Dell Children's Medical Center of Central Texas

Abstract The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

The stigmatization of people with obesity is widespread and causes harm. Weight stigma is often propagated and tolerated in society because of beliefs that stigma and shame will motivate people to lose weight. However, rather than motivating positive change, this stigma contributes to behaviors such as binge eating, social isolation, avoidance of health care services, decreased physical activity, and increased weight gain, which worsen obesity and create additional barriers to healthy behavior change. Furthermore, experiences of weight stigma also dramatically impair quality of life, especially for youth. Health care professionals continue to seek effective strategies and resources to address the obesity epidemic; however, they also frequently exhibit weight bias and stigmatizing behaviors. This policy statement seeks to raise awareness regarding the prevalence and negative effects of weight stigma on pediatric patients and their families and provides 6 clinical practice and 4 advocacy recommendations regarding the role of pediatricians in addressing weight stigma. In summary, these recommendations include improving the clinical setting by modeling best practices for nonbiased behaviors and language; using empathetic and empowering counseling techniques, such as motivational interviewing, and addressing weight stigma and bullying in the clinic visit; advocating for inclusion of training and education about weight stigma in medical schools, residency programs, and continuing medical education programs; and empowering families to be advocates to address weight stigma in the home environment and school setting.

Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

IMPORTANCE: Previous assessments of readiness of emergency departments (EDs) have not been comprehensive and have shown relatively poor pediatric readiness, with a reported weighted pediatric readiness score (WPRS) of 55. OBJECTIVES: To assess US EDs for pediatric readiness based on compliance with the 2009 guidelines for care of children in EDs; to evaluate the effect of physician/nurse pediatric emergency care coordinators (PECCs) on pediatric readiness; and to identify gaps for future quality initiatives by a national coalition. DESIGN, SETTING, AND PARTICIPANTS: Web-based assessment of US EDs (excluding specialty hospitals and hospitals without an ED open 24 hours per day, 7 days per week) for pediatric readiness. All 5017 ED nurse managers were sent a 55-question web-based assessment. Assessments were administered from January 1 through August 23, 2013. Data were analyzed from September 12, 2013, through January 11, 2015. MAIN OUTCOMES AND MEASURES: A modified Delphi process generated a WPRS. An adjusted WPRS was calculated excluding the points received for the presence of physician and nurse PECCs. RESULTS: Of the 5017 EDs contacted, 4149 (82.7%) responded, representing 24 million annual pediatric ED visits. Among the EDs entered in the analysis, 69.4% had low or medium pediatric volume and treated less than 14 children per day. The median WPRS was 68.9 (interquartile range [IQR] 56.1-83.6). The median WPRS increased by pediatric patient volume, from 61.4 (IQR, 49.5-73.6) for low-pediatric-volume EDs compared with 89.8 (IQR, 74.7-97.2) for high-pediatric-volume EDs (P < .001). The median percentage of recommended pediatric equipment available was 91% (IQR, 81%-98%). The presence of physician and nurse PECCs was associated with a higher adjusted median WPRS (82.2 [IQR, 69.7-92.5]) compared with no PECC (66.5 [IQR, 56.0-76.9]) across all pediatric volume categories (P < .001). The presence of PECCs increased the likelihood of having all the recommended components, including a pediatric quality improvement process (adjusted relative risk, 4.11 [95% CI, 3.37-5.02]). Barriers to guideline implementation were reported by 80.8% of responding EDs. CONCLUSIONS AND RELEVANCE: These data demonstrate improvement in pediatric readiness of EDs compared with previous reports. The physician and nurse PECCs play an important role in pediatric readiness of EDs, and their presence is associated with improved compliance with published guidelines. Barriers to implementation of guidelines may be targeted for future initiatives by a national coalition whose goal is to ensure day-to-day pediatric readiness of our nation's EDs.

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid β, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep‐deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13 C 6 ‐leucine to measure amyloid β kinetics. We found that sleep deprivation increased overnight amyloid β38, amyloid β40, and amyloid β42 levels by 25 to 30% via increased overnight amyloid β production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid β production. Ann Neurol 2018;83:197–204

Reanalysis of Clinical Exome Data and Diagnostic Yield As knowledge about genetic causes of disease improves, periodic reanalysis of clinical exome sequence could yield new genetic information. Thi...

