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ObjectiveTo explore trends in blood pressure (BP) control before and during the COVID-19 pandemic.Patients and methodsHealth systems participating in the National Patient-Centered Clinical Research Network (PCORnet) Blood Pressure Control Laboratory Surveillance System responded to data queries, producing 9 BP control metrics. Averages of the BP control metrics (weighted by numbers of observations in each health system) were calculated and compared between two 1-year measurement periods (January 1, 2019, through December 31, 2019, and January 1, 2020, through December 31, 2020).ResultsAmong 1,770,547 hypertensive persons in 2019, BP control to

Duchenne muscular dystrophy (DMD) is a serious, rare genetic disease, affecting primarily boys. It is caused by mutations in the DMD gene and is characterized by progressive muscle degeneration that results in loss of function and early death due to respiratory and/or cardiac failure. Although limited treatment options are available, some for only small subsets of the patient population, DMD remains a disease with large unmet medical needs. The adeno-associated virus (AAV) vector is the leading gene delivery system for addressing genetic neuromuscular diseases. Since the gene encoding the full-length dystrophin protein exceeds the packaging capacity of a single AAV vector, gene replacement therapy based on AAV-delivery of shortened, yet, functional microdystrophin genes has emerged as a promising treatment. This article seeks to explain the rationale for use of the accelerated approval pathway to advance AAV microdystrophin gene therapy for DMD. Specifically, we provide support for the use of microdystrophin expression as a surrogate endpoint that could be used in clinical trials to support accelerated approval.

BackgroundDiagnostic errors, reframed as missed opportunities for improving diagnosis (MOIDs), are poorly understood in the paediatric emergency department (ED) setting. We investigated the clinical experience, harm and contributing factors related to MOIDs reported by physicians working in paediatric EDs.MethodsWe developed a web-based survey in which physicians participating in the international Paediatric Emergency Research Network representing five out of six WHO regions, described examples of MOIDs involving their own or a colleague's patients. Respondents provided case summaries and answered questions regarding harm and factors contributing to the event.ResultsOf 1594 physicians surveyed, 412 (25.8%) responded (mean age=43 years (SD=9.2), 42.0% female, mean years in practice=12 (SD=9.0)). Patient presentations involving MOIDs had common undifferentiated symptoms at initial presentation, including abdominal pain (21.1%), fever (17.2%) and vomiting (16.5%). Patients were discharged from the ED with commonly reported diagnoses, including acute gastroenteritis (16.7%), viral syndrome (10.2%) and constipation (7.0%). Most reported MOIDs (65%) were detected on ED return visits (46% within 24 hours and 76% within 72 hours). The most common reported MOID was appendicitis (11.4%), followed by brain tumour (4.4%), meningitis (4.4%) and non-accidental trauma (4.1%). More than half (59.1%) of the reported MOIDs involved the patient/parent-provider encounter (eg, misinterpreted/ignored history or an incomplete/inadequate physical examination). Types of MOIDs and contributing factors did not differ significantly between countries. More than half of patients had either moderate (48.7%) or major (10%) harm due to the MOID.ConclusionsAn international cohort of paediatric ED physicians reported several MOIDs, often in children who presented to the ED with common undifferentiated symptoms. Many of these were related to patient/parent-provider interaction factors such as suboptimal history and physical examination. Physicians' personal experiences offer an underexplored source for investigating and mitigating diagnostic errors in the paediatric ED.

Background Uncontrolled blood pressure (BP) remains a leading cause of death in the United States. The American Medical Association developed a quality improvement program to improve BP control, but it is unclear how to efficiently implement this program at scale across multiple health systems. Methods and Results We conducted BP MAP (Blood Pressure Measure Accurately, Act Rapidly, and Partner With Patients), a comparative effectiveness trial with clinic-level randomization to compare 2 scalable versions of the quality improvement program: Full Support (with support from quality improvement expert) and Self-Guided (using only online materials). Outcomes were clinic-level BP control (

BackgroundTrichotillomania (TTM) and skin picking disorder (SPD) are common and often debilitating mental health conditions, grouped under the umbrella term of body-focused repetitive behaviors (BFRBs). Recent clinical subtyping found that there were three distinct subtypes of TTM and two of SPD. Whether these clinical subtypes map on to any unique neurobiological underpinnings, however, remains unknown.MethodsTwo hundred and fifty one adults [193 with a BFRB (85.5% [n = 165] female) and 58 healthy controls (77.6% [n = 45] female)] were recruited from the community for a multicenter between-group comparison using structural neuroimaging. Differences in whole brain structure were compared across the subtypes of BFRBs, controlling for age, sex, scanning site, and intracranial volume.ResultsWhen the subtypes of TTM were compared, low awareness hair pullers demonstrated increased cortical volume in the lateral occipital lobe relative to controls and sensory sensitive pullers. In addition, impulsive/perfectionist hair pullers showed relative decreased volume near the lingual gyrus of the inferior occipital-parietal lobe compared with controls.ConclusionsThese data indicate that the anatomical substrates of particular forms of BFRBs are dissociable, which may have implications for understanding clinical presentations and treatment response.

ObjectiveLactation consultants (LCs) positively impact chestfeeding rates by providing in-person support to struggling parents. In Brazil, LCs are a scarce resource and in high demand, risking chestfeeding rates across many communities nationwide. The transition to remote consultations during the COVID-19 pandemic made LCs face several challenges to solve chestfeeding problems due to limited technical resources for management, communication, and diagnosis. This study investigates the main technological issues LCs have in remote consultations and what technology features are helpful for chestfeeding problem-solving in remote settings.MethodsThis paper implements qualitative investigation through a contextual study ( n=10 ) and a participatory session ( n=5 ) to determine stakeholders' preferences for technology features in solving chestfeeding problems.FindingsThe contextual study with LCs in Brazil characterized (1) the current appropriation of technologies that help during consultations, (2) technology limitations that affect LCs' decision-making, (3) challenges and benefits of remote consultations, and (4) cases that are easy and difficult to solve remotely. The participatory session brings LCs' perceptions on (1) components for an effective remote evaluation, (2) preferred elements by professionals when providing remote feedback to parents, and (3) feelings about using technology resources for remote consultations.ConclusionFindings suggest that LCs adapted their methodologies for remote consultations, and the perceived benefits of this modality show interest in continuing to provide remote care as long as more integrative and nurturing applications are offered to their clients. We learned that fully remote lactation care might not be the main objective for overall populations in Brazil, but as a hybrid mode of care that benefits parents by having both modalities of consultations available to them. Finally, remote support helps reduce financial, geographic, and cultural barriers in lactation care. However, future research must identify how generalized solutions for remote lactation care can be, especially for different cultures and regions.

