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Objectives were to describe any bothersome symptom and severely bothersome symptoms in inpatient children with cancer and hematopoietic stem cell transplant (HSCT) recipients. We included children 8–18 years of age with cancer or HSCT recipients who were receiving active treatment for cancer, admitted to hospital, and expected to be in hospital 3 days later. We administered the self‐report Symptom Screening in Pediatrics Tool (SSPedi). We described those who identified any degree of symptom bother (at least “a little”) and those who rated the degree of bother as severe (“a lot” or “extremely”). Factors associated with severe symptoms and total SSPedi scores were examined using multiple logistic and linear regression. Among the 302 patients, 298 (98.7%) reported having any bothersome symptom and 181 (59.9%) had at least one severely bothersome symptom. In multiple regression, older children were significantly more likely to have at least one severely bothersome symptom (15–18 and 11–14 years vs. 8–10 years; P = 0.008) and to have higher total SSPedi scores (P = 0.0003). Those with relapsed disease were more likely to have at least one severely bothersome symptom (odds ratio 2.1, 95% confidence interval 1.1–4.3; P = 0.037) and HSCT recipients were more likely to have higher symptom scores (β = 3.48, standard error = 1.6; P = 0.030). Almost all children receiving cancer therapies experience bothersome symptoms and 60% have at least one severely bothersome symptom. Older children experienced more severely bothersome symptoms and higher symptom scores. Future studies should follow children longitudinally to better understand the symptom trajectory and should institute interventions to manage symptoms.

Rationale: Diaphragm dysfunction worsens outcomes in mechanically ventilated patients, but the clinical impact of potentially preventable changes in diaphragm structure and function caused by mechanical ventilation is unknown.Objectives: To determine whether diaphragm atrophy developing during mechanical ventilation leads to prolonged ventilation.Methods: Diaphragm thickness was measured daily by ultrasound in adults requiring invasive mechanical ventilation; inspiratory effort was assessed by thickening fraction. The primary outcome was time to liberation from ventilation. Secondary outcomes included complications (reintubation, tracheostomy, prolonged ventilation, or death). Associations were adjusted for age, severity of illness, sepsis, sedation, neuromuscular blockade, and comorbidity.Measurements and Main Results: Of 211 patients enrolled, 191 had two or more diaphragm thickness measurements. Thickness decreased more than 10% in 78 patients (41%) by median Day 4 (interquartile range, 3–5). Developme...

Background The objective was to evaluate the reliability and validity of the self-report Symptom Screening in Pediatrics Tool (SSPedi) from the perspective of children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Methods In this multicenter study, respondents were children age eight to 18 years who had cancer or had received HSCT, and their parents. Two different child respondent populations were targeted. More symptomatic respondents were receiving active treatment for cancer, admitted to the hospital, and expected to be in the hospital three days later. Less symptomatic respondents were in maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Children completed SSPedi and then responded to validated self-report measures of mucositis, nausea, pain, and global quality of life. Children in the more symptomatic group repeated SSPedi and a global symptom change scale three days later. Parent proxy-report was optional. Reliability was evaluated using intraclass correlations while convergent validity was evaluated using Spearman correlations. Results Of 502 children enrolled, 302 were in the more symptomatic group and 200 were in the less symptomatic group. Intraclass correlation coefficients were 0.88 (95% confidence interval [CI] = 0.82 to 0.92) for test-retest reliability and 0.76 (95% CI = 0.71 to 0.80) for inter-rater reliability. The mean difference in SSPedi scores between more and less symptomatic groups was 7.8 (95% CI = 6.4 to 9.2). SSPedi was responsive to change in global symptoms. All hypothesized relationships among measures were observed. Conclusions SSPedi is a self-report symptom bother tool for children with cancer and HSCT recipients that is reliable, valid, and responsive to change. SSPedi can be used for clinical and research purposes. Future work should focus on integration into care delivery.

BACKGROUND Strategies to improve bone health care in men receiving androgen deprivation therapy (ADT) are not consistently implemented. The authors conducted a phase 2 randomized controlled trial of 2 education-based models-of-care interventions to determine their feasibility and ability to improve bone health care. METHODS A single-center parallel-group randomized controlled trial of men with prostate cancer who were receiving ADT was performed. Participants were randomized 1:1:1 to 1) a patient bone health pamphlet and brief recommendations for their family physician (BHP+FP); 2) a BHP and support from a bone health care coordinator (BHP+BHCC); or 3) usual care. The primary efficacy outcome was receipt of a bone mineral density (BMD) test within 6 months. Secondary efficacy outcomes included guideline-appropriate calcium and vitamin D use and bisphosphonate prescriptions for men at high fracture risk. Feasibility endpoints included recruitment, retention, satisfaction, contamination, and outcome capture. The main analysis used logistic regression with a 1-sided P of .10. The trial is registered at ClinicalTrials.gov (identifier NCT02043236). RESULTS A total of 119 men were recruited. The BHP+BHCC strategy was associated with a greater percentage of men undergoing a BMD test compared with the usual-care group (78% vs 36%; P

Objectives We conducted a meta-analysis to summarize diagnostic properties of risk factors and clinical prediction rules for diagnosing infective endocarditis (IE) in Staphylococcus aureus bacteraemia (SAB). Methods We searched MEDLINE, Embase, and the Cochrane Database from inception to 6 January 2016 to identify studies evaluating risk factors and clinical prediction rules for IE in SAB patients. Pooled estimates of diagnostic properties for main risk factors were calculated using a bivariate random effects model. Results Of 962 articles identified, 30 studies were included. These involved 16 538 SAB patients including 1572 IE cases. Risk factors with positive likelihood ratio (PLR) greater than 5 included embolic events (PLR 12.7, 95% CI 9.2–17.7), pacemakers (PLR 9.7, 95% CI 3.7–21.2), history of previous IE (PLR 8.2, 95% CI 3.1–22.0), prosthetic valves (PLR 5.7, 95% CI 3.2–9.5), and intravenous drug use (PLR 5.2, 95% CI 3.8–6.9). The only clinical factor with negative likelihood ratio (NLR) less than 0.5 was documented clearance of bacteraemia within 72 hours (NLR range 0.32–0.35). Of the nine published clinical prediction rules for ruling out IE, five had an NLR below 0.1. Conclusions SAB patients with high-risk features (embolic events, pacemakers, prosthetic valves, previous IE, or intravenous drug use) should undergo a trans-esophageal echocardiography (TEE) for IE. Clinical prediction rules show promise in safely ruling out endocarditis, but require validation in future studies.

Study Objectives: In heart failure (HF), we observed two patterns of hyperpnea during Cheyne-Stokes respiration with central sleep apnea (CSR-CSA): a positive pattern where end-expiratory lung volume remains at or above functional residual capacity, and a negative pattern where it falls below functional residual capacity. We hypothesized the negative pattern is associated with worse HF. Methods: Patients with HF underwent polysomnography. During CSR-CSA, hyperpnea, apnea-hyperpnea cycle, and lung to finger circulation times (LFCT) were measured. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration and left ventricular ejection fraction (LVEF) were assessed. Results: Of 33 patients with CSR-CSA (31 men, mean age 68 years), 9 had a negative hyperpnea pattern. There was no difference in age, body mass index, and apnea-hypopnea index between groups. Patients with a negative pattern had longer hyperpnea time (39.5 ± 6.4 versus 25.8 ± 5.9 seconds, P < .01), longer cycle time (67.8 ± 15.9 versus 51.7 ± 9.9 seconds, P < .01), higher NT-proBNP concentrations (2740 [6769] versus 570 [864] pg/ml, P = .01), and worse New York Heart Association class (P = .02) than those with a positive pattern. LFCT and LVEF did not differ between groups. Conclusions: Patients with HF and a negative CSR-CSA pattern have evidence of worse cardiac function than those with a positive pattern. Greater positive expiratory pressure during hyperpnea is likely generated during the negative pattern and might support stroke volume in patients with worse cardiac function. Commentary: A commentary on this article appears in this issue on page 1227. Clinical Trial Registration: The trial is registered with Current Controlled Trials (www.controlled-trials.com; ISRCTN67500535) and Clinical Trials (www. clinicaltrials.gov; NCT01128816).