INTRODUCTION: Acne vulgaris is one of the most common skin conditions in children and adolescents. The presentation, differential diagnosis, and association of acne with systemic pathology differs by age of presentation. Current acknowledged guidelines for the diagnosis and management of pediatric acne are lacking, and there are variations in management across the spectrum of primary and specialty care. The American Acne and Rosacea Society convened a panel of pediatric dermatologists, pediatricians, and dermatologists with expertise in acne to develop recommendations for the management of pediatric acne and evidence-based treatment algorithms. METHODS: Ten major topic areas in the diagnosis and treatment of pediatric acne were identified. A thorough literature search was performed and articles identified, reviewed, and assessed for evidence grading. Each topic area was assigned to 2 expert reviewers who developed and presented summaries and recommendations for critique and editing. Furthermore, the Strength of Recommendation Taxonomy, including ratings for the strength of recommendation for a body of evidence, was used throughout for the consensus recommendations for the evaluation and management of pediatric acne. Practical evidence-based treatment algorithms also were developed. RESULTS: Recommendations were put forth regarding the classification, diagnosis, evaluation, and management of pediatric acne, based on age and pubertal status. Treatment considerations include the use of over-the-counter products, topical benzoyl peroxide, topical retinoids, topical antibiotics, oral antibiotics, hormonal therapy, and isotretinoin. Simplified treatment algorithms and recommendations are presented in detail for adolescent, preadolescent, infantile, and neonatal acne. Other considerations, including psychosocial effects of acne, adherence to treatment regimens, and the role of diet and acne, also are discussed. CONCLUSIONS: These expert recommendations by the American Acne and Rosacea Society as reviewed and endorsed by the American Academy of Pediatrics constitute the first detailed, evidence-based clinical guidelines for the management of pediatric acne including issues of special concern when treating pediatric patients.

BACKGROUND: Despite estimates that waste constitutes up to 20% of healthcare expenditures in the United States, overuse of tests and therapies is significantly under-recognized in medicine, particularly in pediatrics. The American Board of Internal Medicine Foundation developed the Choosing Wisely campaign, which challenged medical societies to develop a list of 5 things physicians and patients should question. The Society of Hospital Medicine (SHM) joined this effort in the spring of 2012. This report provides the pediatric work group's results. METHODS: A work group of experienced and geographically dispersed pediatric hospitalists was convened by the Quality and Safety Committee of the SHM. This group developed an initial list of 20 recommendations, which was pared down through a modified Delphi process to the final 5 listed below. RESULTS: The top 5 recommendations proposed for pediatric hospital medicine are: (1) Do not order chest radiographs in children with asthma or bronchiolitis. (2) Do not use systemic corticosteroids in children under 2 years of age with a lower respiratory tract infection. (3) Do not use bronchodilators in children with bronchiolitis. (4) Do not treat gastroesophageal reflux in infants routinely with acid suppression therapy. (5) Do not use continuous pulse oximetry routinely in children with acute respiratory illness unless they are on supplemental oxygen. CONCLUSION: We recommend that pediatric hospitalists use this list to prioritize quality improvement efforts and include issues of waste and overuse in their efforts to improve patient care.

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD pathogenesis has not yet been fully elucidated, many risk factors, both genetic and environmental, have been extensively reported. Classically divided in two main sub-groups (open and closed defects) NTDs present extremely variable prognosis mainly depending on the site of the lesion. Herein, we review the literature on the histological and pathological features, epidemiology, prenatal diagnosis, and prognosis, based on the type of defect, with the aim of providing important information based on NTDs classification for clinicians and scientists.

OBJECTIVE: To provide updated guidelines for pharmacologic management of juvenile idiopathic arthritis (JIA), focusing on treatment of oligoarthritis, temporomandibular joint (TMJ) arthritis, and systemic JIA with and without macrophage activation syndrome. Recommendations regarding tapering and discontinuing treatment in inactive systemic JIA are also provided. METHODS: We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: Similar to those published in 2019, these JIA recommendations are based on clinical phenotypes of JIA, rather than a specific classification schema. This guideline provides recommendations for initial and subsequent treatment of JIA with oligoarthritis, TMJ arthritis, and systemic JIA as well as for tapering and discontinuing treatment in subjects with inactive systemic JIA. Other aspects of disease management, including factors that influence treatment choice and medication tapering, are discussed. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional. CONCLUSION: This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis. It serves as a tool to support clinicians, patients, and caregivers in decision-making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision-making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.

Live pentavalent human-bovine reassortant rotavirus vaccine is recommended in the United States for routine immunization of infants. We describe three infants, two with failure to thrive, who had dehydration and diarrhea within 1 month after their first or second rotavirus immunization and subsequently received a diagnosis of severe combined immunodeficiency. Rotavirus was detected, by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, in stool specimens obtained from all three infants, and gene-sequence analysis revealed the presence of vaccine rotavirus. These infections raise concerns regarding the safety of rotavirus vaccine in severely immunocompromised patients.