BackgroundSeasonal outbreaks of infectious conjunctivitis remain a public health issue. Determination of outbreak etiologies in the context of a worldwide pandemic may provide useful information to guide public health strategies. The aim of this study was to identify pathogens associated with outpatient infectious conjunctivitis during the COVID-19 Delta surge.MethodsThis prospective study was conducted from April 2021 to September 2021. All outpatients presenting to the Aravind Eye Center (Madurai, India) with signs and symptoms consistent with acute infectious conjunctivitis were eligible. Three swabs were obtained from each participant: one from each conjunctiva and one from the anterior nares. Samples were processed for metagenomic RNA deep sequencing (RNA-seq).ResultsSamples from 106 study participants were sequenced. The most common presenting symptoms were tearing (86%) and itching (71%). Preauricular lymphadenopathy was present in 38% of participants. 20% of participants had close contacts with similar symptoms. Systemic symptoms such as coughing, runny nose, vomiting or diarrhea were uncommonly reported. 60% of all participants used some medicated eye drops upon enrollment. 75% of study participants demonstrated infection with human adenovirus D (HAdV-D). 11% of conjunctivitis was associated with SARS-CoV-2. 15% had no definitive pathogen detected. 8% of all participants had codetection of more than one pathogen on RNA-seq.ConclusionsDuring the COVID-19 Delta surge in India, HAdV-D was the most common pathogen associated with infectious conjunctivitis. SARS-CoV-2 was the second most common associated pathogen. Seasonal surveillance may be necessary for the determination of emerging and reemerging pathogens responsible for infectious conjunctivitis.

ObjectivesWait time for emergency care is a quality measure that affects clinical outcomes and patient satisfaction. It is unknown if there is racial/ethnic variability in this quality measure in pediatric emergency departments (PEDs). We aim to determine whether racial/ethnic differences exist in wait times for children presenting to PEDs and examine between-site and within-site differences.MethodsWe conducted a retrospective cohort study for PED encounters in 2016 using the Pediatric Emergency Care Applied Research Network Registry, an aggregated deidentified electronic health registry comprising 7 PEDs. Patient encounters were included among all patients 18 years or younger at the time of the ED visit. We evaluated differences in emergency department wait time (time from arrival to first medical evaluation) considering patient race/ethnicity as the exposure.ResultsOf 448,563 visits, median wait time was 35 minutes (interquartile range, 17-71 minutes). Compared with non-Hispanic White (NHW) children, non-Hispanic Black (NHB), Hispanic, and other race children waited 27%, 33%, and 12% longer, respectively. These differences were attenuated after adjusting for triage acuity level, mode of arrival, sex, age, insurance, time of day, and month [adjusted median wait time ratios (95% confidence intervals): 1.11 (1.10-1.12) for NHB, 1.12 (1.11-1.13) for Hispanic, and 1.05 (1.03-1.06) for other race children compared with NHW children]. Differences in wait time for NHB and other race children were no longer significant after adjusting for clinical site. Fully adjusted median wait times among Hispanic children were longer compared with NHW children [1.04 (1.03-1.05)].ConclusionsIn unadjusted analyses, non-White children experienced longer PED wait times than NHW children. After adjusting for illness severity, patient demographics, and overcrowding measures, wait times for NHB and other race children were largely determined by site of care. Hispanic children experienced longer within-site and between-site wait times compared with NHW children. Additional research is needed to understand structures and processes of care contributing to wait time differences between sites that disproportionately impact non-White patients.

SARS-CoV-2 accesses host cells via angiotensin-converting enzyme-2, which is also affected by commonly used angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), raising concerns that ACEI or ARB exposure may portend differential COVID-19 outcomes. In parallel cohort studies of outpatient and inpatient COVID-19-diagnosed adults with hypertension, we assessed associations between antihypertensive exposure (ACEI/ARB vs. non-ACEI/ARB antihypertensives, as well as between ACEI- vs. ARB) at the time of COVID-19 diagnosis, using electronic health record data from PCORnet health systems. The primary outcomes were all-cause hospitalization or death (outpatient cohort) or all-cause death (inpatient), analyzed via Cox regression weighted by inverse probability of treatment weights. From February 2020 through December 9, 2020, 11,246 patients (3477 person-years) and 2200 patients (777 person-years) were included from 17 health systems in outpatient and inpatient cohorts, respectively. There were 1015 all-cause hospitalization or deaths in the outpatient cohort (incidence, 29.2 events per 100 person-years), with no significant difference by ACEI/ARB use (adjusted HR 1.01; 95% CI 0.88, 1.15). In the inpatient cohort, there were 218 all-cause deaths (incidence, 28.1 per 100 person-years) and ACEI/ARB exposure was associated with reduced death (adjusted HR, 0.76; 95% CI, 0.57, 0.99). ACEI, versus ARB exposure, was associated with higher risk of hospitalization in the outpatient cohort, but no difference in all-cause death in either cohort. There was no evidence of effect modification across pre-specified baseline characteristics. Our results suggest ACEI and ARB exposure have no detrimental effect on hospitalizations and may reduce death among hypertensive patients diagnosed with COVID-19.