ObjectiveTo compare inhospital mortality of general internal medicine (GIM) patients bedspaced to off-service wards with GIM inpatients admitted to assigned GIM wards.MethodA retrospective cohort study of consecutive GIM admissions between 1 January 2015 and 1 January 2016 was conducted at a large tertiary care hospital in Canada.Inhospital mortality was compared between patients admitted to off-service wards (bedspaced) and assigned GIM wards using a Cox proportional hazards model and a competing risk model. Sensitivity analyses included propensity score and pair matching based on GIM service team, workload, demographics, time of admission, reasons for admission and comorbidities.ResultsAmong 3243 consecutive GIM admissions, more than a third (1125, 35%) were bedspaced to off-service wards with the rest (2118, 65%) admitted to assigned GIM wards. In hospital, 176 (5%) patients died: 88/1125 (8%) bedspaced patients and 88/2118 (4%) assigned GIM ward patients. Compared with assigned GIM wards patients, bedspaced patients had an HR of 3.42 (95% CI 2.23 to 5.26; PConclusionsBedspaced patients had significantly higher inhospital mortality than patients admitted to assigned GIM wards. The risk was highest at admission and subsequently declined. The results of this single centre study may not be generalisable to other hospitals and may be influenced by residual confounding. Despite these limitations, the relationship between bedspacing and patient outcomes requires investigation at other institutions to determine if this common practice represents a modifiable patient safety indicator.

Contrast-enhanced magnetic resonance imaging (MRI) remains the most comprehensive modality to assess juvenile idiopathic arthritis (JIA)-related inflammation and osteochondral damage in the temporomandibular joints (TMJ). This study tested the reliability of a new JIA MRI scoring system for TMJ (JAMRIS-TMJ) and the impact of variations in calibration and reader specialty. Thirty-one MRI exams of bilateral TMJs were scored independently using the JAMRIS-TMJ by 20 readers consisting of radiologists and non-radiologist clinicians in three reading groups, with or without a calibrating atlas and/or tutorial. The inter-reader reliability in the multidisciplinary cohort assessed by the generalizability coefficient was 0.61–0.67 for the inflammatory and 0.66–0.74 for the damage domain. The atlas and tutorial did not improve agreement within radiologists, but improved the agreement between radiologist and non-radiologist groups. Agreements between different calibration levels were 0.02 to 0.08 lower by the generalizability coefficient compared to agreement within calibration levels, agreement between specialty groups was 0.04 to 0.10 lower than within specialty groups. Averaging two radiologists raised the reliability above 0.8 for both domains. Therefore, the reliability of JAMRIS-TMJ was moderate-to-good depending on the presence of specialty and calibration differences. The atlas and tutorial are necessary to improve reliability when the reader cohort consists of multiple specialties.

Introduction: Transcranial Doppler (TCD) screening data from Uganda, Tanzania, and Nigeria have documented elevated velocities in >20% of children with sickle cell anemia (SCA) not receiving hydroxyurea treatment. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has demonstrated the safety, feasibility, and benefits of hydroxyurea for children with SCA living in sub-Saharan Africa, especially when escalated to maximum tolerated dose (MTD). Whether hydroxyurea also confers protection against stroke risk in this setting remains unproven, though hydroxyurea-associated increases in hemoglobin and fetal hemoglobin, plus decreases in TCD arterial flow velocities, should lower the risk of both primary and secondary stroke. The availability of TCD equipment and appropriately trained and certified TCD examiners to perform this non-invasive and inexpensive procedure is an important limitation in low-resource settings. Methods: REACH teams in Angola, Democratic Republic of Congo, Kenya, and Uganda identified two local persons at each site to receive formal TCD training and certification from two experienced and certified super-users, one from Uganda and one from the US. Initial training included hands-on teaching at each site by the Ugandan trainer, followed by didactic teaching and hands-on examinations at a central African location with both trainers and all four REACH teams. Follow-up training included monthly web-based teaching sessions of TCD technique and discussion of centrally reviewed exams. Each local examiner had at least 30 completed examinations reviewed, critiqued, and discussed together with the trainers before becoming formally certified as a REACH TCD examiner. After certification, all REACH participants taking hydroxyurea at a stable dose were eligible for TCD using a standardized protocol with identical Sonara/tek advanced non-imaging TCD ultrasound units with 2MHz probes and version 7 software (Natus, Middleton, WI). Time-averaged maximum velocities (TAMV) were measured in the middle cerebral artery, distal internal carotid artery, and the bifurcation. The highest TAMV was recorded and categorized as normal ( Results: Between November 2018 and March 2020, a total of 481 children in REACH received TCD screening; the average age was 9.3 ± 2.6 years, on hydroxyurea for 43 ± 8 months at an average dose of 23.5 ± 5.0 mg/kg/day with good response (Hb = 8.4 ± 1.3 g/dL, HbF = 23.9 ± 5.0%). There were 16 (3.3%) inadequate exams, defined as no vessel flow in either hemisphere; 5 inadequate exams were in children with prior stroke at hydroxyurea initiation and 1 with stroke on treatment. Of 465 adequate exams, the overall median TAMV was 128 cm/sec (IQR 25 cm/sec) with 449 normal velocities (96.6% overall, range by site 95.1-99.2%), 16 conditional velocities (3.4% overall, range by site 2.3-4.9%), and no abnormal velocities. In univariate analysis, maximum TAMV was inversely correlated with hemoglobin (r = -0.29, p Conclusions: Robust TCD screening capability was developed in REACH with detailed training, certification, and oversight of local personnel, most of whom had no prior experience. Compared to untreated children, very few REACH participants had elevated TAMV velocities, confirming that hydroxyurea lowers TCD velocities and reduces stroke risk for children with SCA in sub-Saharan Africa. The observed associations between TAMV and both hemoglobin and fetal hemoglobin document the importance of escalating hydroxyurea to achieve and maintain an optimized dose. In low-resource settings, TCD screening efforts by trained and certified examiners should be aligned with hydroxyurea treatment protocols that feature dose escalation, to provide a feasible and effective stroke prevention program. TCD screening of African children with SCA will allow early identification of stroke risk and optimized hydroxyurea dosing, thereby reducing morbidity and mortality in this vulnerable population. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; National Institute of Nursing Research: Research Funding.

Introduction: Hydroxyurea is a potent therapeutic agent for sickle cell anemia (SCA), and treatment at maximum tolerated dose (MTD) is becoming the standard of care. Hydroxyurea exerts its disease-modifying effects primarily through induction of fetal hemoglobin (HbF), although the cellular and molecular mechanisms by which hydroxyurea increases HbF expression remain unclear. Children with SCA treated with hydroxyurea at MTD have substantial phenotypic variation, however, as some have higher HbF responses than others. We hypothesized that unknown quantitative trait loci modulate the pharmacological induction of HbF, so we performed a large genome wide association study (GWAS) of hydroxyurea-associated HbF responses for children with SCA treated prospectively with dose escalation to MTD. Methods: We analyzed genomic DNA from 831 children with SCA enrolled in pediatric research trials from the US (HUSTLE, SWiTCH, TWiTCH), the Caribbean (EXTEND, SACRED) and sub-Saharan Africa (REACH, NOHARM); all of these trials reported robust treatment responses with average HbF >20%. Study participants received hydroxyurea with dose escalation to MTD based on mild myelosuppression. Whole blood DNA was genotyped using the H3Africa SNP array (Illumina) with whole exome sequencing (WES) using NimbleGen VCRome 2.1 capture reagents and the Illumina HiSeq2500 platform. A transformed z-score for each study cohort gave a standardized measure of HbF induction relative to their steady-state level and their treatment HbF level at MTD. These standardized z-score HbF values were then used as a continuous variable for association testing using single-locus mixed model (EMMAX) adjusted for population stratification, using age, hydroxyurea dose at MTD, and sex as co-variates. We first performed an initial GWAS discovery using hydroxyurea response data from four distinct African populations (n=377). Single nucleotide variants (SNVs) with nominal significance (p Results: In the discovery GWAS step, no variant passed genome wide significance (p Conclusions: This large GWAS using global cohorts of children with SCA and robust prospective HbF phenotype data has identified genetic predictors of HbF hydroxyurea treatment responses. Three novel genetic loci, PTPRD, RPH3AL, and ELL2 have SNVs associated with lower HbF responses. PTPRD is a protein tyrosine phosphatase receptor involved in cellular processes such as cell growth and differentiation, while RPH3AL, a rabphilin 3A like protein, is known to be involved in calcium-ion-dependent exocytosis. ELL2 is an elongation factor for RNA polymerase II and could modify RNA processing under the cytostatic effects of hydroxyurea. These genes and variants will be investigated to determine how they impact individual HbF responses to hydroxyurea treatment. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding.

Quantifying the contribution of rheumatoid arthritis to the acquisition of subsequent health care costs is an emerging focus of the rheumatologic community and payers of health care. Our objective was to determine the healthcare costs before and after diagnosis of rheumatoid arthritis (RA) from the public payer’s perspective. The study design was a longitudinal observational administrative data-based cohort with RA cases from Ontario Canada (n = 104,933) and two control groups, matched 1:1 on year of cohort entry from 2001 to 2016. The first control group was matched on age, sex and calendar year of cohort entry (diagnosis year for those with RA); the second group added medical history to the match before RA diagnosis year. The main exposure was new onset RA. The secondary exposure was calendar year of RA diagnosis to compare attributable costs over the study observation window. Main outcomes were health care costs in 2015 Canadian dollars, overall and by cost category. We used attribution methods to classify costs into those associated with RA, those associated with comorbidities, and age/sex-related underlying costs. Health care costs associated with RA increased up to the year of diagnosis, where they reached $8,591: $4,142 in RA associated costs; $1,242 in RA comorbidity associated costs; and $3,207 in underlying costs. In the eighth-year post diagnosis, the RA costs declined to $2,567 while the RA comorbidity associated costs remained relatively constant at $1,142, and the underlying age/sex related cost increased to $4,426. RA patients had lower costs when diagnosed in later calendar years. Our results suggest a large proportion of disease related health care costs are a result of costs associated with RA comorbidities, which may appear many years before diagnosis.

