Pregnancy Outcomes in Patients Treated with Upadacitinib: Analysis of Data from Clinical Trials and Postmarketing Reports.

BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVie's safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Malignancy in the Upadacitinib Clinical Trials for Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis.

INTRODUCTION: This article aims to describe malignancies in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or non-radiographic axial spondyloarthritis (nr-axSpA) treated with upadacitinib (UPA) or active comparators. METHODS: This integrated safety analysis includes data from 11 phase 3 UPA trials across RA (6 trials), PsA (2 trials), AS (2 trials; one phase 2b/3), and nr-axSpA (1 trial). Treatment-emergent adverse events (TEAEs) were summarized for RA (pooled UPA 15 mg [UPA15], pooled UPA 30 mg [UPA30], adalimumab 40 mg [ADA], methotrexate monotherapy [MTX]), PsA (pooled UPA15, pooled UPA30, ADA), AS (pooled UPA15), and nr-axSpA (UPA15). TEAEs were reported as exposure-adjusted event rates (events/100 patient-years). RESULTS: Median treatment duration ranged from 1.0 to 4.0 years (with a maximum of 6.6 years in RA). Across treatments and indications, rates of malignancy excluding nonmelanoma skin cancer (NMSC) ranged from 0.2 to 1.1, while NMSC ranged from 0.0 to 1.4. In RA, rates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX (breast and lung cancer were the most common). In RA and PsA, Kaplan-Meier analyses revealed no differences in event onset of malignancy excluding NMSC with UPA15 versus UPA30 over time. In RA, NMSC rates were higher with UPA30 than UPA15; both UPA15 and UPA30 were higher than ADA and MTX. In PsA, rates of malignancy excluding NMSC and NMSC were generally similar between UPA15, UPA30, and ADA. In AS and nr-axSpA, malignancies were reported infrequently. Few events of lymphoma were reported across the clinical programs. CONCLUSION: Rates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX and were consistent across RA, PsA, AS, and nr-axSpA. A dose-dependent increased rate of NMSC was observed with UPA in RA. TRIAL REGISTRATION: ClinicaTrials.gov identifier: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847, NCT03086343, NCT03104400, NCT03104374, NCT03178487, and NCT04169373.

MACE and VTE across upadacitinib clinical trial programmes in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

OBJECTIVES: To provide an integrated analysis of major adverse cardiovascular events (MACEs) and events of venous thromboembolism (VTE) and associated risk factors across rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) phase 2b/3 upadacitinib clinical programmes. METHODS: Data were analysed and summarised from clinical trials of RA, PsA and AS treated with upadacitinib 15 mg once daily (QD) and 30 mg QD (as of 30 June 2021). Data from adalimumab (RA and PsA) and methotrexate (RA) arms were included as comparators. Adjudicated MACEs and VTE events were presented as exposure-adjusted rates per 100 patient-years (E/100 PY). Univariable Cox proportional hazard regression analyses assessed potential associations of risk factors for MACE and VTE. RESULTS: In total, 4298 patients received upadacitinib 15 mg (RA n=3209, PsA n=907 and AS n=182) and 2125 patients received upadacitinib 30 mg (RA n=1204 and PsA n=921). In patients with RA and PsA, rates of MACE (0.3-0.6 E/100 PY) and VTE (0.2-0.4 E/100 PY) were similar across upadacitinib doses; in patients with AS, no MACEs and one VTE event occurred. Most patients experiencing MACEs or VTE events had two or more baseline cardiovascular risk factors. Across RA and PsA groups, rates of MACEs and VTE events were similar. CONCLUSIONS: Rates of MACEs and VTE events with upadacitinib were consistent with previously reported data for patients receiving conventional synthetic and biologic disease-modifying anti-rheumatic drugs and comparable with active comparators adalimumab and methotrexate. Associated patient characteristics are known risk factors for MACEs and VTE events. TRIAL REGISTRATION NUMBERS: RA (SELECT-NEXT: NCT02675426; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847; SELECT-COMPARE: NCT02629159; SELECT-EARLY: NCT02706873, SELECT-CHOICE: NCT03086343), PsA (SELECT-PsA 2: NCT03104374; SELECT-PsA 1: NCT03104400), and AS (SELECT-AXIS 1: NCT03178487).

Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme.

OBJECTIVE: Increased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular (CV) risk (ORAL Surveillance). We assessed post hoc the potential risk of upadacitinib in a similar RA population. METHODS: Pooled safety data from six phase III trials were evaluated post hoc for AEs in patients receiving upadacitinib 15 mg once a day (with or without conventional synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant methotrexate (MTX), or MTX monotherapy in the overall trial population and in a subset of patients with higher CV risk (aged ≥50 years, ≥1 CV risk factor). Higher-risk patients from a head-to-head study of upadacitinib 15 mg versus adalimumab (SELECT-COMPARE) were assessed in parallel. Exposure-adjusted incidence rates for treatment-emergent AEs were summarised based on exposure to upadacitinib or comparators. RESULTS: A total of 3209 patients received upadacitinib 15 mg, 579 received adalimumab and 314 received MTX monotherapy; ~54% of the patients were included in the overall and SELECT-COMPARE higher-risk populations. Major adverse cardiovascular events (MACE), malignancy (excluding non-melanoma skin cancer (NMSC)) and venous thromboembolism (VTE) were more frequent in the higher-risk cohorts versus the overall population but were generally similar across treatment groups. Rates of serious infections in higher-risk populations and herpes zoster (HZ) and NMSC in all populations were higher with upadacitinib 15 mg than comparators. CONCLUSIONS: An increased risk of MACE, malignancy (excluding NMSC) and VTE was observed in higher-risk populations with RA, yet risk was comparable between upadacitinib-treated and adalimumab-treated patients. Higher rates of NMSC and HZ were observed with upadacitinib versus comparators across all populations, and increased rates of serious infections were detected in upadacitinib-treated patients at higher CV risk. TRIAL REGISTRATION NUMBERS: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847 and NCT03086343.

Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis.

OBJECTIVE: To evaluate the long-term safety profile for upadacitinib across rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and atopic dermatitis (AD). METHODS: Safety data from clinical trials of upadacitinib 15 mg and upadacitinib 30 mg (AD only) for treating RA, PsA, AS and AD as of 30 June 2021 were analysed; some RA and PsA studies included adalimumab and methotrexate as active comparators. Treatment-emergent adverse events (TEAEs) were presented by disease as exposure-adjusted event rates per 100 patient years (E/100 PY). RESULTS: The analysis included 6991 patients (RA, n=3209; PsA, n=907; AS, n=182; AD, n=2693) who received at least one dose of upadacitinib, representing 15 425 PY of exposure (maximum duration 2.75-5.45 years) across diseases. Rates (E/100 PY) of any TEAE (205.5-278.1) and TEAE leading to discontinuation (4.5-5.4) were similar across diseases; serious TEAEs were numerically higher in patients with RA and PsA. Rates of herpes zoster (1.6-3.6), non-melanoma skin cancer (0-0.8) and elevations in creatine phosphokinase levels (4.4-7.9) were higher with upadacitinib than with active comparators in the RA and PsA populations. Deaths (0-0.8), serious infections (0-3.9), major adverse cardiovascular events (0-0.4), venous thromboembolism (<0.1-0.4) and malignancies (0.3-1.4) were observed, with rates generally lowest in AS and AD. Increased rates of acne were observed in patients with AD only. CONCLUSIONS: Findings from this analysis demonstrate that upadacitinib is generally well tolerated with observed differences in safety profiles likely reflective of varying patient characteristics across RA, PsA, AS and AD populations. TRIAL REGISTRATION NUMBERS: NCT02675426, NCT02706951, NCT02706847, NCT02629159, NCT02706873, NCT03086343, NCT03104374, NCT03104400, NCT03178487, NCT03569293, NCT03568318 and NCT03607422.

Hospital Discharge Instructions: Characteristics, Accessibility, and National Guideline Adherence.