Background The National Patient-Centered Clinical Research Network Blood Pressure Control Laboratory Surveillance System was established to identify opportunities for blood pressure (BP) control improvement and to provide a mechanism for tracking improvement longitudinally. Methods and Results We conducted a serial cross-sectional study with queries against standardized electronic health record data in the National Patient-Centered Clinical Research Network (PCORnet) common data model returned by 25 participating US health systems. Queries produced BP control metrics for adults with well-documented hypertension and a recent encounter at the health system for a series of 1-year measurement periods for each quarter of available data from January 2017 to March 2020. Aggregate weighted results are presented overall and by race and ethnicity. The most recent measurement period includes data from 1 737 995 patients, and 11 956 509 patient-years were included in the trend analysis. Overall, 15% were Black, 52% women, and 28% had diabetes. BP control (

Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.

ObjectivesThe Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks.MethodsThe Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children.ResultsBeginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings.ConclusionsThe Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will involve focus in 4 areas: (1) expanding the capacity for global randomized controlled trials; (2) deepening the focus on implementation science; (3) increasing attention to healthcare disparities and their origins, with growing momentum toward equity; and (4) expanding PERN's global reach through addition of sites and networks from resource-restricted regions. Through these actions, PERN will be able to build on successes to face the challenges ahead and meet the needs of acutely ill and injured children throughout the world.

As part of an investment by the Bill & Melinda Gates Foundation to support the Government of Bihar to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide, BBC Media Action implemented multiple communication tools to support front-line worker (FLW) outreach. We analyse the impacts of a package of mHealth audio messaging and paper-based job aids used by FLWs during government-sponsored village health, sanitation and nutrition days (VHSNDs) on knowledge and practices of childbearing women across the RMNCHN continuum of care. Data from two surveys collected between July and September 2016 were analysed using logistic regression to compare health-related knowledge and behaviours between women who had been exposed at VHSNDs to the mHealth GupShup Potli (GSP) audio recordings or interpersonal communication (IPC) tools versus those who were unexposed. Exposure to GSP recordings (n=2608) was associated with improved knowledge across all continuum-of-care domains, as well as improved health-related behaviours in some domains. The odds of having taken iron-folic acid (IFA) tablets were significantly higher in exposed women (OR 1.5, 95% CI 1.1 to 2.2), as was contraceptive use (OR 2.0, 95% CI 1.2 to 3.2). There were no differences in birth preparedness or complementary feeding practices between groups. Exposure to IPC paper-based tools (n=2002) was associated with a twofold increased odds of IFA consumption (OR 2.3, 95% CI 1.7 to 3.2) and contraceptive use (OR 1.8, 95% CI 1.2 to 2.8). Women exposed to both tools were generally at least twice as likely to subsequently discuss the messages with others. BBC Media Action's mHealth audio messaging job aids and paper-based IPC tools were associated with improved knowledge and practices of women who were exposed to them across multiple domains, suggesting their important potential for improving health outcomes for beneficiaries at scale in low-resource settings. NCT02726230.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

ObjectiveTo quantify the association between early neurologic recovery, practice pattern variation, and endotracheal intubation during established status epilepticus, we performed a secondary analysis within the cohort of patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT).MethodsWe evaluated factors associated with the endpoint of endotracheal intubation occurring within 120 minutes of ESETT study drug initiation. We defined a blocked, stepwise multivariate regression, examining 4 phases during status epilepticus management: (1) baseline characteristics, (2) acute treatment, (3) 20-minute neurologic recovery, and (4) 60-minute recovery, including seizure cessation and improving responsiveness.ResultsOf 478 patients, 117 (24.5%) were intubated within 120 minutes. Among high-enrolling sites, intubation rates ranged from 4% to 32% at pediatric sites and 19% to 39% at adult sites. Baseline characteristics, including seizure precipitant, benzodiazepine dosing, and admission vital signs, provided limited discrimination for predicting intubation (area under the curve [AUC] 0.63). However, treatment at sites with an intubation rate in the highest (vs lowest) quartile strongly predicted endotracheal intubation independently of other treatment variables (adjusted odds ratio [aOR] 8.12, 95% confidence interval [CI] 3.08-21.4, model AUC 0.70). Site-specific variation was the factor most strongly associated with endotracheal intubation after adjustment for 20-minute (aOR 23.4, 95% CI 6.99-78.3, model AUC 0.88) and 60-minute (aOR 14.7, 95% CI 3.20-67.5, model AUC 0.98) neurologic recovery.ConclusionsEndotracheal intubation after established status epilepticus is strongly associated with site-specific practice pattern variation, independently of baseline characteristics, and early neurologic recovery and should not alone serve as a clinical trial endpoint in established status epilepticus.Trial registration informationClinicalTrials.gov Identifier: NCT01960075.

Body-focused repetitive behavior disorders (BFRBs) include Trichotillomania (TTM; Hair pulling disorder) and Excoriation (Skin Picking) Disorder (SPD). These conditions are prevalent, highly heterogeneous, under-researched, and under-treated. In order for progress to be made in optimally classifying and treating these conditions, it is necessary to identify meaningful subtypes. 279 adults (100 with TTM, 81 with SPD, 40 with both TTM and SPD, and 58 controls) were recruited for an international, multi-center between-group comparison using mixture modeling, with stringent correction for multiple comparisons. The main outcome measure was to examine distinct subtypes (aka latent classes) across all study participants using item-level data from gold-standard instruments assessing detailed clinical measures. Mixture models identified 3 subtypes of TTM (entropy 0.98) and 2 subtypes of SPD (entropy 0.99) independent of the control group. Significant differences between these classes were identified on measures of disability, automatic and focused symptoms, perfectionism, trait impulsiveness, and inattention and hyperactivity. These data indicate the existence of three separate subtypes of TTM, and two separate subtypes of SPD, which are distinct from controls. The identified clinical differences between these latent classes may be useful to tailor future treatments by focusing on particular traits. Future work should examine whether these latent subtypes relate to treatment outcomes, or particular psychobiological findings using neuroimaging techniques.