BACKGROUND: The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial showed that the combined treatment of clopidogrel and aspirin decreases the 90-day risk of stroke without increasing hemorrhage in comparison with aspirin alone, but provided insufficient data to establish whether the benefit persisted over a longer period of time beyond the trial termination. We report the 1-year follow-up outcomes of this trial. METHODS AND RESULTS: The trial was a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China. We randomly assigned 5170 patients within 24 hours after onset of minor stroke or high-risk transient ischemic attack to clopidogrel-aspirin therapy (loading dose of 300 mg of clopidogrel on day 1, followed by 75 mg of clopidogrel per day for 90 days, plus 75 mg of aspirin per day for the first 21 days) or to the aspirin-alone group (75 mg/d for 90 days). The primary outcome was stroke event (ischemic or hemorrhagic) during 1-year follow-up. Differences in outcomes between groups were assessed by using the Cox proportional hazards model. Stroke occurred in 275 (10.6%) patients in the clopidogrel-aspirin group, in comparison with 362 (14.0%) patients in the aspirin group (hazard ratio, 0.78; 95% confidence interval, 0.65-0.93; P=0.006). Moderate or severe hemorrhage occurred in 7 (0.3%) patients in the clopidogrel-aspirin group and in 9 (0.4%) patients in the aspirin group (P=0.44). CONCLUSIONS: The early benefit of clopidogrel-aspirin treatment in reducing the risk of subsequent stroke persisted for the duration of 1-year of follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

OBJECTIVE: Two studies examined the efficacy of the Self-Compassion for Healthcare Communities (SCHC) program for enhancing wellbeing and reducing burnout among healthcare professionals. METHOD: Study 1 (N = 58) had a quasi-experimental design and compared wellbeing outcomes for the SCHC group compared to a waitlist control group. Study 2 (N = 23) did not include a control group and examined the effect of SCHC on burnout. RESULTS: Study 1 found that SCHC significantly increased self-compassion and wellbeing. All gains were maintained for three months. Study 2 found that in addition to enhancing wellbeing, SCHC significantly reduced secondary traumatic stress and burnout. Changes in self-compassion explained gains in other outcomes, and initial levels of self-compassion moderated outcomes so that those initially low in self-compassion benefitted more. CONCLUSIONS: Findings suggest that the SCHC program may be an effective way to increase self-compassion, enhance wellbeing, and reduce burnout for healthcare professionals.

The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers. To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed "how to" and description of individual point-of-care ultrasound examinations. Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines.

Background Among patients with nonvalvular atrial fibrillation (AF) and an elevated stroke risk, guidelines recommend direct oral anticoagulants (DOACs) over warfarin for stroke prevention. Changes in DOAC use over the past decade have not been well described. Methods and Results We evaluated trends in use of DOACs and warfarin from 2011 to 2020 among adults with AF and a CHA 2 DS 2 ‐VASc score ≥2 based on electronic health record data from 88 health systems in the United States contributing to Cerner Real World Data. The use of DOACs and warfarin was described over time, by age, sex, race, and ethnicity, and at the health‐system level. We identified 436 864 patients with AF at risk for stroke (median age, 78 years; 52.1% men). From 2011 to 2020, overall anticoagulation rates increased from 56.3% to 64.7%, as DOAC use increased steadily (from 4.7% to 47.9%), while warfarin use declined (from 52.4% to 17.7%). DOAC uptake was similar across age, sex, and race and ethnicity groups but varied by health system. In 2020, the median health‐system‐level proportion of patients with AF on a DOAC was 49% (interquartile range, 40%–54%). Conclusions Over the past decade, anticoagulation rates for patients with AF have increased modestly as DOACs largely replaced warfarin, though significant gaps remain: One in 3 high‐risk patients with AF is not on any anticoagulant. While DOAC adoption was generally consistent across major demographic groups, use between health systems remained highly variable, suggesting that provider and system factors influence DOAC uptake use more than patient‐level factors.

Background: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. Methods: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN , and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. Results: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [ P *]=1.2×10 –46 ). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P *=7.0×10 –8 ), DSP (odds ratio=14.9, P *=1.0×10 –8 ), and BAG3 (odds ratio=53.1, P *=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P =2.5×10 –4 ), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. Conclusions: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

BACKGROUND: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes. METHODS: We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or higher risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival. RESULTS: The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a higher relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone. CONCLUSIONS: Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or higher risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).