Chiropractic care is popular for low back pain, but may increase the risk for acute lumbar disc herniation (LDH). Low back pain is a common early (prodromal) symptom of LDH and commonly precedes LDH diagnosis. Our objective was to investigate the association between chiropractic care and acute LDH with early surgical intervention, and contrast this with the association between primary care physician (PCP) care and acute LDH with early surgery. Using a self-controlled case series design and population-based healthcare databases in Ontario, Canada, we investigated all adults with acute LDH requiring emergency department (ED) visit and early surgical intervention from April 1994 to December 2004. The relative incidence of acute LDH with early surgery in exposed periods after chiropractic visits relative to unexposed periods was estimated within individuals, and compared with the relative incidence of acute LDH with early surgery following PCP visits. 195 cases of acute LDH with early surgery (within 8 weeks) were identified in a population of more than 100 million person-years. Strong positive associations were found between acute LDH and both chiropractic and PCP visits. The risk for acute LDH with early surgery associated with chiropractic visits was no higher than the risk associated with PCP visits. Both chiropractic and primary medical care were associated with an increased risk for acute LDH requiring ED visit and early surgery. Our analysis suggests that patients with prodromal back pain from a developing disc herniation likely seek healthcare from both chiropractors and PCPs before full clinical expression of acute LDH. We found no evidence of excess risk for acute LDH with early surgery associated with chiropractic compared with primary medical care.

Over the past decade, the number of advertised tenure-track faculty positions in higher education institutions in the United States and abroad has steadily declined while the competition for these ...

Introduction Both types of sleep-disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo-ventilation (ASV) in such patients reduces morbidity and mortality. Aim ADVENT-HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF. Methods ADVENT-HF is a multicentre, multinational, randomized, parallel-group, open-label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea–hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all-cause mortality, cardiovascular hospital admissions, new-onset atrial fibrillation requiring anti-coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter-defibrillator not resulting in hospitalization during a maximum follow-up time of 5 years. Conclusion The ADVENT-HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality.

Background The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown. Methods We conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects. Results A total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N-acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11–0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01– 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06–0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05–0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death. Conclusion Moderate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention.

Background:Costing studies require long-term follow-up data ideally within a homogenous payment structure without multiple potential insurers. We examined trends in associated costs of rheumatoid arthritis from the public payer’s perspective over time.Objectives:The purpose of this study was to measure the population RA associated direct and indirect health care costs using statistical attribution methods among a population with identical health care coverage.Methods:The study was matched longitudinal study of patients with algorithm defined RA residing in Ontario Canada with an RA diagnosis from 2001-2016 (n=104,933). Cases were matched 1:1 during the year of first diagnosis to 2 distinct control groups without RA. Control group 1 were matched on year of birth, and sex (underlying costs). Control group 2 were matched on year of birth, sex, and medical history. Medical history was measured using The John Hopkins Expanded Diagnostic Clusters, a tool that categorizes people with similar conditions based upon their use of healthcare services (physician visits, hospitalizations, emergency department visits, ambulatory care). After matching, healthcare costs were reported in 2015 Canadian Dollars (CAD) overall and by cost sub-category by exposure group and calendar year before versus after RA diagnosis. RA-associated costs were measured as the difference in costs among RA patients and their corresponding matched comparators.Results:At the year of diagnosis, RA cases were predominantly female (70%, n=72,873), mean year of birth 1950, (SD=17.7, Range=1910-2000), with mean year of diagnosis 2006, (SD=6.3, Range=2001-2016). RA patients experienced inceased indirect cost acquisition compared to the direct costs of RA alone. The health care costs of RA patients were identical to age/sex/medical history matched controls yet rising up until 2 years before RA diagnosis where they diverged from age/sex/disease matched controls $3,585/ptyr compared to $3,352/ptyr. The costs of RA patients were highest $8,468 CAD/ptyr ($888,572,644 total) in the year of diagnosis declining to a steady state by 2 years post diagnosis $7,867/ptyr with a slight increase in costs by 8 years post diagnosis $8,035/ptyr in (Figure 1). Differences age/sex matched controls were detectable throughout the study time period even up to 19-years pre-diagnosis. In the year of diagnosis, the direct costs of RA were $4046/ptyr (8468-4422), while the indirect costs of RA were $1254/ptyr ($4422-$3168) and the underlying age-sex specific costs were $3,168/ptyr. Our analysis suggest that both the direct and inflammatory costs of RA are growing over time compared to matched controls (Figure 1) by year 8 the direct joint-related costs of RA were 2528 (8035-5507) the indirect costs were 1,144 (5507-4363) and the age/sex underlying costs were 4,363.Figure 1.Annual Per-Patient Total Health Care Costs Over Time Grouped by Exposure Before and After Rheumatoid Arthritis DiagnosisConclusion:The costs of RA have grown over time with medications representing a smaller than expected portion of total costs but a large increase in costs relative to matched controls. These results indicate that the direct costs of RA are decreasing over time compared to matched controls at 8 years post diagnosis and that over time, the indirect associated portion of costs remains almost constant, showing that over time the costs of indirectly related issues are becoming a larger proportion of total costs. Methodological advancements in costing attribution over time could contribute to understanding the patterns in health care resource usage among populations with chronic diseases.Disclosure of Interests:Mark Tatangelo: None declared, George Tomlinson: None declared, J Michael Paterson: None declared, Nick Bansback: None declared, Edward Keystone Grant/research support from: AbbVie; Amgen; Gilead Sciences, Inc; Lilly Pharmaceuticals; Merck; Pfizer Pharmaceuticals; PuraPharm; Sanofi, Consultant of: AbbVie; Amgen; AstraZeneca Pharma; Bristol-Myers Squibb Company; Celltrion; F. Hoffman-La Roche Ltd.; Genentech, Inc; Gilead Sciences, Inc.; Janssen, Inc; Lilly Pharmaceuticals; Merck; Myriad Autoimmune; Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis., Speakers bureau: AbbVie; Amgen; Bristol-Myers Squibb; Celltrion; F. Hoffman-La Roche Ltd, Janssen, Inc; Merck; Pfizer Pharmaceuticals; Sanofi-Genzyme; UCB, Claire Bombardier Grant/research support from: Dr Bombardier reports sources of funding for Ontario Best Practice Research Initiative Research grants from Abbvie, Janssen, Amgen, Medexus, Merck, Pfizer, and Novartis outside of the submitted work. Consulting Agreements: Abbvie, Covance, Janssen, Merck, Pfizer, Sanofi and Novartis outside of the submitted work. Advisory Board Membership: Hospira, Sandoz, Merck, Pfizer and Novartis outside of the submitted work.

The interrelationships between obstructive sleep apnea (OSA) and obesity are complex and bidirectional; however, current evidence regarding their combined effect on cardiovascular risk is limited and conflicting. Animal studies suggest that obesity may exacerbate the cardiovascular consequences of intermittent hypoxemia.In this historical observational study, we investigated whether obesity increases the effect of nocturnal hypoxemia on the incidence of cardiovascular events in adults with suspected OSA.All adults with suspected OSA who underwent diagnostic polysomnography at a large academic hospital between 1994 and 2010 were linked to provincial health administrative data to determine a composite cardiovascular outcome (hospitalization due to heart failure, myocardial infarction, stroke, or revascularization procedures). Using a competing-risk model and controlling for confounders, hazards were compared between four groups: group 1 comprised obese patients (body mass index30 kg/mA total of 10,149 participants were followed, with 17%, 25%, 8%, and 50% in groups 1-4, respectively. Over a median of 7.8 years, 896 (8.8%) first cardiovascular events occurred. Group 1 was associated with the highest hazard compared with the other groups, using group 4 as a reference (hazard ratio [HR] for group 1, 1.84; 95% confidence interval [CI], 1.46-2.32; HR for group 2, 1.59, 95% CI, 1.29-1.95; HR for group 3, 1.51; 95% CI, 1.15-1.98). The relative excess risk due to interaction was -0.25 (95% CI, -0.78 to 0.27), indicating no interaction.In adults with suspected OSA, the highest cardiovascular risk was found in obese patients with nocturnal oxygen desaturation; however, the effect of these two factors together does not exceed the effect of each factor considered individually.