In 2010, the Bill and Melinda Gates Foundation (BMGF) partnered with the Government of Bihar (GoB), India to launch the Ananya program to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) outcomes. The program sought to address supply- and demand-side barriers to the adoption, coverage, quality, equity and health impact of select RMNCHN interventions. Approaches included strengthening frontline worker service delivery; social and behavior change communications; layering of health, nutrition and sanitation into women's self-help groups (SHGs); and quality improvement in maternal and newborn care at primary health care facilities. Ananya program interventions were piloted in approximately 28 million population in eight innovation districts from 2011-2013, and then beginning in 2014, were scaled up by the GoB across the rest of the state's population of 104 million. A Bihar Technical Support Program provided techno-managerial support to governmental Health as well as Integrated Child Development Services, and the JEEViKA Technical Support Program supported health layering and scale-up of the GoB's SHG program. The level of support at the block level during statewide scale-up in 2014 onwards was approximately one-fourth that provided in the pilot phase of Ananya in 2011-2013. This paper - the first manuscript in an 11-manuscript and 2-viewpoint collection on Learning from Ananya: Lessons for primary health care performance improvement - seeks to provide a broad description of Ananya and subsequent statewide adaptation and scale-up, and capture the background and context, key objectives, interventions, delivery approaches and evaluation methods of this expansive program. Subsequent papers in this collection focus on specific intervention delivery platforms. For the analyses in this series, Stanford University held key informant interviews and worked with the technical support and evaluation grantees of the Ananya program, as well as leadership from the India Country Office of the BMGF, to analyse and synthesise data from multiple sources. Capturing lessons from the Ananya pilot program and statewide scale-up will assist program managers and policymakers to more effectively design and implement RMNCHN programs at scale through technical assistance to governments.

BackgroundMobile health (mHealth) tools have potential for improving the reach and quality of health information and services through community health workers in low- and middle-income countries. This study evaluates the impact of an mHealth tool implemented at scale as part of the statewide reproductive,maternal, newborn and child health and nutrition (RMNCHN) program in Bihar, India.MethodsThree survey-based data sets were analysed to compare the health-related knowledge, attitudes and behaviours amongst childbearing women exposed to the Mobile Kunji and Dr. Anita mHealth tools during their visits with frontline workers compared with those who were unexposed.ResultsAn evaluation by Mathematica (2014) revealed that exposure to Mobile Kunji and Dr. Anita recordings were associated with significantly higher odds of consuming iron-folic acid tablets (odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.8-3.1) as well as taking a set of three measures for delivery preparedness (OR = 2.8, 95% CI = 1.9-4.2) and appropriate infant complementary feeding (OR = 1.9, 95% CI = 1.0-3.5). CARE India's Community-based Household Surveys (2012-2017) demonstrated significant improvements in early breastfeeding (OR = 1.64, 95% CI = 1.5-1.78) and exclusive breastfeeding (OR = 1.46, 95% CI = 1.33-1.62) in addition to birth preparedness practices. BBC Media Action's Usage & Engagement Survey (2014) demonstrated a positive association between exposure to Mobile Kunji and Dr. Anita and exclusive breastfeeding (58% exposed vs 43% unexposed, P

BackgroundIsocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma.MethodsThis multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857.FindingsBetween Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

To test the hypotheses that minority children with long-bone fractures are less likely to (1) receive analgesics, (2) receive opioid analgesics, and (3) achieve pain reduction. We performed a 3-year retrospective cross-sectional study of children

PurposeTo map and measure the depths of corneal neovascularization (NV) using 3-dimensional optical coherence tomography angiography (OCTA) at 2 different wavelengths.MethodsCorneal NV of varying severity, distribution, and underlying etiology was examined. Average NV depth and vessel density were measured using 840-nm spectral-domain OCTA and 1050-nm swept-source OCTA. The OCTA results were compared with clinical slit-lamp estimation of NV depth.ResultsTwelve eyes with corneal NV from 12 patients were imaged with OCTA. Clinically "superficial," "midstromal," and "deep" cases had an average vessel depth of 23%, 39%, and 66% on 1050-nm OCTA, respectively. Average vessel depth on OCTA followed a statistically significant ordinal trend according to the clinical classification of vessel depth (Jonckheere-Terpstra test, P < 0.001). In 8 cases where both 840-nm OCTA and 1050-nm OCTA were acquired, there was excellent agreement in the mean vessel depth between the 2 systems (concordance correlation coefficient = 0.94, P < 0.001). The average vessel density measured by 840-nm OCTA was higher (average 1.6-fold) than that measured by 1050-nm OCTA.ConclusionsCorneal OCTA was able to map corneal NV in 3 dimensions and measure vessel depth and density. The depth of corneal NV varied between different pathologies in a manner consistent with previous pathologic studies. The measured vessel density appeared to be affected by the interscan time, which affects blood flow velocity sensitivity, and the wavelength, which affects the ability to penetrate through opacity. These findings suggest possible clinical applications of OCTA for the diagnosis of corneal pathology and quantitative monitoring of therapeutic response in patients with corneal NV.

ObjectiveDifferences in the quality of emergency department (ED) care are often attributed to nonclinical factors such as variations in the structure, systems, and processes of care. Few studies have examined these associations among children. We aimed to determine whether process measures of quality of care delivered to patients receiving care in children's hospital EDs were associated with physician-level or hospital-level factors.MethodsWe included children (

BackgroundBenzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.MethodsIn this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.FindingsBetween Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.InterpretationChildren, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.FundingNational Institute of Neurological Disorders and Stroke, National Institutes of Health.

