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Abstract Background Community-acquired pneumonia (CAP) in children is usually treated with 10 days of antibiotics. Shorter antibiotic courses may be beneficial if proven effective, with potentially fewer antibiotic adverse effects and decreased antibiotic exposure. Methods This randomized, double-blind, placebo-controlled superiority trial (NCT02891915) compared a strategy of short vs standard course ß-lactam therapy for outpatient CAP in children ages 6–71 months. Children demonstrating clinical improvement by day 3–5 of initial therapy were considered for enrollment. Enrolled children were randomized 1:1 to receive either 5 additional days of the originally prescribed antibiotic (standard) or matching placebo (short). The Desirability of Outcome Ranking (DOOR; PMID: 26113652) was the primary outcome, and was defined by classifying the global experience of children into an ordinal clinical response (OCR) that combined the response to CAP treatment and antibiotic adverse effects 11–15 days after the start of therapy. For those subjects with equivalent OCR, documented days of antibiotic administration was used to further rank the desirability of the outcome with the a priori assumption that shorter antibiotic exposure was more desirable. The OCR was a secondary outcome. The intention to treat population was used to estimate the probability of a more desirable outcome for the strategy of short vs. standard course therapy for both outcomes. Results 385 children were enrolled; 380 had complete data for analysis. Baseline characteristics were similar between the two strategies. In both strategies, > 90% of children had an adequate response to CAP treatment and most antibiotic adverse effects were minor (Table). In the OCR analysis, short course therapy had a 48% probability (95% CI: 42%-53%) of a more desirable outcome. In the DOOR analysis, short course therapy was superior to standard therapy with a 69% probability (95% CI: 63%-72%; p< 0.001) of a more desirable outcome. Conclusion Among children with CAP demonstrating initial clinical improvement with outpatient therapy, both strategies had a similar response to CAP treatment and antibiotic adverse effects, but short course therapy was superior in our a priori defined outcome that incorporated decreased antibiotic exposure. Disclosures Emmanuel B. Walter, MD, MPH, Moderna (Grant/Research Support)Pfizer (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) W. Charles Huskins, MD, MSc, ADMA Biologics (Consultant)Pfizer, Inc (Consultant)

Objective: The aim of this work is to formulate recommendations based on global expert consensus to guide the surgical community on the safe resumption of surgical and endoscopic activities. Background: The COVID-19 pandemic has caused marked disruptions in the delivery of surgical care worldwide. A thoughtful, structured approach to resuming surgical services is necessary as the impact of COVID-19 becomes better controlled. The Coronavirus Global Surgical Collaborative sought to formulate, through rigorous scientific methodology, consensus-based recommendations in collaboration with a multidisciplinary group of international experts and policymakers. Methods: Recommendations were developed following a Delphi process. Domain topics were formulated and subsequently subdivided into questions pertinent to different aspects of surgical care in the COVID-19 crisis. Forty-four experts from 15 countries across 4 continents drafted statements based on the specific questions. Anonymous Delphi voting on the statements was performed in 2 rounds, as well as in a telepresence meeting. Results: One hundred statements were formulated across 10 domains. The statements addressed terminology, impact on procedural services, patient/staff safety, managing a backlog of surgeries, methods to restart and sustain surgical services, education, and research. Eighty-three of the statements were approved during the first round of Delphi voting, and 11 during the second round. A final telepresence meeting and discussion yielded acceptance of 5 other statements. Conclusions: The Delphi process resulted in 99 recommendations. These consensus statements provide expert guidance, based on scientific methodology, for the safe resumption of surgical activities during the COVID-19 pandemic.

Background: Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease. Methods: Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband and relative(s) with cardiomyopathy. Whole genome sequencing data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction. Results: A pathogenic MYBPC3 nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular noncompaction, and 2 fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic RYR2 missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic RYR2 exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia and his father with left ventricular noncompaction and catecholaminergic polymorphic ventricular tachycardia. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in MYH6 ( P =0.000068). Rare, predicted-damaging MYH6 variants were identified in 10% of probands in our cohort—4 with familial congenital heart disease, 4 with compound heterozygosity (3 with systolic ventricular dysfunction), and 4 with MYH6 – FLNC synergistic heterozygosity. Conclusions: Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation.

AbstractClinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Abstract BackgroundOverexpression of c-Myc is required for the progression of pre-malignant plasma cells in monoclonal gammopathy of undetermined significance (MGUS) to malignant plasma cells in multiple myeloma (MM). c-Myc also increases glutamine anaplerosis into the tricarboxylic acid (TCA) cycle within cancer cells. Whether increased glutamine anaplerosis is associated with the progression of pre-malignant to malignant plasma cells is unknown.MethodsHuman volunteers (N = 7) and patients with MGUS (N = 11) and MM (N = 12) were prospectively recruited to undergo an intravenous infusion of 13C-labelled glutamine followed by a bone marrow aspiration to obtain bone marrow cells and plasma.ResultsDespite notable heterogeneity, stable isotope resolved metabolomics (SIRM) revealed that the mean 13C-labelled glutamine anaplerosis into the TCA cycle was higher in malignant compared to pre-malignant bone marrow plasma cells relative to the remainder of their paired bone marrow mononuclear cells. RNA sequencing demonstrated a higher relative mRNA expression of c-Myc and glutamine transporters such as ASCT2 and SN2 in malignant compared to pre-malignant bone marrow plasma cells. Finally, higher quantitative levels of TCA cycle intermediates in the bone marrow plasma differentiated MM from MGUS patients.ConclusionMeasurement of the in vivo activity of glutamine anaplerosis into the TCA cycle provides novel insight into the metabolic changes associated with the transformation of pre-malignant plasma cells in MGUS to malignant plasma cells in MM.

AbstractBackgroundInterdisciplinary cognitive behavioural therapy (CBT) for chronic pain is effective at improving function, mood and pain interference among individuals with disabling chronic pain. Traditionally, CBT assumes that cognitive change is an active therapeutic ingredient in the determination of treatment outcome. Pain catastrophizing, a cognitive response style that views the experience of pain as uncontrollable, permanent and destructive, has been identified as an important maladaptive cognition which contributes to difficulties with the management of chronic pain. Consequently, pain catastrophizing is commonly targeted in CBT for chronic pain.ObjectivesTo examine change trajectories in pain catastrophizing during treatment and assess the relevance of these trajectories to outcomes at posttreatment.MethodsParticipants included individuals with chronic pain (N = 463) who completed a 3‐week program of interdisciplinary CBT. Pain catastrophizing was assessed weekly over the 3 weeks of treatment and latent growth curve modelling was used to identify trajectories of change.ResultsFindings indicated the presence of two classes of linear change, one with a significant negative slope in pain catastrophizing (i.e. improved class) and the other with a non‐significant slope (i.e. unchanged class). Next, latent growth mixture modelling examined treatment outcome in relation to class membership. These results indicated that individuals in the ‘improved’ PCS class had significantly greater improvement in pain interference and mood, as well as physical and mental quality of life compared to the ‘unchanged’ class.ConclusionsImplications for our findings, in relation to the CBT model, are discussed.

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to parents the proband’s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.