OBJECTIVES: The content of pediatric hospital discharge instructions is highly variable. This study aimed to describe the characteristics, accessibility per patient literacy level and language, and national guideline adherence of pediatric hospital discharge instructions. METHODS: This retrospective study assessed discharge instructions at a tertiary children's hospital. Patient and instruction characteristics, including patient health literacy level, grade level of instructions, patient language preference, and language of instructions were collected via chart review and electronic medical record query. Standard admission processes assessed health literacy via Brief Health Literacy Screening. The association between demographic and clinical characteristics and adherence to Solutions for Patient Safety guidelines was analyzed by using unadjusted and adjusted analysis methods. RESULTS: Of 240 discharge instructions, 25% were missing at least 1 recommended content area: signs of worsening, where to seek help, or medication reconciliation. A patient health literacy deficit was identified in 15%; the mean grade level of instructions was 10.1. Limited English proficiency was reported among 17% one quarter of whom received language concordant instructions. Use of discharge instruction templates and discharge services were associated with improved guideline adherence (P <.001). Almost one-half of the study population had a complex medical history, which was associated with decreased guideline adherence (P = .04). CONCLUSIONS: One-quarter of discharge instructions for this predominantly medically complex population failed to meet national standards. Accessibility was often limited by the reading grade level or discordant language of instructions. Templates may be a valuable tool for improving discharge instruction content, accessibility, and adherence to national guidelines.

Interactive Inpatient Asthma Education: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Inpatient asthma education interventions provide benefit compared with usual care, but evaluation of the most effective educational model is needed. We compared the impact of interactive versus didactic inpatient pediatric asthma education on subsequent emergency department (ED) visits and hospitalizations. METHODS: Children (aged 2‒16) with asthma admitted to a tertiary care children's hospital with an asthma exacerbation between October 2016 and June 2017 were randomly assigned to interactive or didactic (control) asthma education. The primary outcome was asthma ED visits at 6 and 12 months; secondary outcomes included hospitalizations (6 and 12 months), inhaler technique, asthma knowledge, symptoms, quality of life, and parental management skills at baseline, discharge, and/or 12 months. RESULTS: One hundred forty participants (69 interactive, 71 control) completed the study. There were no differences in ED visits at 6 or 12 months. Compared to controls, the interactive group had fewer hospitalizations (10.1% vs 22.5%; P = .04) at 6 months. Inhaler technique in the interactive group improved at discharge (mean change 4.07 [95% confidence interval (CI): 3.21-4.94]) and remained increased at 12 months (P = .03). Patient-reported asthma symptoms and quality of life were similar in both groups at baseline (19.9 vs 20.62, best possible score 8) and significantly improved in the interactive group at 12 months (least square mean change, 3.52 vs -1.75; P < .01). CONCLUSIONS: There were no differences in ED visits; however, the interactive education reduced asthma hospitalizations over a 6-month period. These findings demonstrate that educational delivery methods can play a role in improving clinical outcomes for asthma.

Comparison of Two Assessment Tools for Hospitalized Subjects With Asthma.

BACKGROUND: Pediatric Asthma Assessment tools used to guide the weaning of inhaled therapies during inpatient hospitalization require further evaluation and validation. This study aimed to compare 2 asthma assessment tools: an asthma scale versus an asthma score. METHODS: A prospective, physician-blinded, comparison study was conducted in 2 separate 6-week phases of patients > 2 y old admitted to a tertiary care children's hospital with status asthmaticus between July and November 2014. The asthma scale categorized 5 components (oxygen, auscultation, dyspnea, breathing frequency, and pulse oximetry) into 1 of 3 respiratory assessments: mild, moderate, or severe. The asthma score used a sum of the components, resulting in a score of 1-15. Study tool predictability was measured using a metric based on hours on continuous albuterol, with area under the curve ≥ 0.8 indicating good predictability. Agreement between clinicians was measured using the Cohen kappa statistic. Study tool clinical correlation was measured using Spearman coefficient. Usability was evaluated using web-based surveys. RESULTS: Phase 1 included 1,971 assessments (97 unique subjects), whereas phase 2 included 607 assessments (69 unique subjects). Using the continuous albuterol metric, predictability of the asthma scale had an area under the curve of 0.62 versus the asthma score area under the curve of 0.80. Agreement early in hospitalization for the asthma scale was kappa = 0.34 (95% CI 0.18-0.5; n = 84) versus kappa = 0.55 (95% CI 0.35-0.76; n = 44) for the asthma score. Agreement late in hospitalization for the asthma scale was kappa = 0.38 (95% CI 0.17-0.59; n = 66) versus kappa = 0.41 (95% CI 0.13-0.69; n = 33) for the asthma score. Clinical correlation for the asthma scale (no. = 1,908) was r = 0.57 (P < .001) versus r = 0.80 (P < .001) for the asthma score (no. = 558). Mean asthma scale usability was 3.38 versus 3.68 for the asthma score. CONCLUSIONS: The asthma score showed better clinical predictability and clinical correlation compared to the asthma scale. Numerical scores provided more objective assessments compared to categorical scores. Validated scoring tools such as the asthma score are crucial to the success of management of inpatient asthma care.