BackgroundUncontrolled blood pressure (BP) is a leading preventable cause of death that remains common in the US population despite the availability of effective medications. New technology and program innovation has high potential to improve BP but may be expensive and burdensome for patients, clinicians, health systems, and payers and may not produce desired results or reduce existing disparities in BP control.Methods and resultsThe PCORnet Blood Pressure Control Laboratory is a platform designed to enable national surveillance and facilitate quality improvement and comparative effectiveness research. The platform uses PCORnet, the National Patient-Centered Clinical Research Network, for engagement of health systems and collection of electronic health record data, and the Eureka Research Platform for eConsent and collection of patient-reported outcomes and mHealth data from wearable devices and smartphones. Three demonstration projects are underway: BP track will conduct national surveillance of BP control and related clinical processes by measuring theory-derived pragmatic BP control metrics using electronic health record data, with a focus on tracking disparities over time; BP MAP will conduct a cluster-randomized trial comparing effectiveness of 2 versions of a BP control quality improvement program; BP Home will conduct an individual patient-level randomized trial comparing effectiveness of smartphone-linked versus standard home BP monitoring. Thus far, BP Track has collected electronic health record data from over 826 000 eligible patients with hypertension who completed ≈3.1 million ambulatory visits. Preliminary results demonstrate substantial room for improvement in BP control (

ObjectivesWomen face distinct barriers to meeting their reproductive health needs postpartum, especially women who deliver preterm. Pediatric encounters present unique opportunities to address women's family planning, particularly within 18 months of a prior pregnancy, when pregnancy has an elevated risk of an adverse outcome, such as preterm birth. To ensure maternal family planning initiatives are designed in a patient-centered manner, we explored perspectives on addressing reproductive health in a pediatric setting among women with and without a recent preterm delivery.MethodsWe conducted semi-structured, qualitative interviews with 41 women (66% delivered preterm). Women who delivered at any gestational age were interviewed at a pediatric primary care clinic. We also interviewed women whose infants were either in a level II intensive care nursery or attending a high-risk infant follow-up clinic, all of whom had delivered preterm. Data were analyzed using team-based coding and theme analysis.ResultsWhile women's preferred timing and setting for addressing peripartum contraception varied, they largely considered pediatric settings to be an acceptable place to discuss family planning. A few women felt family planning fell outside of the pediatric scope or distracted from the child focus. Women discussed various barriers to accessing family planning care postpartum, including circumstances unique to women who delivered preterm.Conclusions for practiceFamily planning interventions in pediatric settings were overall an acceptable approach to reducing barriers to care among our sample of women who predominantly delivered preterm. These exploratory findings justify further investigation to assess their generalizability and to develop maternal family planning interventions for pediatric settings.

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

BackgroundDuplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype.MethodsTo test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome (n = 27) to (1) the pharmacological effects of the GABAA modulator midazolam (n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children (n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A-silenced allele).ResultsPeak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels (f = 23.0 Hz) as Dup15q syndrome (f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort.ConclusionsOur results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome.

BackgroundThe choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.MethodsIn a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.ResultsA total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.ConclusionsIn the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

While improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis sparked us to reexamine a large kindred originally reported over 50 years ago with an autosomal dominant inheritance pattern of chronic pancreatitis, diabetes and pancreatic adenocarcinoma. Whole exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease Elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines and in CRISPR-Cas9 engineered mice indicate that this mutation causes translational upregulation of CELA3B, which upon secretion and activation by trypsin leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatitic proteases have been previously linked to hereditary pancreatitis, this is the first known instance of a mutation in CELA3B and a defect in translational control contributing to this disease.

Brain metastases (BM) from extracranial cancer are associated with significant morbidity and mortality. Effective local treatment options are stereotactic radiotherapy, including radiosurgery or fractionated external beam radiotherapy, and surgical resection. The use of systemic treatment for intracranial disease control also is improving. BM diagnosis, treatment planning, and follow-up is most often based on contrast-enhanced magnetic resonance imaging (MRI). However, anatomic imaging modalities including standard MRI have limitations in accurately characterizing posttherapeutic reactive changes and treatment response. Molecular imaging techniques such as positron emission tomography (PET) characterize specific metabolic and cellular features of metastases, potentially providing clinically relevant information supplementing anatomic MRI. Here, the Response Assessment in Neuro-Oncology working group provides recommendations for the use of PET imaging in the clinical management of patients with BM based on evidence from studies validated by histology and/or clinical outcome.

Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.

Chronic kidney disease (CKD) is a major non-communicable disease associated with high rates of premature morbidity and mortality. The prevalence of hypovitaminosis D (deficiency of 25(OH)D or 25D) is greater in racial/ethnic minorities and in patients with CKD than the general population. Low 25D is associated with bone and mineral disorders as well as immune, cardiometabolic and cardiovascular (CV) diseases. Thus, it has been suggested that low 25D contributes to the poor outcomes in patients with CKD. The prevalence of hypovitaminosis D rises progressively with advancing severity of kidney disease with over 30% of patients with CKD stage 3 and 70% patients with CKD stage 5 estimated to have low levels of 25D. This report describes several of the abnormal physiologic and counter-regulatory actions related to low 25D in CKD such as those in oxidative stress and inflammatory systems, and some of the preclinical and clinical evidence, or lack thereof, of normalizing serum 25D levels to improve outcomes in patients with CKD, and especially for the high risk subset of racial/ethnic minorities who suffer from higher rates of advanced CKD and hypovitaminosis D.

BackgroundTo overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288).MethodsA total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS).ResultsVolumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS.ConclusionsT1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

Background:Corticosteroids are the mainstay of treatment for peritumor edema but are often associated with significant side effects. Therapies that can reduce corticosteroid use would potentially be of significant benefit to patients. However, currently there are no standardized endpoints evaluating corticosteroid use in neuro-oncology clinical trials. Methods:The Response Assessment in Neuro-Oncology (RANO) Working Group has developed consensus recommendations for endpoints evaluating corticosteroid use in clinical trials in both adults and children with brain tumors. Results:Responders are defined as patients with a 50% reduction in total daily corticosteroid dose compared with baseline or reduction of the total daily dose to ≤2 mg of dexamethasone (or equivalent dose of other corticosteroid); baseline dose must be at least 4 mg of dexamethasone daily (or equivalent dose of other corticosteroids) for at least one week. Patients must have stable or improved Neurologic Assessment in Neuro-Oncology (NANO) score or Karnofsky performance status score or Eastern Cooperative Oncology Group (ECOG) (Lansky score for children age

