Citations

Abstract Various risk models with differing discriminatory power and predictive accuracy have been used to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. There remains an unmet need for a contemporary risk score for continuous flow (CF)‐LVADs. We sought to independently validate and compare existing risk models in a large cohort of patients and develop a simple, yet highly predictive risk score for acute, severe RVF. Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF‐LVAD implantation, were randomly divided into equal‐sized derivation and validation samples. RVF scores were calculated for the entire sample, and the need for a right ventricular assist device (RVAD) was the primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified. A risk score was developed based on the identified variables and their respective regression coefficients. Between May 2004 and September 2014, 734 patients underwent implantation of CF‐LVADs [HeartMate II LVAD, 76% ( n = 560), HeartWare HVAD, 24% ( n = 174)]. A RVAD was required in 4.5% ( n = 33) of the patients [Derivation cohort, n = 15 (4.3%); Validation cohort, n = 18 (5.2%); P = 0.68)]. 19.5% of the patients ( n = 143) were female, median age at implant was 59 years (IQR, 49.4–65.3), and median INTERMACS profile was 3 (IQR, 2–3). RVAD was required in 4.5% ( n = 33) of the patients. Correlates of acute, severe RVF in the final model included heart rate, albumin, BUN, WBC, cardiac index, and TR severity. Areas under the curves (AUC) for most commonly used risk predictors ranged from 0.61 to 0.78. The AUC for the new model was 0.89 in the derivation and 0.92 in the validation cohort. Proposed risk model provides very high discriminatory power predicting acute severe right ventricular failure and can be reliably applied to patients undergoing placement of contemporary continuous flow left ventricular assist devices.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

Background Bivalirudin may be an effective alternative anticoagulant to heparin for use in percutaneous peripheral interventions. We aimed to compare the safety and efficacy of bivalirudin versus heparin as the procedural anticoagulant agent in patients undergoing percutaneous peripheral intervention. Methods For this meta-analysis and systematic review, we conducted a search in PubMed, Medline, Embase, and Cochrane for all the clinical studies in which bivalirudin was compared to heparin as the procedural anticoagulant in percutaneous peripheral interventions. Outcomes studied included all-cause mortality, all-bleeding, major and minor bleeding, and access site complications. Results Eleven studies were included in the analysis, totaling 20,137 patients. There was a significant difference favoring bivalirudin over heparin for all-cause mortality (risk ratio 0.58, 95% CI 0.39–0.87), all-bleeding (risk ratio 0.62, 95% CI 0.50–0.78), major bleeding (risk ratio 0.61, 95% CI 0.39–0.96), minor bleeding (risk ratio 0.66, 95% CI 0.47–0.92), and access site complications (risk ratio 0.66, 95% CI 0.51–0.84). There was no significant difference in peri-procedural need for blood transfusions (risk ratio 0.79, 95% CI 0.57–1.08), myocardial infarction (risk ratio 0.87, 95% CI 0.59–1.28), stroke (risk ratio 0.77, 95% CI 0.59–1.01), intracranial bleeding (risk ratio 0.77, 95% CI 0.29–2.02), or amputations (OR 0.75, 95% CI 0.53–1.05). Conclusion Our meta-analysis suggests that bivalirudin use for percutaneous peripheral interventions is associated with lower all-cause mortality, bleeding, and access site complications as compared to heparin. Further large randomized trials are needed to confirm the current results.

Abstract Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439

Abstract Background Achieving appropriate therapy for BSI caused by Gram-negative rods (GNR) is challenging. The availability of AST results allows de-escalation from broad- to narrow-spectrum agents. De-escalation is a goal of antimicrobial stewardship (AS). Through the analysis of inpatient BL antibiotic regimens in a nationwide cohort of patients with Escherichia coli and Klebsiella pneumoniae BSI, we compared the relative spectrum of empiric and definitive treatments to AST results and identified opportunities for de-escalation. Methods Using a cohort of patients hospitalized within VHA, we identified patients with a blood culture positive for E. coli or K. pneumoniae between 2006 and 2015. We analyzed the subset of patients receiving inpatient BLs before and after Gram stain (GS) and AST results. BLs were grouped into five tiers of increasing spectrum, both with and without a requirement for anaerobic activity (Figure 1). Tiers of BLs across the treatment periods were summarized and compared with the lowest-spectrum tier with an active agent. Rates of inactive, optimal, and overly broad BL therapy were summarized by organism and treatment period. Results Of 36,531 BSI identified, we analyzed a subset of 10,825 (7,100 E. coli, 3,725 K. pneumoniae) that met our inclusion criteria (Figure 2). The use of inactive BL agents decreased across time, falling from 11% in early empiric to 4.5% in definitive treatments. The proportion of patients receiving the narrowest available effective BL therapy (“optimal” therapy) increased from 5% to 8% after GS results and to 14% after AST results (Figure 3). De-escalation to optimal therapy after AST results was observed in only 7% of opportunities. If anaerobic activity was required, a smaller proportion of cases would be considered overtreated in the empiric periods (45–46%), but de-escalation after AST results was observed in only 10% of these cases. Conclusion Changes in BL agents across treatment periods reflect an escalation to active treatment, but the absence of de-escalation after AST results was available. This was true both with and without considering a need for anaerobic activity. Expansion of this analysis to include additional classes such as fluoroquinolones may reveal opportunities for AS and de-escalation to optimal therapy in the treatment of E. coli and K. pneumoniae BSI. Disclosures R. Patel, CD Diagnostics, BioFire, Curetis, Merck, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, Allergan, and The Medicines Company: Grant Investigator, Research grant – monies paid to Mayo Clinic. Curetis, Specific Technologies, Selux Dx, GenMark Diagnostics, PathoQuest and Genentech: Consultant and Scientific Advisor, Consulting fee – monies paid to Mayo Clinic. ASM and IDSA: Travel reimbursement and editor’s stipends, Travel reimbursement and editor’s stipends. NBME, Up-to-Date and the Infectious Diseases Board Review Course: Varies, Honoraria. Mayo Clinic: Employee, Salary. R. Banerjee, Accelerate Diagnostics, Biomerieux, BioFire: Grant Investigator, Research grant and Research support.

Abstract Purpose: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors. Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. Results: The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n = 6) and fatigue (n = 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%–17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%–50.2%) in MET-amplified patients; median (range) duration of response was 202 (51–1,430+) days in all patients and 197 (64–1,430+) days in MET-amplified patients. Conclusions: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation. See related commentary by Ma, p. 2375