SCN2A-Developmental and Epileptic Encephalopathies: Challenges to trial-readiness for non-seizure outcomes.

OBJECTIVE: SCN2A-associated developmental and epileptic encephalopathies (DEEs) present with seizures, developmental impairments, and often both. We sought to characterize the level and pattern of development in children with SCN2A variants, and to address the sensitivity of the Vineland Adaptive Behavior Scales (VABS) in measuring changes over time in children with SCN2A-DEEs. METHODS: Clinical histories for participants with pathogenic SCN2A variants in the Simons SearchLight project were analyzed for descriptive purposes. VABS scores obtained at study entry and yearly thereafter were analyzed for floor and ceiling effects, change with age, and association with epilepsy through use of regression and longitudinal regression methods. RESULTS: Sixty-four participants (50 with epilepsy, 30 [47%] female, median age 49 months, interquartile range [IQR] 28 to 101) were included. Histories of birth complications (N = 34, 54%), neonatal neurological signs (N = 45, 74%), and other neurological symptoms (N = 31, 48%) were common and similar in epilepsy and nonepilepsy subgroups. Mean standardized VABS scores (Composite 53.5; Motor, 55.8, Communication, 54.1, Socialization, 59.4, and Daily living skills, 55.1) reflected performance ~3 standard deviations below the normative test average. In longitudinal regression analyses, standardized scores decreased between 1.3 and 2.8 points per year, suggesting regression of abilities. Raw score analyses, however, revealed several subdomains with substantial floor effects (eg, community use); other raw scores increased with increasing age. Participants with epilepsy scored 0.6 to 1 SD lower than those without epilepsy (all P's < .05). SIGNIFICANCE: The VABS, as standardly administered, has shortcomings for addressing growth or regression in individuals with SCN2A-DEEs. Some subdomain raw scores reflected substantial floor effects. Raw scores increased so slowly over time that standardized scores declined. Alternative measures sensitive to incremental meaningful change are required if outcomes such as adaptive behavior are to be primary outcomes in short-term clinical trials.

Natural history of burnout, stress, and fatigue in a pediatric resident cohort over three years.