Objective:To determine whether there is an association between carotid artery web and ischemic stroke.Methods:This was a single-center, age- and sex-matched, case-control study. Cases were consecutive patients with anterior circulation ischemic stroke of undetermined etiology (Trial of Org 10172 in Acute Stroke Treatment [TOAST] classification). Controls were consecutive patients with cerebral aneurysms, arteriovenous malformations, or primary intracerebral hemorrhages. Additional inclusion criteria were age Results:Fifty-three of 62 cases (85%) were matched by age (within 1 year) and by sex to 102 controls. There was a carotid web in 4 of 53 cases (9.4%) vs 1 of 102 controls (1.0%, odds ratio = 8.0, 95% confidence interval = 1.2–67, p = 0.032). There was no significant difference in the prevalence of nonstenotic carotid atherosclerotic plaque between the case and control groups. There was agreement on diagnosis of web for 163 of 164 patients (99%) and 7 of 8 webs (88%), and the Cohen κ for interobserver agreement was 0.93.Conclusions:There is an association between carotid artery web and ischemic stroke in patients who lack an alternative cause of stroke. Carotid web may be an underappreciated risk factor for stroke.

Evidence-based medicine requires strong scientific evidence upon which to base treatment. In rare diseases, study populations are often small, and thus this evidence is difficult to accrue. Investigators, though, should be creative and develop a flexible toolkit of methods to deal with the problems inherent in the study of rare disease. This narrative review presents alternative clinical trial designs for studying treatments of rare diseases, including cross-over and n-of-1 trials, randomized placebo-phase design, enriched enrollment, randomized withdrawal design, and classes of adaptive designs. Examples of applications of these designs are presented along with their advantages and disadvantages. Additional analytical considerations such as Bayesian analysis, internal pilots, and use of biomarkers as surrogate outcomes are further discussed. A framework for selecting appropriate clinical trial design is proposed to guide investigators in the process of selecting alternative designs for rare diseases. © 2016 Wiley Periodicals, Inc.

Background Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI. Methods In a phase 2/3, single-center, open-label trial, participants from Ontario, Canada, experiencing recurrence of CDI were randomly assigned in a 1:1 ratio to 14 days of oral vancomycin treatment followed by a single 500-mL FT by enema, or a 6-week taper of oral vancomycin. Patients with significant immunocompromise, history of fulminant CDI, or irreversible bleeding disorders were excluded. The primary endpoint was CDI recurrence within 120 days. Microbiota analysis was performed on fecal filtrate from donors and stool samples from FT recipients, as available. Results The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon. Conclusions In patients experiencing an acute episode of recurrent CDI, a single FT by enema was not significantly different from oral vancomycin taper in reducing recurrent CDI. Further research is needed to explore optimal donor selection, FT preparation, route, timing, and number of administrations. Clinical Trials Registration NCT01226992.

ObjectiveWe previously developed the paper-based Symptom Screening in Pediatrics Tool (SSPedi) designed for paediatric cancer symptom screening. Objectives were to evaluate and refine the electronic mobile application (app) of SSPedi using the opinions of children with cancer.MethodsParticipants were children 8–18 years of age with cancer. Participants completed electronic SSPedi on their own and then responded to semistructured questions to determine whether they found electronic SSPedi easy or difficult to complete and understand, understood and liked the app features (audio and animation), and understood previously difficult to understand concepts with the introduction of a help menu. After each group of 10 children, responses were reviewed to determine whether modifications were required.Results20 children evaluated electronic SSPedi. None found electronic SSPedi difficult to complete or understand. All children understood the app features and each of the 4 more difficult to understand concepts after using the help menu. 19 of 20 children thought the app was a good way to communicate with doctors and nurses.ConclusionsWe finalised an electronic version of SSPedi that is easy to use and understand with features specifically designed to facilitate child self-report. Future work will evaluate the psychometric properties of electronic SSPedi.

Achalasia is a chronic, progressive, and incurable esophageal motility disease. There is clinical uncertainty about which treatment should be recommended as first-line therapy. Our objective was to evaluate the effectiveness of pneumatic dilation compared with laparoscopic Heller myotomy with partial fundoplication in improving achalasia-specific quality of life.This was a prospective, multicenter, randomized trial at five academic hospitals in Canada. Fifty previously untreated adults with a clinical diagnosis of primary achalasia, confirmed by manometric testing, were enrolled between November 2005 and March 2010, and followed for 5 years after treatment. Randomization was stratified by site, in random blocks of size four and with balanced allocation. Patients were treated with pneumatic dilation or laparoscopic Heller myotomy with partial fundoplication. The primary outcome was the difference between the treatments in the mean improvement of the achalasia severity questionnaire (ASQ) score at 1 year from baseline. Prespecified secondary outcomes included general and gastrointestinal quality of life, symptoms, esophageal physiology measures (lower esophageal sphincter relaxation and pressure, esophageal emptying, abnormal esophageal acid exposure), complications, and incidence of retreatment. Functional and imaging studies were performed blinded and all outcome assessors were blinded.There were no significant differences between treatments in the improvement of ASQ score at 1 year from baseline (27.5 points in the Heller myotomy arm vs. 20.2 points in the pneumatic dilation arm; difference 7.3 points, 95% confidence interval -4.7 to 19.3; P=0.23). There were no differences between treatments in improvement of symptoms, general and gastrointestinal quality of life, or measures of esophageal physiology. Improvements in ASQ score diminished over time for both interventions. At 5 years, there were no differences between treatments in improvement of ASQ score, symptoms, and general or gastrointestinal quality of life. There were no serious adverse events. No patient who received Heller myotomy required retreatment, whereas five patients treated initially with pneumatic dilation required retreatment.Treatment with pneumatic dilation or laparoscopic Heller myotomy similarly improves achalasia-specific disease severity at 1 year. Either of the therapeutic approaches can be used as first-line therapy for previously untreated adults with achalasia.

When people die in intensive care units (ICUs), as many as half of their family members may experience a severe grief reaction. While families report a need for bereavement support, most ICUs do not routinely follow-up with family members. Clinicians are typically involved in supporting families during death and dying, yet little is known about how they work with families in bereavement. Our goal was to explore how clinicians support bereaved families, identify factors that facilitate and hinder support, and understand their interest and needs for follow-up.Mixed-methods study of nurses and physicians working in one of nine adult medical-surgical ICUs in academic hospitals across Canada. Qualitative interviews followed quantitative surveys to reflect, expand, and explain the quantitative results.Both physicians and nurses perceived that they provided empathetic support to bereaved families. Emotional engagement was a crucial element of support, but clinicians were not always able to engage with families because of their roles, responsibilities, experiences, or unit resources. Another important factor that could facilitate or challenge engagement was the degree to which families accepted death. Clinicians were interested in participating in a follow-up bereavement program, but their participation was contingent on time, training, and the ability to manage their own emotions related to death and bereavement in the ICU.Multiple opportunities were identified to enhance current bereavement support for families, including the desire of ICU clinicians for formal follow-up programs. Many psychological, sociocultural, and structural factors would need to be considered in program design.RéSUMé: OBJECTIF: Lorsque des personnes décèdent dans une unité de soins intensifs (USI), jusqu’à la moitié des membres de leur famille pourraient souffrir d’une réaction émotionnelle grave. Bien que les familles rapportent le besoin d’un soutien en cas de deuil, la plupart des USI ne font pas un suivi de routine avec les membres de la famille. Les cliniciens sont traditionnellement impliqués dans le soutien aux familles pendant la mort et le décès, mais nous ne connaissons que peu de choses concernant leur travail avec les familles en deuil. Notre objectif était d’explorer la façon dont les cliniciens viennent en soutien aux familles en deuil, d’identifier les facteurs qui facilitent ou entravent le soutien, et de comprendre leur intérêt et leurs besoins en matière de suivi. MéTHODE: Nous avons réalisé une étude par méthodes mixtes auprès du personnel infirmier et des médecins travaillant dans l’une de neuf USI médico-chirurgicales pour adultes dans des hôpitaux universitaires du Canada. Des entretiens qualitatifs suivaient des sondages quantitatifs afin de refléter, approfondir et expliquer les résultats quantitatifs. RéSULTATS: Selon leur perception, les médecins et le personnel infirmier fournissent un soutien empathique aux familles en deuil. L’implication émotionnelle a été identifiée comme étant un élément crucial du soutien, mais les cliniciens ne sont pas toujours capables de s’impliquer auprès des familles en raison de leurs rôles, de leurs responsabilités, de leurs expériences ou des ressources de l’unité. Un autre facteur important qui pourrait faciliter ou au contraire entraver leur implication est la mesure dans laquelle les familles acceptent la mort. Les cliniciens seraient intéressés à participer à un programme de suivi de deuil, mais leur participation dépend de leur temps, de leur formation et de leur capacité à gérer leurs propres émotions liées à la mort et au deuil à l’USI. CONCLUSION: De nombreuses cibles ont été identifiées pour améliorer le soutien actuel aux familles en deuil, y compris le désir des cliniciens de l’USI de disposer de programmes formels de suivi. Il faudra toutefois tenir compte de nombreux facteurs psychologiques, socioculturels et structurels dans la conception de tels programmes.

