvent intense dans les diverses populations de patients atteints d'IRC, ce qui confirme la gestion de la douleur chronique comme priorité clinique et de recherche. Les recherches futures devraient permettre une meilleure compréhension des déterminants de la douleur chronique et évaluer l'efficacité des stratégies de gestion de la douleur en accordant une attention particulière aux résultats des patients, notamment au fardeau global des symptômes, à la fonction physique et à la qualité de vie. La capacité de regrouper des données ou de faire des comparaisons entre les études est limitée par la variabilité actuelle des mesures utilisées pour évaluer la douleur, ce qui entravera les futures évaluations de l'efficacité des traitements. Des recommandations pour mesurer et signaler la douleur dans les futures études sur l'IRC sont fournies.

Association between Respiratory Failure and Clinical Outcomes in Patients with Acute Heart Failure: Analysis of 5 Pooled Clinical Trials.

BACKGROUND: Despite a temporal increase in respiratory failure in patients hospitalized with acute heart failure (HF), clinical trials have largely not reported the incidence or associated clinical outcomes for patients requiring mechanical ventilation. METHODS AND RESULTS: After pooling 5 acute HF clinical trials, we used multivariable logistic regression adjusted for demographics, comorbidities, examinations, and laboratory findings to assess associations between mechanical ventilation and clinical outcomes. Among the 8296 patients, 210 (2.5%) required mechanical ventilation. Age, sex, smoking history, baseline ejection fraction, HF etiology, and the proportion of patients randomized to treatment or placebo in the original clinical trial were similar between groups (all, P > 0.05). Baseline diabetes mellitus was more common in the mechanical ventilation group (P = 0.02), but other comorbidities, including chronic lung disease, were otherwise similar (all P > 0.05). HF rehospitalization at 30 days (12.7% vs 6.6%, P < 0.001) and all-cause 60-day mortality (33.3% vs 6.1%, P < 0.001) was higher among patients requiring mechanical ventilation. After multivariable adjustment, mechanical ventilation use was associated with an increased 30-day HF rehospitalization (odds ratio 2.03; 95% confidence interval, 1.29-3.21, P = 0.002), 30-day mortality (odds ratio 10.40; 95% confidence interval, 7.22-14.98, P < 0.001), and 60-day mortality (odds ratio 7.68; 95% confidence interval, 5.50-10.74, P < 0.001). The influence of mechanical ventilation did not differ by HF etiology or baseline ejection fraction (both, interaction P > 0.20). CONCLUSIONS: Respiratory failure during an index hospitalization for acute HF was associated with increased rehospitalization and all-cause mortality. The development of respiratory failure during an acute HF admission identifies a particularly vulnerable population, which should be identified for closer monitoring.

Analgesic Use in Patients With Advanced Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Pain is common in patients with chronic kidney disease (CKD). Analgesics may be appropriate for some CKD patients. OBJECTIVES: To determine the prevalence of overall analgesic use and the use of different types of analgesics including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), adjuvants, and opioids in patients with CKD. DESIGN: Systematic review and meta-analysis. SETTING: Interventional and observational studies presenting data from 2000 or later. Exclusion criteria included acute kidney injury or studies that limited the study population to a specific cause, symptom, and/or comorbidity. PATIENTS: Adults with stage 3-5 CKD including dialysis patients and those managed conservatively without dialysis. MEASUREMENTS: Data extracted included title, first author, design, country, year of data collection, publication year, mean age, stage of CKD, prevalence of analgesic use, and the types of analgesics prescribed. METHODS: Databases searched included MEDLINE, CINAHL, EMBASE, and Cochrane Library. Two reviewers independently screened all titles and abstracts, assessed potentially relevant articles, and extracted data. We estimated pooled prevalence of analgesic use and the I 2 statistic was computed to measure heterogeneity. Random-effects models were used to account for variations in study design and sample populations, and a double arcsine transformation of the prevalence variables was used to accommodate potential overweighting of studies with very large or very small prevalence measurements. Sensitivity analyses were performed to determine the magnitude of publication bias and assess possible sources of heterogeneity. RESULTS: Forty studies were included in the analysis. The prevalence of overall analgesic use in the random-effects model was 50.8%. The prevalence of acetaminophen, NSAIDs, and adjuvant use was 27.5%, 17.2%, and 23.4%, respectively, while the prevalence of opioid use was 23.8%. Due to the possibility of publication bias, the actual prevalence of acetaminophen use in patients with advanced CKD may be substantially lower than this meta-analysis indicates. A trim-and-fill analysis decreased the pooled prevalence estimate of acetaminophen use to 5.4%. The prevalence rate for opioid use was highly influenced by 2 large US studies. When these were removed, the estimated prevalence decreased to 17.3%. LIMITATIONS: There was a lack of detailed information regarding the analgesic regimen (such as specific analgesics used within each class and inconsistent accounting for patients on multiple drugs and the use of over-the-counter analgesics such as acetaminophen and NSAIDs), patient characteristics, type of pain being treated, and the outcomes of treatment. Data on adjuvant use were very limited. These results, therefore, must be interpreted with caution. CONCLUSIONS: There was tremendous variability in the prescribing patterns of both nonopioid and opioid analgesics within and between countries suggesting widespread uncertainty about the optimal pharmacological approach to treating pain. Further research that incorporates robust reporting of analgesic regimens and links prescribing patterns to clinical outcomes is needed to guide optimal clinical practice.