BACKGROUND: Burnout is known to be high amongst physician trainees. Factors such as stress, fatigue, social environment, and resilience could affect burnout. Cross-sectional data describe burnout in pediatric residents, but the trajectory of burnout in a cohort of residents followed longitudinally through the full course of residency training has not been reported. We prospectively examined the prevalence and trajectory of burnout, stress, fatigue, social connectedness, and resilience in a pediatric resident cohort from orientation through three years of residency. The cohort (N = 33) was surveyed six times between 2015-2018 using the Abbreviated Maslach Burnout Inventory (AMBI), Perceived Stress Scale (PSS), Epworth Sleepiness Scale (ESS), Social Connectedness Scale-Revised (SCS-R), and Connor-Davidson Resilience Scale (CD-RISC10). Data were analyzed using repeated measures mixed effects models. Significant change from baseline was considered to be adjusted p < 0.05. Response rate was >50% at each timepoint; 69% of trainees completed surveys ≥4 times. Scores were significantly worse than baseline in all surveys, at every timepoint, with the exception of AMBI-PA (personal accomplishment) at the PGY1/PGY2 transition and SCS-R and CD-RISC10 at the end of training. The most significant changes from baseline occurred mid-PGY1 to mid-PGY2. At least 65% of residents demonstrated worse scores than baseline on 36/40 (90%) follow-up surveys. Furthermore, ≥65% met criteria for emotional exhaustion and moderate stress at every timepoint. SCS-R was the only survey measure to improve at residency completion compared to baseline. CONCLUSION: Within 6 months of starting residency this pediatric resident cohort became burned out, stressed, fatigued, less socially connected, and less resilient. Burnout is only one factor that indicates impaired resident well-being. To fully address this, a comprehensive examination of how residents are trained is needed to identify effective interventions. ABBREVIATIONS: MBI - Maslach Burnout Inventory; AMBI - Abbreviated Maslach Burnout Inventory; AMBI-EE - Emotional Exhaustion; AMBI-D - Depersonalization; AMBI-PA - Personal Accomplishment; AMBI-SAT - Satisfaction with Medicine; LCH - Ann & Robert H. Lurie Children's Hospital of Chicago/Lurie Children's Hospital; P/CN - Pediatrics/Child Neurology; PSS - Perceived Stress Scale; ESS - Epworth Sleepiness Scale; CD-RISC10 - Resilience; SCS-R - Social Connectedness Scale Revised; PGY - Post-Graduate Year.

The Importance of Engaging Children in Research Decision-Making: A Preliminary Mixed-Methods Study.

Studies demonstrate deficiencies in parents' and children's comprehension of research and lack of child engagement in research decision-making. We conducted a cross-sectional and interview-based study of 31 parent-child dyads to describe decision-making preferences, experiences, and comprehension of parents and children participating in research. Parents and children reported that parents played a greater role in decisions about research participation than either parents or children preferred. The likelihood of child participation was associated with the extent of input the parent permitted the child to have in the decision-making process, the child's comprehension, whether the study team asked the child about participation, whether the child read study-related materials, the parent's marital status, and the child's race. Children had lower comprehension than adults. Comprehension was related to age, education, verbal intelligence, and reading of study-related information. Parent understanding was associated with prospect for benefit and illness severity. Child participation may be improved by increasing parent-child communication, emphasizing important relational roles between parent and child, respecting the developing autonomy of the child, increasing engagement with the study team, providing appropriate reading materials, and assessing comprehension.

Low prevalence of clinical decision support to calculate caloric and fluid intake for infants in the neonatal intensive care unit.

BACKGROUND: Clinical decision support (CDS) improves nutrition delivery for infants in the neonatal intensive care unit (NICU), however, the prevalence of CDS to support nutrition is unknown. METHODS: Online surveys, with telephone and email validation of responses, were administered to NICU clinicians in the Children's Hospital Neonatal Consortium (CHNC). We determined and compared the availability of CDS to calculate calories and fluid received in the prior 24 h, stratified by enteral and parenteral intake, using McNemar's test. RESULTS: Clinicians at all 34 CHNC hospitals responded with 98 of 108 (91%) surveys completed. NICUs have considerably less CDS to calculate enteral calories received than enteral fluid received (32% vs. 82%, p < 0.001) and less CDS to calculate parenteral calories received than parenteral fluid received (29% vs. 82%, p < 0.001). DISCUSSION: Most CHNC NICUs are unable to reliably and consistently monitor caloric intake delivered to critically ill infants at risk for growth failure.

Impact of Elagolix on Workplace and Household Productivity Among Women with Moderate to Severe Pain Associated with Endometriosis: A Pooled Analysis of Two Phase III Trials.