ObjectiveTo evaluate the consistency, reliability, and validity of an implicit review instrument that measures the quality of care provided to children in the emergency department (ED).Data sources/study settingMedical records of randomly selected children from 12 EDs in the Pediatric Emergency Care Applied Research Network (PECARN).Study designEight pediatric emergency medicine physicians applied the instrument to 620 medical records.Data collection/extraction methodsWe determined internal consistency using Cronbach's alpha and inter-rater reliability using the intraclass correlation coefficient (ICC). We evaluated the validity of the instrument by correlating scores with four condition-specific explicit review instruments.Principal findingsIndividual reviewers' Cronbach's alpha had a mean of 0.85 with a range of 0.76-0.97; overall Cronbach's alpha was 0.90. The ICC was 0.49 for the summary score with a range from 0.40 to 0.46. Correlations between the quality of care score and the four condition-specific explicit review scores ranged from 0.24 to 0.38.ConclusionsThe quality of care instrument demonstrated good internal consistency, moderate inter-rater reliability, high inter-rater agreement, and evidence supporting validity. The instrument could be useful for systems' assessment and research in evaluating the care delivered to children in the ED.

ObjectiveQuality of care delivered to adult patients in the emergency department (ED) is often associated with demographic and clinical factors such as a patient's race/ethnicity and insurance status. We sought to determine whether the quality of care delivered to children in the ED was associated with a variety of patient-level factors.MethodsThis was a retrospective, observational cohort study. Pediatric patients (

BackgroundThe World Health Organization recommends that human growth should be monitored with the use of international standards. However, in obstetric practice, we continue to monitor fetal growth using numerous local charts or equations that are based on different populations for each body structure. Consistent with World Health Organization recommendations, the INTERGROWTH-21st Project has produced the first set of international standards to date pregnancies; to monitor fetal growth, estimated fetal weight, Doppler measures, and brain structures; to measure uterine growth, maternal nutrition, newborn infant size, and body composition; and to assess the postnatal growth of preterm babies. All these standards are based on the same healthy pregnancy cohort. Recognizing the importance of demonstrating that, postnatally, this cohort still adhered to the World Health Organization prescriptive approach, we followed their growth and development to the key milestone of 2 years of age.ObjectiveThe purpose of this study was to determine whether the babies in the INTERGROWTH-21st Project maintained optimal growth and development in childhood.Study designIn the Infant Follow-up Study of the INTERGROWTH-21st Project, we evaluated postnatal growth, nutrition, morbidity, and motor development up to 2 years of age in the children who contributed data to the construction of the international fetal growth, newborn infant size and body composition at birth, and preterm postnatal growth standards. Clinical care, feeding practices, anthropometric measures, and assessment of morbidity were standardized across study sites and documented at 1 and 2 years of age. Weight, length, and head circumference age- and sex-specific z-scores and percentiles and motor development milestones were estimated with the use of the World Health Organization Child Growth Standards and World Health Organization milestone distributions, respectively. For the preterm infants, corrected age was used. Variance components analysis was used to estimate the percentage variability among individuals within a study site compared with that among study sites.ResultsThere were 3711 eligible singleton live births; 3042 children (82%) were evaluated at 2 years of age. There were no substantive differences between the included group and the lost-to-follow up group. Infant mortality rate was 3 per 1000; neonatal mortality rate was 1.6 per 1000. At the 2-year visit, the children included in the INTERGROWTH-21st Fetal Growth Standards were at the 49th percentile for length, 50th percentile for head circumference, and 58th percentile for weight of the World Health Organization Child Growth Standards. Similar results were seen for the preterm subgroup that was included in the INTERGROWTH-21st Preterm Postnatal Growth Standards. The cohort overlapped between the 3rd and 97th percentiles of the World Health Organization motor development milestones. We estimated that the variance among study sites explains only 5.5% of the total variability in the length of the children between birth and 2 years of age, although the variance among individuals within a study site explains 42.9% (ie, 8 times the amount explained by the variation among sites). An increase of 8.9 cm in adult height over mean parental height is estimated to occur in the cohort from low-middle income countries, provided that children continue to have adequate health, environmental, and nutritional conditions.ConclusionThe cohort enrolled in the INTERGROWTH-21st standards remained healthy with adequate growth and motor development up to 2 years of age, which supports its appropriateness for the construction of international fetal and preterm postnatal growth standards.

BackgroundCabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM).MethodsPatients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety.ResultsAmong 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions.ConclusionsCabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM.Clinical trials registration numberNCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).

BackgroundCabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM).MethodsPatients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety.ResultsAmong 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome.ConclusionsCabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions.Clinical trials registration numberNCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).

Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), CSF cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined. We recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other Response Assessment in Neuro-Oncology recommendations, these need to now be prospectively validated in clinical trials.

Background and Objective: One third of children with epilepsy are refractory to medications. Growing data support a role of common childhood infections with neurotropic viruses and inflammation in epileptogenesis. Our objective was to determine the frequency of Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) infection and cytokine levels in saliva from children with seizures compared to healthy controls and to controls with a febrile illness without seizures. Methods: In this cross-sectional multi-center study, we collected saliva from 115 consecutive children with acute seizures (cases), 51 children with a fever and no seizures or underlying neurological disease (fever controls) and 46 healthy children (healthy controls). Specimens were analyzed by a novel droplet digital PCR for HHV-6 and EBV viral DNA and a bead-based immunoassay for neuroinflammatory cytokines. Results: Cases included febrile seizures (n = 30), acute seizures without (n = 53) and with fever (n = 4) in chronic epilepsy, new onset epilepsy (n = 13), febrile status epilepticus (n = 3), and first lifetime seizure (n = 12). HHV-6 DNA was found in 40% of cases vs. 37% fever controls and 35% healthy controls, with no statistically significant differences. EBV DNA was also detected with no differences in 17% cases, 16% fever controls, and 28% healthy controls. IL-8 and IL-1β were increased in saliva of 32 random samples from cases compared with 30 fever controls: IL-8 cases mean (SD): 1158.07 pg/mL (1427.41); controls 604.92 (754.04); p = 0.02. IL-1β 185.76 (230.57); controls 86.99 (187.39); p = 0.0002. IL-1β level correlated with HHV6 viral load (p = 0.007). Conclusion: Increase in inflammatory cytokines may play a role in the onset of acute seizures and saliva could represent an inexpensive and non-invasive method for detection of viral DNA and cytokines.