Supportive care Prioritization, Assessment and Recommendations for Kids (SPARK) is a web-based application that enables symptom screening and access to clinical practice guidelines for symptom management. Objective was to determine the feasibility of a randomized trial of daily symptom screening for 5 days among children receiving cancer treatments. We included English-speaking pediatric cancer and hematopoietic stem cell transplantation (HSCT) patients who were 8–18 years of age at enrollment and who were expected to be in the hospital or in clinic daily for five consecutive days. We randomized children to either undergo daily symptom screening with symptom reports provided to the healthcare team using the SPARK vs. standard of care. The primary endpoint was feasibility, defined as being able to enroll at least 30 participants within 1 year, and among those randomized to intervention, at least 75% completing symptom screening on at least 60% of on-study days. From July 2018 to November 2018, we enrolled and randomized 30 participants. The median age at enrollment was 12.5 (range 8–18) years. Among the intervention group, the median number of days Symptom Screening in Pediatrics Tool (SSPedi) was completed at least once was 5 (range 4 to 5), with one participant missing 1 day of symptom screening. Among all participants, baseline and day 5 SSPedi scores were obtained in 29/30 participants. A randomized trial of the SPARK with daily symptom screening for 5 days was feasible. It is now appropriate to proceed toward a definitive multi-center trial to test the efficacy of SPARK to improve symptom control.

ObjectiveThis systematic review and meta-analyses assessed seizure outcome following pediatric epilepsy surgery.MethodsMEDLINE, EMBASE, and Cochrane were searched for pediatric epilepsy surgery original research from 1990 to 2017. The outcome was seizure freedom at 12 months or longer follow-up. Using random-effects models, the effect sizes for controlled studies, uncontrolled studies on surgery locations (temporal lobe [TL], extratemporal lobe [ETL], or hemispheric surgery), pathologies, nonlesional epilepsy, and incomplete resection were estimated. Meta-regression assessed the relationship between age at surgery, age at seizure onset, and seizure outcome. Random-effects network meta-analysis was conducted for surgery locations.ResultsTwo hundred fifty-eight studies were included. Surgery achieved higher seizure freedom than medical therapy (odds ratio [OR] = 6.49 [95% confidence interval [CI]: 2.87–14.70], p < 0.001). Seizure freedom declined over time after surgery, from 64.8% (95% CI: 51.2%–76.4%; p = 0.034) at 1 year, to 60.3% (95% CI: 52.9%–67.4%; p = 0.007) at 5 years, and to 39.7% (95% CI: 28.4%–52.2%, p = 0.106) at 10 years. Seizure freedom was (1) highest for hemispheric surgery, followed by TL and ETL surgery, and (2) highest for tumor and lower for malformations of cortical development. Seizure freedom was lower for nonlesional than lesional epilepsy (OR = 0.54 [95% CI: 0.34, 0.88], p = 0.013) and incomplete than complete resection (OR = 0.13 [95% CI: 0.08, 0.21], p < 0.001). Age at surgery and age at seizure onset were associated with seizure freedom for mixed pathologies and surgery locations and TL surgery.ConclusionEpilepsy surgery was more effective than medical therapy to control seizures. Understanding seizure outcomes of different surgery locations, pathologies, nonlesional epilepsy, and incomplete resection will assist with presurgical counseling.

Aims: To examine the relationship between maternal glycaemic control and risk of neonatal hypoglycaemia using conventional and continuous glucose monitoring (CGM) metrics in the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT) participants. Methods: A secondary analysis of CONCEPTT involving 225 pregnant women and their liveborn infants. Antenatal glycaemia was assessed at 12, 24 and 34 weeks gestation. Intrapartum glycaemia was assessed by CGM measures 24 hours prior to delivery. The primary outcome was neonatal hypoglycaemia defined as glucose concentration 97.7th centile (63.2% vs 33.9%; p

The Federal Government of Canada established a $1.1 billion compensation programme in 1999 to support individuals who acquired hepatitis C virus (HCV) through blood products between January 1986 and July 1990. We aimed to describe the morbidity and mortality of this unique post-transfusion cohort (n = 4550) followed for over 15 years from 2000 to 2016. The age-standardized mortality rates were compared with that of the Canadian general population and HCV cohorts from other countries. We evaluated all-cause mortality using Kaplan-Meier survival curves and HCV-related and unrelated mortality using competing risk models. The age-standardized all-cause and HCV-related mortality rates per 10 000 person-years were 127 (95% CI: 117-138) and 76 (95% CI: 69-85) for males, and 77 (95% CI: 69-87) and 43 (95% CI: 37-51) for females, respectively. The risk of death of the post-transfusion cohort was almost twice as high as the Canadian general population (rate ratio = 1.8; 95% CI: 1.7-1.9). All-cause, HCV-related and HCV-unrelated mortality were 20%, 12% and 8%, respectively at 15 years of follow-up. By comparison, HCV-related mortality rates per 10 000 person-years for population-based HCV cohorts varied from 18 and 11 in Australia to 65 and 43 in Scotland for males and females, respectively. We reported long-term follow-up data for the largest post-transfusion cohort in the literature. The all-cause mortality rates were markedly higher than that of the Canadian general population. We also showed that HCV-related mortality were greater compared to other HCV cohorts. This suggests that continued efforts to identify and treat post-transfusion HCV are warranted.

Background Dyssynergic defecation (DD) is present in approximately 30% of patients with idiopathic chronic constipation (CC). Diagnostic criteria for DD require objective testing such as anorectal manometry (ARM); yet, ARM remains a limited resource in Canada. The aim of this study is to determine the predictability of DD in patients with CC using a standardized self-reported symptom questionnaire. Method In this study, 166 consecutive English-speaking patients with CC who were referred for ARM completed a symptom questionnaire. DD was diagnosed if pelvic floor dyssynergy was demonstrated by ARM and balloon expulsion time was more than one minute. Likelihood ratios (LRs) were calculated for individual symptoms and prespecified symptom combinations. Likelihood ratios greater than five or less than 0.2 were considered significant. A recursive partitioning tree was used to find the symptoms best able to predict DD. Results No single constipation symptom was sufficient to predict a diagnosis of DD. Patients who reported sometimes feeling an urge to defecate and a prolonged straining duration of greater than five minutes were more likely to have DD (LR = 7.74). In patients who reported straining often or always and had a short straining duration of less than two minutes, the diagnosis of DD was less likely (LR = 0.04). The recursive partitioning tree analysis similarly identified a sense of urge with a prolonged straining duration as predictor for DD, as well as an incomplete evacuation as another potential predictor. Conclusion Questions regarding need to strain, duration of straining, urge to defecate, and incomplete evacuation are useful to predict the presence of DD in patients with CC. These questions will enable clinicians to make a clinical diagnosis of DD to guide treatment.

Patients with lower socioeconomic status (SES) in the United States have reduced access to many health services including bariatric surgery. It is unclear whether disparities in bariatric surgery exist in countries with government-sponsored universal health benefits. The authors used data from a large regional Canadian bariatric surgery referral center to examine the relationship between SES and receipt of bariatric surgery.The Toronto Western Hospital bariatric surgery registry was used to identify all adults referred for bariatric surgery assessment from 2010 to 2017. The authors compared demographics, SES measures, and clinical measures among patients who did not and did undergo bariatric surgery (Roux-en-Y or sleeve gastrectomy). Multiple logistic regression was used to examine differences in receipt of bariatric surgery according to patient demographic characteristics and SES factors.Among 2417 patients included in the study, 646 (26.7%) did not receive surgery and 1771 patients (73.2%) did. Patients who did not undergo surgery were more likely to be male individual (29.1% vs. 19.3%; P0.001), black (12.1% vs. 8.3%; P=0.005), South Asian/Middle Eastern (8.2% vs. 4.5%; P0.001), and less likely to be white (68.9% vs. 76.7%; P0.001). In multiple logistic regression, factors associated with not receiving surgery were male sex, Black and South Asian/Middle Eastern ethnicity, being single, lack of employment, and history of psychiatric illness.Among patients referred for bariatric surgery, those who were male individuals, nonwhite, single, and unemployed were less likely to undergo surgery. Our results suggest that even with equal insurance, there are disparities in receipt of bariatric surgery.