BACKGROUND: Endometriosis profoundly impairs women's workplace and household productivity. OBJECTIVE: The aim of this study was to evaluate the impact of elagolix on endometriosis-related workplace and household productivity losses. METHODS: Data were pooled from two phase III trials of women aged 18-49 years with moderate to severe endometriosis-associated pain treated for 6 months with elagolix 150 mg daily (QD), 200 mg twice daily (BID), or placebo. The Health-Related Productivity Questionnaire was administered at baseline, Month 3, and Month 6 to determine workplace and household absenteeism and presenteeism. Productivity changes from baseline were compared between placebo and elagolix doses via analysis of covariance. RESULTS: Workplace analyses included 1270 employed women and household analyses included 1565 women. At baseline, women reported average weekly losses of 16 workplace hours, 8.3 household work hours, 45% of scheduled work, and 64% of planned household chores. At Month 6, treatment with elagolix 150 mg QD or 200 mg BID increased productive workplace hours by 1.7 (95% CI 0.1-3.4; p = 0.041) and 5.4 h (95% CI 3.7-7.1; p < 0.001) relative to placebo, corresponding to gains of 5.2% (95% CI 0.7-9.7; p = 0.022) and 14.6% (95% CI 10.0-19.1; p < 0.001) of scheduled work, respectively. Both elagolix doses improved household productivity at Month 6 by 1.7 (95% CI 0.7-2.7) and 3.1 (95% CI 2.1-4.0) hours relative to placebo (both p < 0.001), with increases of 8.8% (95% CI 3.5-14.1; p = 0.001) and 20.4% (95% CI 15.1-25.6; p < 0.001) of planned household work. CONCLUSIONS: Treatment with elagolix improved endometriosis-related workplace and household productivity impairments. TRIAL REGISTRATION: ELARIS EM-I (NCT01620528) and ELARIS EM-II (NCT01931670).

Ideal vs. real: a systematic review on handling covariates in randomized controlled trials.

BACKGROUND: In theory, efficient design of randomized controlled trials (RCTs) involves randomization algorithms that control baseline variable imbalance efficiently, and corresponding analysis involves pre-specified adjustment for baseline covariates. This review sought to explore techniques for handling potentially influential baseline variables in both the design and analysis phase of RCTs. METHODS: We searched PubMed for articles indexed "randomized controlled trial", published in the NEJM, JAMA, BMJ, or Lancet for two time periods: 2009 and 2014 (before and after updated CONSORT guidelines). Upon screening (343), 298 articles underwent full review and data abstraction. RESULTS: Typical articles reported on superiority (86%), multicenter (92%), two-armed (79%) trials; 81% of trials involved covariates in the allocation and 84% presented adjusted analysis results. The majority reported a stratified block method (69%) of allocation, and of the trials reporting adjusted analyses, 91% were pre-specified. Trials published in 2014 were more likely to report adjusted analyses (87% vs. 79%, p = 0.0100) and more likely to pre-specify adjustment in analyses (95% vs. 85%, p = 0.0045). Studies initiated in later years (2010 or later) were less likely to use an adaptive method of randomization (p = 0.0066; 7% of those beginning in 2010 or later vs. 31% of those starting before 2000) but more likely to report a pre-specified adjusted analysis (p = 0.0029; 97% for those initiated in 2010 or later vs. 69% of those started before 2000). CONCLUSION: While optimal reporting procedures and pre-specification of adjusted analyses for RCTs tend to be progressively more prevalent over time, we see the opposite effect on reported use of covariate-adaptive randomization methods.

Critical Errors in Inhaler Technique among Children Hospitalized with Asthma.

Past studies have not evaluated inhaler use in hospitalized children with asthma. The objectives of this study were to evaluate inhaler technique in hospitalized pediatric patients with asthma and identify risk factors for improper use. We conducted a prospective cross-sectional study in a tertiary children's hospital for children 2-16 years of age admitted for an asthma exacerbation, and inhaler technique demonstrations were analyzed. Of 113 participants enrolled, 55% had uncontrolled asthma, and 42% missed a critical step in inhaler technique. More patients missed a critical step when they used a spacer with mouthpiece instead of a spacer with mask (75% [51%-90%] vs 36% [27%-46%]) and were older (7.8 [6.7-8.9] vs 5.8 [5.1-6.5] years). Patients using the spacer with mouthpiece remained significantly more likely to miss a critical step when adjusting for other clinical covariates (odds ratio 6.95 [1.71-28.23], P = .007). Hospital-based education may provide teachable moments to address poor proficiency, especially for older children using a mouthpiece.

Ideal and Actual Impact of Rapid Diagnostic Testing and Antibiotic Stewardship on Antibiotic Prescribing and Clinical Outcomes in Children With Positive Blood Cultures.