BackgroundPrivate health insurance is associated with improved outcomes in patients with cancer. However, to the authors' knowledge, little is known regarding the impact of the Patient Protection and Affordable Care Act Dependent Coverage Expansion (ACA-DCE), which extended private insurance to young adults (to age 26 years) beginning in 2010, on the insurance status of young adults with cancer.MethodsThe current study was a retrospective, population-based analysis of hospitalized young adult oncology patients (aged 22-30 years) in California during 2006 through 2014 (11,062 patients). Multivariable regression analyses examined factors associated with having private insurance. Results were presented as adjusted odds ratios and 95% confidence intervals. A difference-in-difference analysis examined the influence of the ACA-DCE on insurance coverage by race/ethnicity and federal poverty level.ResultsMultivariable regression demonstrated that patients of black and Hispanic race/ethnicity were less likely to have private insurance before and after the ACA-DCE, compared with white patients. Younger age (22-25 years) was associated with having private insurance after implementation of the ACA-DCE (odds ratio, 1.20; 95% confidence interval, 1.06-1.35). In the difference-in-difference analysis, private insurance increased among white patients aged 22 to 25 years who were living in medium-income (2006-2009: 64.6% vs 2011-2014: 69.1%; P = .003) and high-income (80.4% vs 82%; P = .043) zip codes and among Asians aged 22 to 25 years living in high-income zip codes (73.2 vs 85.7%; P = .022). Private insurance decreased for all Hispanic patients aged 22 to 25 years between the 2 time periods.ConclusionsThe ACA-DCE provision increased insurance coverage, but not among all patients. Private insurance increased for white and Asian patients in higher income neighborhoods, potentially widening social disparities in private insurance coverage among young adults with cancer. Cancer 2018;124:110-7. © 2017 American Cancer Society.

Background and objectivesIn the primary care setting, there are racial and ethnic differences in antibiotic prescribing for acute respiratory tract infections (ARTIs). Viral ARTIs are commonly diagnosed in the pediatric emergency department (PED), in which racial and ethnic differences in antibiotic prescribing have not been previously reported. We sought to investigate whether patient race and ethnicity was associated with differences in antibiotic prescribing for viral ARTIs in the PED.MethodsThis is a retrospective cohort study of encounters at 7 PEDs in 2013, in which we used electronic health data from the Pediatric Emergency Care Applied Research Network Registry. Multivariable logistic regression was used to examine the association between patient race and ethnicity and antibiotics administered or prescribed among children discharged from the hospital with viral ARTI. Children with bacterial codiagnoses, chronic disease, or who were immunocompromised were excluded. Covariates included age, sex, insurance, triage level, provider type, emergency department type, and emergency department site.ResultsOf 39 445 PED encounters for viral ARTIs that met inclusion criteria, 2.6% (95% confidence interval [CI] 2.4%-2.8%) received antibiotics, including 4.3% of non-Hispanic (NH) white, 1.9% of NH black, 2.6% of Hispanic, and 2.9% of other NH children. In multivariable analyses, NH black (adjusted odds ratio [aOR] 0.44; CI 0.36-0.53), Hispanic (aOR 0.65; CI 0.53-0.81), and other NH (aOR 0.68; CI 0.52-0.87) children remained less likely to receive antibiotics for viral ARTIs.ConclusionsCompared with NH white children, NH black and Hispanic children were less likely to receive antibiotics for viral ARTIs in the PED. Future research should seek to understand why racial and ethnic differences in overprescribing exist, including parental expectations, provider perceptions of parental expectations, and implicit provider bias.

BackgroundAdolescents and young adults (AYAs) ages 15 to 39 years with cancer continue to experience disparate survival outcomes compared with their younger and older counterparts. This may be caused in part by differential access to specialized cancer centers (SCCs), because treatment at SCCs has been associated with improved overall survival. The authors examined social and clinical factors associated with AYA use of SCCs (defined as Children's Oncology Group-designated or National Cancer Institute-designated centers).MethodsA retrospective, population-based analysis was performed on all hospital admissions of AYA oncology patients in California during 1991 through 2014 (n = 127,250) using the Office of Statewide Health Planning and Development database. Multivariable logistic regression analyses examined the contribution of social and clinical factors on always receiving care from an SCC (vs sometimes or never). Results are presented as adjusted odds ratios (ORs) and 95% confidence intervals (CIs).ResultsOver the past 20 years, the percentage of patients always receiving inpatient care at an SCC increased over time (from 27% in 1991 to 43% in 2014). In multivariable regression analyses, AYA patients were less likely to always receive care from an SCC if they had public insurance (OR, 0.64; 95% CI, 0.62-0.66), were uninsured (OR, 0.51; 95% CI, 0.46-0.56), were Hispanic (OR, 0.88; 95% CI, 0.85-0.91), lived > 5 miles from an SCC, or had a diagnosis other than leukemia and central nervous system tumors.ConclusionsReceiving care at an SCC was influenced by insurance, race/ethnicity, geography, and tumor type. Identifying the barriers associated with decreased SCC use is an important first step toward improving outcomes in AYA oncology patients. Cancer 2017;123:2516-23. © 2017 American Cancer Society.

