Longitudinal Assessment of Growth in Hypoplastic Left Heart Syndrome: Results From the Single Ventricle Reconstruction Trial

Background: We sought to characterize growth between birth and age 3 years in infants with hypoplastic left heart syndrome who underwent the Norwood procedure. Methods and Results: We performed a secondary analysis using the Single Ventricle Reconstruction Trial database after excluding patients 2 SD below normal). Failure to find consistent risk factors supports the strategy of tailoring nutritional therapies to patient‐ and stage‐specific targets. Clinical Trial Registration URL: http://clinicaltrials.gov/. Unique identifier: NCT00115934

Surgical Atrioventricular Valve Replacement With Melody Valve in Infants and Children

Background Pediatric patients with atrioventricular valve disease have limited options for prosthetic valve replacement in sizes <15 mm. Based on successful experience with the stented bovine jugular vein graft (Melody valve) in the right ventricular outflow tract, the prosthesis has been modified for surgical valve replacement in pediatric patients with atrioventricular dysfunction with the intention of subsequent valve expansion in the catheterization laboratory as the child grows. Methods and Results A multicenter, retrospective cohort study was performed among patients who underwent atrioventricular valve replacement with Melody valve at 17 participating sites from North America and Europe, including 68 patients with either mitral (n=59) or tricuspid (n=9) replacement at a median age of 8 months (range, 3 days to 13 years). The median size at implantation was 14 mm (range, 9-24 mm). Immediately postoperatively, the valve was competent with low gradients in all patients. Fifteen patients died; 3 patients underwent transplantation. Nineteen patients required reoperation for adverse outcomes, including valve explantation (n=16), left ventricular outflow tract obstruction (n=1), permanent pacemaker implantation (n=1), and paravalvular leak repair (n=1). Twenty-five patients underwent 41 episodes of catheter-based balloon expansion, exhibiting a significant decrease in median gradient ( P<0.001) with no significant increase in grade of regurgitation. Twelve months after implantation, cumulative incidence analysis indicated that 55% of the patients would be expected to be free from death, heart transplantation, structural valve deterioration, or valve replacement. Conclusions The Melody valve is a feasible option for surgical atrioventricular valve replacement in patients with hypoplastic annuli. The prosthesis shows acceptable short-term function and is amenable to catheter-based enlargement as the child grows. However, patients remain at risk for mortality and structural valve deterioration, despite adequate early valvular function. Device design and implantation techniques must be refined to reduce complications and extend durability. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02505074

Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Partial Order Transport Service: An Analytic Model

Traditional transport service is either (1) reliable and ordered (e.g., TCP) or (2) unreliable and unordered (e.g., UDP). Some new computer applications such as multimedia do not fit perfectly with either of these services. Partial Order Connection (POC), a new transport-layer protocol, tries to fill the gap between (1) and (2). With POC, an application specifies a partial order (PO) for valid orderings of the packets. Packets can be transmitted or delivered by respecting any linear extension (LE) of the given PO. POC provides more generality than traditional transport protocols, which allow a user to specify the order only as a chain or an anti-chain. In POC, the reliability requirements are similarly generalized: rather than a complete guarantee as with TCP, or no guarantee as with UDP, in POC, a user specifies controlled levels of loss. Hence, POC provides partial-order and partial-reliability service. This paper presents an analytic model for POC. Results show that POC provides performance improvements over existing transport services when network service is lossy, the ratio of transmission time to propagation delay is large, or when the PO has few precedence constraints

Use of Oxandrolone to Promote Growth in Neonates following Surgery for Complex Congenital Heart Disease: An Open‐Label Pilot Trial