BACKGROUND: Implementing matrix-assisted laser desorption ionization-time of flight and multiplex polymerase chain reaction has been associated with decreased mortality and hospital length of stay in adults, but the impact in pediatrics is less understood. METHODS: This pre-post quasi-experimental study compared antibiotic prescribing for positive blood cultures in patients ≤21 years of age collected in 2012 (preintervention) and in 2015 (after matrix-assisted laser desorption ionization-time of flight/multiplex polymerase chain reaction). Time to effective and optimal antimicrobial therapy was evaluated using Cox proportional hazards regression. Time to ideal optimal therapy was estimated as the earliest potential initiation of optimal therapy. Antibiotic use and clinical outcomes were measured. RESULTS: There were 242 and 192 positive monomicrobial blood cultures in 2012 and 2015, respectively. Postintervention, time to optimal therapy (73.8 vs. 48.8 hours; P < 0.001) and organism identification (55.6 vs. 29.5 hours; P < 0.001) were reduced, and patients were more likely to receive optimal therapy by 7 days (hazard ratio, 1.85; P < 0.001). In the ideal scenario in 2015, there was an 8.8-hour delay in initiating optimal therapy based on the time that sufficient microbiologic data were available. Postintervention, time to effective therapy (2.8 vs. 2.7 hours; P = 0.782) and clinical outcomes did not differ. Unnecessary antibiotic duration for probable contaminants (skin flora) (43.1 vs. 29.7 hours; P = 0.027), vancomycin for methicillin-sensitive Staphylococcus aureus (54.0 vs. 41.3 hours; P = 0.008) and nonpenicillin/ampicillin antibiotics for group A Streptococcus, group B Streptococcus and Enterococcus faecalis (87.2 vs. 33.4 hours; P < 0.001) were reduced postintervention. CONCLUSIONS: Rapid diagnostics reduced time to optimal antimicrobial therapy and unnecessary antibiotic use without worse clinical outcomes.

A Practical Do-It-Yourself Recruitment Framework for Concurrent eHealth Clinical Trials: Identification of Efficient and Cost-Effective Methods for Decision Making (Part 2).

BACKGROUND: The ability to successfully recruit participants for electronic health (eHealth) clinical trials is largely dependent on the use of efficient and effective recruitment strategies. Determining which types of recruitment strategies to use presents a challenge for many researchers. OBJECTIVE: The aim of this study was to present an analysis of the time-efficiency and cost-effectiveness of recruitment strategies for eHealth clinical trials, and it describes a framework for cost-effective trial recruitment. METHODS: Participants were recruited for one of 5 eHealth trials of interventions for common mental health conditions. A multipronged recruitment approach was used, including digital (eg, social media and Craigslist), research registry-based, print (eg, flyers and posters on public transportation), clinic-based (eg, a general internal medicine clinic within an academic medical center and a large nonprofit health care organization), a market research recruitment firm, and traditional media strategies (eg, newspaper and television coverage in response to press releases). The time costs and fees for each recruitment method were calculated, and the participant yield on recruitment costs was calculated by dividing the number of enrolled participants by the total cost for each method. RESULTS: A total of 777 participants were enrolled across all trials. Digital recruitment strategies yielded the largest number of participants across the 5 clinical trials and represented 34.0% (264/777) of the total enrolled participants. Registry-based recruitment strategies were in second place by enrolling 28.0% (217/777) of the total enrolled participants across trials. Research registry-based recruitment had a relatively high conversion rate from potential participants who contacted our center for being screened to be enrolled, and it was also the most cost-effective for enrolling participants in this set of clinical trials with a total cost per person enrolled at US $8.99. CONCLUSIONS: On the basis of these results, a framework is proposed for participant recruitment. To make decisions on initiating and maintaining different types of recruitment strategies, the resources available and requirements of the research study (or studies) need to be carefully examined.

A Practical Do-It-Yourself Recruitment Framework for Concurrent eHealth Clinical Trials: Simple Architecture (Part 1).