CONTEXTE: La douleur est fréquente chez les patients atteints d'insuffisance rénale chronique (IRC). La prise d'analgésiques peut être nécessaire chez certains patients atteints d'IRC. OBJECTIFS: Établir la prévalence globale de la prise d'analgésiques chez les patients atteints d'IRC puis de la consommation des différents types d'analgésiques (acétaminophène, anti-inflammatoires non stéroïdiens [AINS], adjuvants, opioïdes). TYPE D'ÉTUDE: Revue systématique et méta-analyse. CADRE: Les études observationnelles et interventionnelles présentant des données depuis l'an 2000. Ont été exclus les cas d'insuffisance rénale aigüe et les études portant sur une population, une cause, un symptôme ou une comorbidité en particulier. SUJETS: Des adultes atteints d'IRC de stade 3 à 5, incluant des patients dialysés et des patients non dialysés pris en charge de façon conservatrice. MESURES: Le titre de l'article, le nom de l'auteur principal, le type d'étude, le pays où s'est tenue l'étude, l'année de collection des données, l'année de publication, l'âge médian des sujets, le stade de l'IRC, la prévalence de la prise d'analgésiques et les types d'analgésiques prescrits. MÉTHODOLOGIE: Les données ont été colligées dans MEDLINE, CINAHL, EMBASE et la bibliothèque Cochrane. Deux examinateurs ont trié les titres et les abrégés, évalué les articles potentiellement pertinents et extrait les données de façon indépendante. La prévalence combinée de la prise d'analgésiques a été évaluée et la statistique I 2 a été calculée pour mesurer l'hétérogénéité. Des modèles à effets aléatoires ont été employés pour tenir compte des variations entre les différents types d'études et de populations échantillonnées. Les variables de prévalence ont subi une double transformation arc-sinus pour tenir compte d'une potentielle surpondération des études comportant des mesures de prévalence très importantes ou très faibles. Des analyses de sensibilité ont été effectuées pour mesurer l'ampleur des biais de publication et évaluer de possibles sources d'hétérogénéité. RÉSULTATS: L'analyse porte sur un total de 40 études. Dans les modèles à effets aléatoires, la prévalence globale de prise d'analgésiques était de 50,8 %. Quant à la prévalence selon le type d'analgésique elle s'établissait à 27,5 % pour l'acétaminophène, à 17,2 % pour les AINS, à 23,4 % pour les adjuvants et à 23,8 % pour les opioïdes. Chez les patients atteints d'IRC de stade avancé, de possibles de biais de publication font en sorte que la prévalence réelle de l'acétaminophène pourrait s'avérer nettement inférieure à ce qu'indique cette méta-analyse. Une analyse par la méthode « trim and fill ¼ a réduit à 5,4 % la prévalence groupée estimée pour la prise d'acétaminophène. Le taux de prévalence pour la prise d'opioïdes était fortement influencé par deux vastes études américaines; en les retirant de l'analyse, la prévalence estimée passait à 17,3 %. LIMITES: Ces résultats doivent être interprétés avec prudence puisque des informations détaillées manquaient sur le schéma posologique (analgésiques particuliers utilisés dans chaque classe, comptabilisation incohérente pour les patients prenant plusieurs médicaments, prise d'analgésiques en vente libre tels que l'acétaminophène et les AINS), les caractéristiques des patients, les types de douleurs traitées et les résultats des traitements. De plus, les données sur la prise d'adjuvants étaient très limitées. CONCLUSION: Une très grande variabilité a été observée dans les profils de prescription tant pour les analgésiques opioïdes que pour les non-opioïdes. Une variabilité qui s'observe aussi tant dans un même pays qu'entre les différents pays, ce qui suggère une incertitude généralisée quant à la meilleure approche pharmacologique dans le traitement de la douleur. D'autres recherches intégrant une description rigoureuse du schéma posologique et reliant les profils de prescription aux résultats cliniques sont nécessaires pour guider l'optimisation des pratiques cliniques.