Objective Malnutrition and poor weight gain, common in neonates following repair of complex congenital heart disease (CHD), are associated with increased morbidity and mortality. Oxandrolone, an anabolic steroid, improves weight gain in older children at high‐risk for growth failure. We sought to determine feasibility, safety, and efficacy of oxandrolone therapy in neonates following surgery for complex CHD. Design Neonates with RACHS‐1 score \u3e3 were eligible to receive open‐label oxandrolone for 28 days in this prospective pilot trial. There were 3 cohorts of 5 subjects receiving oxandrolone therapy under 3 specified dosage and preparation protocols: 0.1 mg/kg/day aqueous solution, 0.2 mg/kg/day aqueous solution, and 0.1 mg/kg/day preparation in medium chain triglyceride (MCT) oil. Age‐ and diagnosis‐matched neonates who underwent surgery, but received no oxandrolone, served as a control cohort. Anthropometric measurements, physical examination for virilization, safety labs, and adverse events were monitored. Results Of 25 eligible patients, 15 consented (60%, 13/15 with Norwood procedure). There was no evidence of virilization, no changes in safety labs, and no serious adverse events related to oxandrolone among subjects receiving therapy. No subject met criteria for termination of study drug. There was a significant difference in change in weight‐for‐age z‐score among the four cohorts, with subjects receiving 0.1 mg/kg/day in MCT oil having the lowest decline during the study period (−1.8 ± 0.5 for controls, −1.7 ± 0.4 for 0.1 mg/kg/day aqueous, −1.0 ± 0.4 for 0.2 mg/kg/day aqueous, and −0.6 ± 0.7 for 0.1 mg/kg/day MCT oil, P = .012). Conclusions Oxandrolone therapy at the doses studied appears safe in neonates after surgery for complex CHD. The decline in weight‐for‐age z‐score was lowest in those receiving the MCT oil preparation suggesting better bioavailability of this preparation and a potential growth benefit with oxandrolone therapy. Further investigation is needed to define optimal dosing and assess efficacy

Quantitative Assay Validation for Oxandrolone in Human Plasma Using LC–MS-MS

A high-performance liquid chromatography–tandem mass spectrometry (LC–MS-MS) method for the determination of oxandrolone concentration in human plasma (0.5 mL) was developed and validated according to the 2001 FDA Bioanalytical Guidelines. Oxandrolone is an anabolic steroid used to promote weight gain for cachectic patients with severe burn injuries, HIV/AIDS, hepatitis C and other wasting syndromes. The assay procedure involved a liquid–liquid extraction of oxandrolone and methyltestosterone (the internal standard, IS) from plasma with n-butyl chloride. The organic layer was clarified by centrifugation and evaporated to dryness under a stream of air. The residue was reconstituted in a solution containing 25% methanol and 75% Milli-Q water, and injected onto a Luna C18 reversed-phase HPLC column (30 mm × 2.0 mm, 2 μm). Separation of oxandrolone and methyltestosterone was achieved with a mobile phase starting composition of 55% methanol and 45% ammonium formate buffer at a flow rate of 0.1 mL/min. The total run time was 21 min per sample. Selected reaction monitoring mode was used for quantifying oxandrolone (m/z 307 → 271) and the IS, methyltestosterone (m/z 301 → 149). To the authors\u27 knowledge, this is the first LC–MS-MS method validated for oxandrolone quantification in human plasma. This method can be used in future pharmacokinetic studies involving oxandrolone

Use of Oxandrolone to Promote Growth in Neonates following Surgery for Complex Congenital Heart Disease: An Open‐Label Pilot Trial

Objective Malnutrition and poor weight gain, common in neonates following repair of complex congenital heart disease (CHD), are associated with increased morbidity and mortality. Oxandrolone, an anabolic steroid, improves weight gain in older children at high‐risk for growth failure. We sought to determine feasibility, safety, and efficacy of oxandrolone therapy in neonates following surgery for complex CHD. Design Neonates with RACHS‐1 score \u3e3 were eligible to receive open‐label oxandrolone for 28 days in this prospective pilot trial. There were 3 cohorts of 5 subjects receiving oxandrolone therapy under 3 specified dosage and preparation protocols: 0.1 mg/kg/day aqueous solution, 0.2 mg/kg/day aqueous solution, and 0.1 mg/kg/day preparation in medium chain triglyceride (MCT) oil. Age‐ and diagnosis‐matched neonates who underwent surgery, but received no oxandrolone, served as a control cohort. Anthropometric measurements, physical examination for virilization, safety labs, and adverse events were monitored. Results Of 25 eligible patients, 15 consented (60%, 13/15 with Norwood procedure). There was no evidence of virilization, no changes in safety labs, and no serious adverse events related to oxandrolone among subjects receiving therapy. No subject met criteria for termination of study drug. There was a significant difference in change in weight‐for‐age z‐score among the four cohorts, with subjects receiving 0.1 mg/kg/day in MCT oil having the lowest decline during the study period (−1.8 ± 0.5 for controls, −1.7 ± 0.4 for 0.1 mg/kg/day aqueous, −1.0 ± 0.4 for 0.2 mg/kg/day aqueous, and −0.6 ± 0.7 for 0.1 mg/kg/day MCT oil, P = .012). Conclusions Oxandrolone therapy at the doses studied appears safe in neonates after surgery for complex CHD. The decline in weight‐for‐age z‐score was lowest in those receiving the MCT oil preparation suggesting better bioavailability of this preparation and a potential growth benefit with oxandrolone therapy. Further investigation is needed to define optimal dosing and assess efficacy