BACKGROUND: The ability to identify, screen, and enroll potential research participants in an efficient and timely manner is crucial to the success of clinical trials. In the age of the internet, researchers can be confronted with large numbers of people contacting the program, overwhelming study staff and frustrating potential participants. OBJECTIVE: This paper describes a "do-it-yourself" recruitment support framework (DIY-RSF) that uses tools readily available in many academic research settings to support remote participant recruitment, prescreening, enrollment, and management across multiple concurrent eHealth clinical trials. METHODS: This work was conducted in an academic research center focused on developing and evaluating behavioral intervention technologies. A needs assessment consisting of unstructured individual and group interviews was conducted to identify barriers to recruitment and important features for the new system. RESULTS: We describe a practical and adaptable recruitment management architecture that used readily available software, such as REDCap (Research Electronic Data Capture) and standard statistical software (eg, SAS, R), to create an automated recruitment framework that supported prescreening potential participants, consent to join a research registry, triaging for management of multiple trials, capture of eligibility information for each phase of a recruitment pipeline, and staff management tools including monitoring of participant flow and task assignment/reassignment features. The DIY-RSF was launched in July 2015. As of July 2017, the DIY-RSF has supported the successful recruitment efforts for eight trials, producing 14,557 participant records in the referral tracking database and 5337 participants in the center research registry. The DIY-RSF has allowed for more efficient use of staff time and more rapid processing of potential applicants. CONCLUSIONS: Using tools already supported at many academic institutions, we describe the architecture and utilization of an adaptable referral management framework to support recruitment for multiple concurrent clinical trials. The DIY-RSF can serve as a guide for leveraging common technologies to improve clinical trial recruitment procedures.

Energy and Protein Intake During the Transition from Parenteral to Enteral Nutrition in Infants of Very Low Birth Weight.

OBJECTIVE: To evaluate the association between nutrition delivery practices and energy and protein intake during the transition from parenteral to enteral nutrition in infants of very low birth weight (VLBW). STUDY DESIGN: This was a retrospective analysis of 115 infants who were VLBW from a regional neonatal intensive care unit. Changes in energy and protein intake were estimated during transition phase 1 (0% enteral); phase 2 (>0, ≤33.3% enteral); phase 3 (>33.3, ≤66.7% enteral); phase 4 (>66.7, <100% enteral); and phase 5 (100% enteral). Associations between energy and protein intake were determined for each phase for parenteral nutrition, intravenous lipids, central line, feeding fortification, fluid restriction, and excess non-nutritive fluid intake. RESULTS: In phases 2 and 3, infants receiving feeding fortification received less protein than infants who were unfortified (-1.1 and -0.3 g/kg/d, respectively; P < .001). However, this negative association was not observed after adjusting for relevant nutrition delivery practices. Despite greater enteral protein intake during phases 2 and 3 (0.3 and 0.8 g/kg/d, respectively; P < .001), infants with early fortification received less parenteral protein than infants who were unfortified (-1.4 and -1.1 g/kg/d, respectively; P < .001). Similar patterns were observed for energy intake. Protein intake declined during phases 3 and 4. CONCLUSIONS: Infants paradoxically received less protein and energy on days with early fortification, suggesting that clinicians may lack easily accessible data to detect the association between nutrition delivery practices and overall nutrition in infants who are VLBW.

Use of Metformin for Weight Management in Children and Adolescents With Obesity in the Clinical Setting.

Use of metformin for weight loss for children in a clinical setting has not been well described; therefore, we aimed to identify characteristics of obese patients prescribed metformin in a clinical setting and evaluate changes in anthropometric measures. Records of obese patients aged 10 to 18 years without diabetes attending an academic endocrinology practice from 2009 to 2013 were reviewed. Analyses assessed changes in anthropometric measures (weight, body mass index [BMI], and BMI z-score) over 12 months between those prescribed metformin (n = 49) and those not prescribed metformin (n = 142). Outcomes were standardized before using multivariable linear regression models. Patients prescribed metformin were significantly older, more often female, and had larger baseline anthropometric measures (all P < .05). In the models, subjects prescribed metformin had significantly less gain in standardized weight, BMI, and BMI z-score over 6 and 12 months (all P < .05). Metformin may be a useful weight management aid in children in a clinical setting.