6561 Background: Private health insurance is associated with improved outcomes in cancer patients. We know little, however, about the impact of the ACA-DCE, which extended private insurance to young adults (up to age 26) beginning in 2010, on the insurance status of young adults with cancer. This study sought to determine the effect of the ACA-DCE on having private insurance coverage among hospitalized young adult oncology patients. Methods: We performed a retrospective, population-based analysis of hospitalized young adult oncology patients (22-30 years-old) in California during 2006-2014 (n = 11,062) using the Office of Statewide Health Planning and Development database. Multivariable regression analyses examined the social and clinical predictors of having private insurance. Results are presented as adjusted odds ratios (OR) and 95% confidence intervals (CIs). A difference-in-difference analysis examined the influence of the ACA-DCE on insurance coverage by race/ethnicity and zip code federal poverty level. Results: Multivariable regression demonstrated patients of black and Hispanic race/ethnicity were less likely to have private insurance both before and after the ACA-DCE, compared to non-Hispanic white patients. Younger age (22-25 years) was associated with having private insurance after the ACA-DCE implementation (OR 1.18, CI 1.05-1.33; reference, 27-30 years). In the difference-in-difference analysis, private insurance increased among non-Hispanic whites aged 22-25 living in medium- (2006-2009: 64.6% versus (vs) 2011-2014: 69.1%; p = 0.003) and high-income zip codes (80.4% vs 82%; p = 0.043) and among Asian patients aged 22-25 living in high-income zip codes (73.2 vs 85.7%; p = 0.022). Private insurance decreased for all Hispanic patients aged 22-25 between the two time periods. Conclusions: The ACA-DCE provision was an important first step in increasing coverage, but it was not universal and generated disparity in coverage as gains occurred for non-Hispanic white and Asian patients living in higher income zip codes. This policy change was shown to increase coverage for a traditionally underinsured population and attention should now focus on those remaining uninsured.

ObjectiveTo examine pediatric emergency department (ED) visits over 5 years, trends in injury severity, and associations between injury-related ED visit outcome and patient and community-level sociodemographic characteristics.Study designRetrospective analysis of administrative data provided to the Pediatric Emergency Care Applied Research Network Core Data Project, 2004-2008. Home addresses were geocoded to determine census block group and associated sociodemographic characteristics. Maximum Abbreviated Injury Scale severity and Severity Classification System scores were calculated. Generalized estimating equations were used to test for associations between sociodemographic characteristics and admission or transfer among injury-related ED visits.ResultsOverall ED visits and injury-related visits increased from 2004 to 2008 at study sites. Of 2,833676 successfully geocoded visits, 700,821 (24.7%) were injury-related. The proportion of higher severity injury-related visits remained consistent. Nearly 10% of injury-related visits resulted in admission or transfer each year. After adjusting for age, sex, payer, and injury severity, odds of admission or transfer were lower among minority children and children from areas with moderate and high prevalence of poverty.ConclusionsPediatric injury-related ED visits to included sites increased over the study period while injury severity, anticipated resource utilization, and visit outcomes remained stable, with low rates of admission or transfer. Sociodemographic differences in injury-related visits and ED disposition were apparent. ED-based injury surveillance is essential to understand disparities, inform targets for prevention programs, and reduce the overall burden of childhood injuries.

ObjectivesThis article describes the Standard Interview for Evidence Use (SIEU), a measure to assess the level of engagement in acquiring, evaluating, and applying research evidence in health and social service settings.MethodThree scales measuring input, process, and output of research evidence and eight subscales were identified using principal axis factor analysis and parallel analysis of data collected from 202 state and county child welfare, mental health, and juvenile justice systems leaders.ResultsThe SIEU scales and subscales demonstrate strong internal consistency as well as convergent and discriminant validity.ConclusionsThe SIEU is easy to use and can be administered as a complete scale or as three smaller scales to separately examine evidence in acquisition, evaluation, or application. The measure demonstrates potential in understanding the role of research evidence in service settings and in monitoring the process of evidence-based practice and application of scientific principles in social work practice.

This guideline provides recommendations for the use of PET imaging in gliomas. The review examines established clinical benefit in glioma patients of PET using glucose ((18)F-FDG) and amino acid tracers ((11)C-MET, (18)F-FET, and (18)F-FDOPA). An increasing number of studies have been published on PET imaging in the setting of diagnosis, biopsy, and resection as well radiotherapy planning, treatment monitoring, and response assessment. Recommendations are based on evidence generated from studies which validated PET findings by histology or clinical course. This guideline emphasizes the clinical value of PET imaging with superiority of amino acid PET over glucose PET and provides a framework for the use of PET to assist in the management of patients with gliomas.

PurposeTo differentiate between keratoconus and contact lens-related corneal warpage by combining focal change patterns in anterior corneal topography, pachymetry, and epithelial thickness maps.MethodsPachymetry and epithelial thickness maps of normal, keratoconus, and warpage, and forme fruste keratoconus (FFK) eyes were obtained from a Fourier-domain optical coherence tomography (OCT). Epithelial pattern standard deviation (PSD) was calculated and combined with two novel indices, the Warpage Index and the Anterior Ectasia Index, to differentiate between normal, keratoconus, and warpage eyes. The values of the three parameters were compared between groups.ResultsThe study included 22 normal, 31 keratoconic, 11 warpage, and 8 FFK eyes. The epithelial PSD was normal (< 0.041) for 100% normal eyes and abnormal (> 0.041) for 100% of keratoconic eyes, 81.8% of warpage eyes, and 87.5% of FFK eyes. The Anterior Ectasia Index of normal eyes (1.66 ± 0.74) was significantly lower than that for the keratoconus eyes (17.5 ± 7.17), the warpage eyes (2.98 ± 1.69), and the FFK eyes (6.95 ± 5.86). The Warpage Index was positive in all warpage eyes and negative for all keratoconic and FFK eyes except three wearing rigid gas-permeable contact lens.ConclusionsThe epithelial PSD can distinguish normal from keratoconus or warpage, but does not distinguish between these two conditions. The Anterior Ectasia Index is abnormal in keratoconus but not warpage. The Warpage Index is positive for warpage and negative for keratoconus, except in cases where keratoconus and warpage coexist. Together, the three parameters are strong tripartite discriminators of normal, keratoconus, and warpage.