OBJECTIVE Using a longitudinal observational cohort of ankylosing spondylitis (AS) patients, we sought to identify progression rates and factors predictive of spinal progression. As a secondary aim, we analyzed the effect of tumor necrosis factor inhibitor (TNFi) treatment on radiographic progression. METHODS AS patients who had baseline and follow-up cervical and lumbar radiographs were included in the study. Radiographic damage was assessed by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A change of 2 mSASSS units in 2 years was defined as progression. The characteristics of the study group such as demographic, clinical, laboratory, and treatment history were collected. RESULTS There were 350 patients in the study. The mean ± SD mSASSS increased from 9.3 ± 15.8 units at baseline to 17.7 ± 21.7 units by the sixth year. Mean ± SD changes in mSASSS between the years 0 to 2, 2 to 4, and 4 to 6 were 1.23 ± 2.68, 1.47 ± 2.86, and 1.52 ± 3.7 units, respectively. Overall, 24.3% of the group progressed over 2 years. Male sex (hazard ratio [HR] 2.46 [95% confidence interval (95% CI) 1.05, 5.76]), the presence of baseline damage (HR 7.98 [95% CI 3.98, 16]), increased inflammatory markers (log C-reactive protein level HR 1.35 [95% CI 1.07, 1.70]), and TNFi use (HR 0.82 [95% CI 0.70, 0.96]) were predictive of radiographic progression. There was a 20% reduction in the rate of progression with TNFi. CONCLUSION Male sex, the presence of baseline damage, active disease state, and higher inflammatory markers confer a high risk for disease progression. Treatment with TNFi showed a disease-modifying effect by slowing the rate of radiographic progression.

Background About 70% of all mental health disorders appear before the age of 25 years. When untreated, these disorders can become long-standing and impair multiple life domains. When compared with all Canadian youth (of different ages), individuals aged between 15 and 25 years are significantly more likely to experience mental health disorders, substance dependencies, and risks for suicidal ideation and death by suicide. Progress in the treatment of youth, capitalizing on their online responsivity, can strategically address depressive disorders. Objective We will conduct a randomized controlled trial to compare online mindfulness-oriented cognitive behavioral therapy (CBT-M) combined with standard psychiatric care versus psychiatric care alone in youth diagnosed with major depressive disorder. We will enroll 168 subjects in the age range of 18 to 30 years; 50% of subjects will be from First Nations (FN) backgrounds, whereas the other 50% will be from all other ethnic backgrounds. There will be equal stratification into 2 intervention groups (INT1 and INT2) and 2 wait-list control groups (CTL1 and CTL2) with 42 subjects per group, resulting in an equal number of INT1 and CTL1 of FN background and INT2 and CTL2 of non-FN background. Methods The inclusion criteria are: (1) age 18 to 30 years, FN background or other ethnicity; (2) Beck Depression Inventory (BDI)-II of at least mild severity (BDI-II score ≥14) and no upper limit; (3) Mini-International Neuropsychiatric Interview (MINI)–confirmed psychiatric diagnosis of major depressive disorder; and (4) fluent in English. All patients are diagnosed by a Centre for Addiction and Mental Health psychiatrist, with diagnoses confirmed using the MINI interview. The exclusion criteria are: (1) individuals receiving weekly structured psychotherapy; (2) individuals who meet the Diagnostic and Statistical Manual of Mental Disorders criteria for severe alcohol/substance use disorder in the past 3 months, or who demonstrate clinically significant suicidal ideation defined as imminent intent, or who have attempted suicide in the past 6 months; and (3) individuals with comorbid diagnoses of borderline personality, schizophrenia, bipolar disorder, and/or obsessive compulsive disorder. All subjects are provided standard psychiatric care defined as 1 monthly session that focuses on appropriate medication, with session durations of 15 to 30 min. Experimental subjects receive an additional intervention consisting of the CBT-M online software program (in collaboration with Nex J Health, Inc). Exposure to and interaction with the online workbooks are combined with navigation-coaching delivered by phone and secure text message interactions. Results The outcomes selected, combined with measurement blinding, are key features in assessing whether significant benefits regarding depression and anxiety symptoms occur. Conclusions If results confirm the hypothesis that youth can be effectively treated with online CBT-M, effective services may be widely delivered with less geographic restriction. International Registered Report Identifier (IRRID) PRR1-10.2196/11591

Background: Maternal hyperglycaemia alone does'nt explain the incidence of large for gestational age offspring (LGA) amongst women with T1DM. Placental vascular development is regulated by angiogenic factors. Placental growth factor (PIGF) is such a factor with a PlGF >100 signifying a well-developed placenta. Co-measurement of PlGF and SFLT-1 (soluble receptor antagonist to VEGF), combined as a ratio, is predictive of maternal vascular perfusion. A low sFLT-1:PlGF ( Methods: Amongst 157 women who participated in CONCEPTT; PlGF, sFLT-1:PlGF and a HbA1c< or >6.5% at randomisation and 34 weeks' gestation were assessed. Two separate linear regression models were used to test for a differential effect of placental function on mean birth weight in those with different levels of glycemic control, one using sFLT-1:PlGF and the other PlGF. Results: No significant relationship was found between birthweight and markers of placental function and glycemic control at randomisation. At 34 weeks, the relationship of birth weight to sFLT-1: PlGF differed depending upon HbA1c (p=0.007). Where HbA1c< 6.5%, birth weights were similar for a sFLT-1:PlGF 85 (3699g). Where HbA1c > 6.5%, birthweights were higher with a sFLT-1:PlGF < 85 (3809g) vs. > 85 (3355g). A similar pattern emerged for PlGF alone, with a differential effect of a healthy placenta on birthweight dependent upon glycemic control (p=0.013). Where HbA1c6.5%, an elevated PlGF (>100) resulted in higher birth weight than in those with lower PlGF (3822g ±679 vs. 3344g ±556). Conclusion: In women with T1DM, the combination of a healthy placenta with poor glycemic control resulted in the highest birthweights. Tighter glycemic control to avoid LGA is needed in women with healthy placental function. Disclosure S. Bacon: None. D. Burger: None. M. Tailor: None. G.A. Tomlinson: None. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic.

Background There is high-quality evidence supporting induction of labour (IOL) for a number of maternal and fetal indications. However, one fifth of inductions fail to result in vaginal births, requiring cesarean deliveries. This has negative clinical, emotional and resource implications. The importance of predicting the success of labour induction to enable shared decision-making has been recognized, but existing models are limited in scope and generalizability. Our objective was to derive and internally validate a clinical prediction model that uses variables readily accessible through maternal demographic data, antenatal history, and cervical examination to predict the likelihood of vaginal birth following IOL. Methods Data was extracted from electronic medical records of consecutive pregnant women who were induced between April and December 2016, at Mount Sinai Hospital, Toronto, Canada. A multivariable logistic regression model was developed using 16 readily accessible variables identified through literature review and expert opinion, as predictors of vaginal birth after IOL. The final model was internally validated using 10-fold cross-validation. Results Of the 1123 cases of IOL, 290 (25.8%) resulted in a cesarean delivery. The multivariable logistic regression model found maternal age, parity, pre-pregnancy body mass index and weight, weight at delivery, and cervical dilation at time of induction as significant predictors of vaginal delivery following IOL. The prediction model was well calibrated (Hosmer-Lemeshow χ2 = 5.02, p = 0.76) and demonstrated good discriminatory ability (area under the receiver operating characteristic (AUROC) curve, 0.81 (95% CI 0.78 to 0.83)). Finally, the model showed good internal validity [AUROC 0.77 (95% CI 0.73 to 0.82)]. Conclusions We have derived and internally validated a well-performing clinical prediction model for IOL in a large and diverse population using variables readily accessible through maternal demographic data, antenatal history, and cervical examination. Once prospectively validated in diverse settings, and if shown to be acceptable to pregnant women and healthcare providers as well as clinically and cost-effective, this model has potential for widespread use in clinical practice and research for enhancing patient autonomy, improving induction outcomes, and optimizing allocation of resources. Electronic supplementary material The online version of this article (10.1186/s12884-019-2232-8) contains supplementary material, which is available to authorized users.

Patient-ventilator asynchrony is common among critically ill patients undergoing mechanical ventilation and has been associated with adverse outcomes. Neurally adjusted ventilatory assist is a ventilatory mode that may lead to improved patient-ventilator synchrony. We conducted a systematic review to determine the impact of neurally adjusted ventilatory assist on patient-ventilator asynchrony, other physiologic variables, and clinical outcomes in adult patients undergoing invasive mechanical ventilation in comparison with conventional pneumatically triggered ventilatory modes.We searched Medline, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central, CINAHL, Scopus, Web of Science, conference abstracts, and ClinicalTrials.gov until July 2018.Two authors independently screened titles and abstracts for randomized and nonrandomized controlled trials (including crossover design) comparing the occurrence of patient-ventilator asynchrony between neurally adjusted ventilatory assist and pressure support ventilation during mechanical ventilation in critically ill adults. The asynchrony index and severe asynchrony (i.e., asynchrony index10%) were the primary outcomes.Two authors independently extracted study characteristics and outcomes and assessed risk of bias of included studies.Of 11,139 unique citations, 26 studies (522 patients) met the inclusion criteria. Sixteen trials were included in the meta-analysis using random effects models through the generic inverse variance method. In several different clinical scenarios, the use of neurally adjusted ventilatory assist was associated with significantly reduced asynchrony index (mean difference, -8.12; 95% CI, -11.61 to -4.63; very low quality of evidence) and severe asynchrony (odds ratio, 0.42; 95% CI, 0.23-0.76; moderate quality of evidence) as compared with pressure support ventilation. Furthermore, other measurements of asynchrony were consistently improved during neurally adjusted ventilatory assist.Neurally adjusted ventilatory assist improves patient-ventilator synchrony; however, its effects on clinical outcomes remain uncertain. Randomized controlled trials are needed to determine whether the physiologic efficiency of neurally adjusted ventilatory assist affects patient-important outcomes in critically ill adults.

Background Heart failure (HF) is a complex chronic condition, leading to frequent hospitalization, decreased quality of life, and increased mortality. Current guidelines recommend that multidisciplinary care be provided in specialized HF clinics. A number of studies have demonstrated the effectiveness of these clinics; however, there is a wide range in the services provided across different clinics. This network meta-analysis will aim to identify the aspects of HF clinic care that are associated with the best outcomes: a reduction in mortality, hospitalization, and visits to emergency department (ED) and improvements to quality of life. Methods Relevant electronic databases will be systematically searched to identify eligible studies. Controlled trials and observational cohort studies of adult (≥ 18 years of age) patients will be eligible for inclusion if they evaluate at least one component of guideline-based HF clinic care and report all-cause or HF-related mortality, hospitalizations, or ED visits or health-related quality of life assessed after a minimum follow-up of 30 days. Both controlled trials and observational studies will be included to allow us to compare the efficacy of the interventions in an ideal context versus their effectiveness in the real world. Two reviewers will independently perform both title and abstract full-text screenings and data abstraction. Study quality will be assessed through a modified Cochrane risk of bias tool for randomized controlled trials (RCTs) or the ROBINS-I tool for observational studies. The strength of evidence will be assessed using a modified Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. Network meta-analysis methods will be applied to synthesize the evidence across included studies. To contrast findings between study designs, data from RCTs will be analyzed separately from non-randomized controlled trials and cohort studies. We will estimate both the probability that a particular component of care is the most effective and treatment effects for specified combinations of care. Discussion To our knowledge, this will be the first study to evaluate the comparative effectiveness of the different components of care offered in HF clinics. The findings from this systematic review will provide valuable insight about which components of HF clinic care are associated with improved outcomes, potentially informing clinical guidelines as well as the design of future care interventions in dedicated HF clinics. Systematic review registration PROSPERO CRD42017058003 Electronic supplementary material The online version of this article (10.1186/s13643-019-0953-4) contains supplementary material, which is available to authorized users.

Epidemiologic data suggest that high levels of physical activity (PA) may reduce the risk of disease progression in men with prostate cancer (PCa), but it is unknown whether PA can delay the requirement for definitive treatment for those on active surveillance (AS). We investigated the influence of PA post-diagnosis on AS discontinuation in men with low-risk disease. The effect of PA on the time to AS discontinuation was assessed in 421 patients, of whom 107 underwent additional PCa treatment over a median of 2.5 years. Using Cox regression models, we found that PA was not significantly associated with time to curative treatment initiation. Prostate-specific antigen (PSA) most proximal to AS initiation (HR, 1.11; 95% CI 1.03 to 1.21) and the number of positive cores (HR, 1.34; 95% CI 1.12 to 1.61) at diagnosis were associated with a significantly increased risk of discontinuing AS. Our findings suggest that PA during AS for PCa does not significantly influence time to curative treatment.

International audience; Importance:Bayesian analysis of clinical trial data may provide useful information to aid in study interpretation, especially when trial evidence suggests that the benefits of an intervention are uncertain, such as in a trial that evaluated early extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS).Objective:To demonstrate the potential utility of Bayesian analyses by estimating the posterior probability, under various assumptions, that early ECMO was associated with reduced mortality in patients with very severe ARDS in a randomized clinical trial (RCT).Design and Evidence:A post hoc Bayesian analysis of data from an RCT (ECMO to Rescue Lung Injury in Severe ARDS [EOLIA]) that included 249 patients with very severe ARDS who had been randomized to receive early ECMO (n = 124; mortality at 60 days, 35%) vs initial conventional lung-protective ventilation with the option for rescue ECMO (n = 125, mortality at 60 days, 46%). The trial was designed to detect an absolute risk reduction (ARR) of 20%, relative risk (RR) of 0.67. Statistical prior distributions were specified to represent varying levels of preexisting enthusiasm or skepticism for ECMO and by Bayesian meta-analysis of previously published studies (with downweighting to account for differences and quality between studies). The RR, credible interval (CrI), ARR, and probability of clinically important mortality benefit (varying from RR less than 1 to RR less than 0.67 and ARR from 2% or more to 20% or more) were estimated with Bayesian modeling.Findings:Combining a minimally informative prior distribution with the findings of the EOLIA trial, the posterior probability of RR less than 1 for mortality at 60 days after randomization was 96% (RR, 0.78 [95% CrI, 0.56-1.04]); the posterior probability of RR less than 0.67 was 18%, the probability of ARR of 2% or more was 92%, and the probability of ARR of 20% or more was 2%. With a moderately enthusiastic prior, equivalent to information from a trial of 264 patients with an RR of 0.78, the estimated RR was 0.78 (95% CrI, 0.63-0.96), the probability of RR less than 1 was 99%, the probability of RR less than 0.67 was 8%, the probability of ARR of 2% or more was 97%, and the probability of ARR of 20% or more was 0%. With a strongly skeptical prior, equivalent to information from a trial of 264 patients with an RR of 1.0, the estimated RR was 0.88 (95% CrI, 0.71-1.09), the probability of RR less than 1 was 88%, the probability of RR less than 0.67 was 0%, the probability of ARR of 2% or more was 78%, and the probability of ARR of 20% or more was 0%. If the prior was informed by previous studies, the estimated RR was 0.71 (95% CrI, 0.55-0.94), the probability of RR less than 1 was 99%, the probability of RR less than 0.67 was 48%, the probability of ARR of 2% or more was 98%, and the probability of ARR of 20% or more was 4%.Conclusions and Relevance:Post hoc Bayesian analysis of data from a randomized clinical trial of early extracorporeal membrane oxygenation compared with conventional lung-protective ventilation with the option for rescue extracorporeal membrane oxygenation among patients with very severe acute respiratory distress syndrome provides information about the posterior probability of mortality benefit under a broad set of assumptions that may help inform interpretation of the study findings.

Moderate to severe depressive symptoms occur in up to one-third of patients at 1 year following ICU discharge, negatively affecting patient outcomes. This study evaluated patient and caregiver factors associated with the development of these symptoms.This study used the Rehabilitation and Recovery in Patients after Critical Illness and Their Family Caregivers (RECOVER) Program (Phase 1) cohort of 391 patients from 10 medical/surgical university-affiliated ICUs across Canada. We determined the association between patient depressive symptoms (captured by using the Beck Depression Inventory II [BDI-II]), patient characteristics (age, sex, socioeconomic status, Charlson score, and ICU length of stay [LOS]), functional independence measure (FIM) motor subscale score, and caregiver characteristics (Caregiver Assistance Scale and Center for Epidemiologic Studies-Depression Scale) by using linear mixed models at time points 3, 6, and 12 months.BDI-II data were available for 246 patients. Median age at ICU admission was 56 years (interquartile range, 45-65 years), 143 (58%) were male, and median ICU LOS was 19 days (interquartile range, 13-32 days). During the 12-month follow-up, 67 of 246 (27.2%) patients had a BDI-II score ≥ 20, indicating moderate to severe depressive symptoms. Mixed models showed worse depressive symptoms in patients with lower FIM motor subscale scores (1.1 BDI-II points per 10 FIM points), lower income status (by 3.7 BDI-II points; P = .007), and incomplete secondary education (by 3.8 BDI-II points; P = .009); a curvilinear relation with age (P = .001) was also reported, with highest BDI-II at ages 45 to 50 years. No associations were found between patient BDI-II and comorbidities (P = .92), sex (P = .25), ICU LOS (P = .51), or caregiver variables (Caregiver Assistance Scale [P = .28] and Center for Epidemiologic Studies Depression Scale [P = .74]).Increased functional dependence, lower income, and lower education are associated with increased severity of post-ICU depressive symptoms, whereas age has a curvilinear relation with symptom severity. Knowledge of risk factors may inform surveillance and targeted mental health follow-up. Early mobilization and rehabilitation aiming to improve function may serve to modify mood disorders.

A systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating the core components of cardiac rehabilitation (CR), nutritional counseling (NC), risk factor modification (RFM), psychosocial management (PM), patient education (PE), and exercise training (ET)) was undertaken. Published RCTs were identified from database inception dates to April 2017, and risk of bias assessed using Cochrane’s tool. Endpoints included mortality (all-cause and cardiovascular (CV)) and morbidity (fatal and non-fatal myocardial infarction (MI), coronary artery bypass surgery (CABG), percutaneous coronary intervention (PCI), and hospitalization (all-cause and CV)). Meta-regression models decomposed treatment effects into the main effects of core components, and two-way or all-way interactions between them. Ultimately, 148 RCTs (50,965 participants) were included. Main effects models were best fitting for mortality (e.g., for all-cause, specifically PM (hazard ratio HR = 0.68, 95% credible interval CrI = 0.54⁻0.85) and ET (HR = 0.75, 95% CrI = 0.60⁻0.92) components effective), MI (e.g., for all-cause, specifically PM (hazard ratio HR = 0.76, 95% credible interval CrI = 0.57⁻0.99), ET (HR = 0.75, 95% CrI = 0.56⁻0.99) and PE (HR = 0.68, 95% CrI = 0.47⁻0.99) components effective) and hospitalization (e.g., all-cause, PM (HR = 0.76, 95% CrI = 0.58⁻0.96) effective). For revascularization (including CABG and PCI individually), the full interaction model was best-fitting. Given that each component, individual or in combination, was associated with mortality and/or morbidity, recommendations for comprehensive CR are warranted.

ObjectivesPaediatric patients with leukaemia with relapse or induction failure have poor prognosis. Anticipated quality of life (QoL) is important in treatment decision making. The objective was to determine if curative intent at relapse or induction failure, when compared with palliative intent, was associated with child’s physical health, pain or general fatigue and parents’ QoL over time among patients with paediatric leukaemia in El Salvador.MethodsThis was a prospective observational cohort study. Children 2–18 years with acute leukaemia at first relapse or induction failure were eligible. Assessments occurred every 2 months for up to 2 years using validated proxy report and self-report scales, where guardians were the primary respondents. Initial curative or palliative intent was categorised at enrolment by physicians. The impact of initial intent on QoL was assessed using linear mixed effects models and interaction between QoL and time.ResultsOf the 60 families enrolled, initial treatment intent was curative in 31 (51.7%) and palliative in 29 (48.3%). During the 2-year observation period, 44 children died. Initial curative intent significantly improved child’s physical health (estimate=8.4, 95% CI 5.1 to 11.6), pain (estimate=5.4, 95% CI 1.5 to 9.2) and fatigue (estimate=6.6, 95% CI 3.2 to 9.9) compared with palliative intent, but not parents’ QoL (estimate=1.0, 95% CI −0.8 to 2.8).ConclusionsAmong paediatric patients with acute leukaemia at relapse or induction failure, initial curative intent treatment plan was associated with better physical health, pain and fatigue when compared with palliative intent. A curative approach may be a reasonable option for patients with acute leukaemia even when prognosis is poor.

Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is an open-label study of hydroxyurea for children with sickle cell anemia (SCA) in sub-Saharan Africa (Angola, DR Congo, Kenya, and Uganda). Initial results documented the feasibility, safety, and benefits of hydroxyurea for SCA in sub-Saharan Africa but guidance for optimizing hydroxyurea therapy is needed. We describe 5 years of hydroxyurea dosing and monitoring in the largest prospective cohort of children with SCA receiving hydroxyurea to date. Methods: Children 1-10 years of age with SCA were enrolled. The hydroxyurea dose was fixed at 15-20 mg/kg/day for the first 6 months with monthly complete blood counts (CBCs) to ensure safety. From month 6-24, the dose was escalated (5 mg/kg every 8 weeks) to maximum tolerated dose (MTD), defined as mild myelosuppression with absolute neutrophil count (ANC) 7.0 g/dL, or platelets Results: A total of 606 children initiated hydroxyurea and currently 555 (92%) remain on treatment, with average treatment duration of 48 ± 12 months and a total of 2,441 patient-years of hydroxyurea treatment. Over 85% achieved MTD with an average hydroxyurea dose of 22.5 ± 5.0 mg/kg/day, ranging from 19.0 mg/kg/day in Angola to 25.4 mg/kg/day in Uganda. With dose increases over time, the most recent average dose is 23.9 ± 5.4 mg/kg/day (site range 22.9-24.6 mg/kg/day). Lab benefits have been sustained; Hb increased from 7.3 g/dL at baseline to 8.4 g/dL at MTD and remains 8.3 g/dL at Month 60. Similarly, the average HbF increased from 11% baseline to 25% at MTD and remains 23% at Month 60. The average ANC decreased from 6.8 x 109/L at baseline to 3.2 x 109/L at MTD and remains 3.5 x 109/L at Month 60. Lab toxicities are infrequent, transient, and mostly incidental. Of 19,730 CBCs obtained during the treatment phase, 421 (2.1%) in 225 participants included a DLT. The most common DLT was thrombocytopenia (33%), with only 4 platelet counts Conclusions: Hydroxyurea is safe, well-tolerated, and effective for children with SCA living in sub-Saharan Africa. Treatment responses are robust and sustained in REACH across all 4 clinical sites and unaffected by baseline Z-score. Hydroxyurea optimization requires periodic dose escalation for weight gain and titration to mild myelosuppression. Deletional α-thalassemia trait significantly influences the hydroxyurea dose and treatment responses, but the lab benefits with optimized dosing are still robust regardless of the α-globin genotype. Lab toxicities from hydroxyurea are uncommon and typically asymptomatic, suggesting that routine CBC monitoring is needed only at 3-month intervals once a stable dose is achieved, more to optimize the dose than to identify incidental toxicities. This approach to optimizing hydroxyurea therapy will allow more widespread utilization in low-resource settings with limited laboratory monitoring. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background Isolation precautions have negative effects on patient safety, psychological well-being, and healthcare worker contact. However, it is not known whether isolation precautions affect certain hospital-related outcomes.

Critical illness survivors often experience permanent functional disability due to intensive care unit (ICU)-acquired weakness. The mechanisms responsible for long-term weakness persistence versus resolution are unknown.To delineate cellular mechanisms underlying long-term weakness persistence in ICU survivors.We conducted a nested, prospective study of critically ill patients mechanically ventilated for 7 days or longer. The patients were recruited from the RECOVER program and serially assessed over 6 months after ICU discharge. Twenty-seven of 82 patients consented to participate; 15 and 11 patients were assessed at 7 days and 6 months after ICU discharge, respectively.We assessed motor functional capacity, quadriceps size, strength, and voluntary contractile capacity and performed electromyography, nerve conduction studies, and vastus lateralis biopsies for histologic, cellular, and molecular analyses. Strength and quadriceps cross-sectional areas were decreased 7 days after ICU discharge. Weakness persisted to 6 months and correlated with decreased function. Quadriceps atrophy resolved in 27% patients at 6 months. Muscle mass reconstitution did not correlate with resolution of weakness, owing to persistent impaired voluntary contractile capacity. Compared with Day 7, increased ubiquitin-proteasome system-mediated muscle proteolysis, inflammation, and decreased mitochondrial content all normalized at 6 months. Autophagy markers were normal at 6 months. Patients with sustained atrophy had decreased muscle progenitor (satellite) cell content.Long-term weakness in ICU survivors results from heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity. These findings are not explained by ongoing muscle proteolysis, inflammation, or diminished mitochondrial content. Sustained muscle atrophy is associated with decreased satellite cell content and compromised muscle regrowth, suggesting impaired regenerative capacity.

Disability risk groups and 1-year outcome after greater than or equal to 7 days of mechanical ventilation (MV) in medical/surgical intensive care unit (ICU) patients are unknown and may inform education, prognostication, rehabilitation, and study design.To stratify patients for post-ICU disability and recovery to 1 year after critical illness.We evaluated a multicenter cohort of 391 medical/surgical ICU patients who received greater than or equal to 1 week of MV at 7 days and 3, 6, and 12 months after ICU discharge. Disability risk groups were identified using recursive partitioning modeling.The 7-day post-ICU Functional Independence Measure (FIM) determined the recovery trajectory to 1-year after ICU discharge and was an independent risk factor for 1-year mortality. The 7-day post-ICU FIM was predicted by age and ICU length of stay. By 2 weeks of MV, ICU patients could be stratified into four disability groups characterized by increasing risk for post ICU disability, ICU and post-ICU healthcare use, and disposition. Patients less than 42 years with ICU length of stay less than 2 weeks had the best function and fewest deaths at 1 year compared with patients greater than 66 years with ICU length of stay greater than 2 weeks who sustained the worst disability and 40% 1-year mortality. Depressive symptoms (17%) and post-traumatic stress disorder (18%) persisted at 1 year.ICU survivors of greater than or equal to 1 week of MV may be stratified into four disability groups based on age and ICU length of stay. These groups determine 1-year recovery and healthcare use and are independent of admitting diagnosis and illness severity. Clinical trial registered with www.clinicaltrials.gov (NCT 00896220).