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In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms.

In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms.

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak–Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1 . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex’s Lemonade Stand Foundation.) Pacak–Zhuang syndrome is an inherited tumor-predisposition disorder characterized by polycythemia and paragangliomas. A patient with this disorder had polycythemia, headache, hypertension, and norepinephrine-secreting paragangliomas. She had activating mutations in HIF2A . Use of belzutifan, a HIF2α inhibitor, led to paraganglioma regression, normalized hemoglobin levels, and symptom resolution.

ObjectivesTo evaluate the antenatal sickle cell and thalassaemia screening programme in England over 10 years from 1 April 2007 to 31 March 2017.MethodsFour routine data sources were used: antenatal screening laboratory data; key performance indicator data from maternity trusts; prenatal diagnosis (PND) laboratory data and data from screening incidents.ResultsFor the 10 years examined a total of 6608 575 booking samples were reported as screened, and 154 196 pregnant women required further testing. There were 3941 reported PND tests of which there were 964 affected fetal results. Antenatal test coverage and Family Origin Questionnaire completion rates are high and increasing; the proportion of tests declined has decreased. However, there is wide variation in the timing of antenatal tests and completeness of follow-up and testing. Since 2014/2015 a lower proportion of PND tests are performed by the programme standard of 12+6 weeks. Results suggest that PND timing affects reproductive choices as those with an affected fetus identified by PND testing earlier are more likely to terminate the pregnancy.ConclusionsThe screening programme appears to be widely accepted as part of routine antenatal care in England. However, the timeliness of screening and subsequent PND testing has consistently not met programme standards. Improving timeliness would enable individuals to consider their options to make informed choices for their pregnancies at the appropriate time. This paper reports carrier rates for an almost complete cohort of women which provides important epidemiological information on the genetic profile of women in England.

Introduction/Objectives: Delivering optimal patient care is impacted by a physician’s ability to build trusting relationships with patients. Identifying techniques for rapport building is important for promoting patient-physician collaboration and improved patient outcomes. This study sought to characterize the approaches highly skilled primary care physicians (PCPs) use to effectively connect with diverse patients. Methods: Using an inductive thematic analysis approach, we analyzed semi-structured interview transcripts with 10 PCPs identified by leadership and/or colleagues for having exceptional patient communication skills. PCPs practiced in 3 diverse clinic settings: (1) academic medical center, (2) Veterans Affairs clinic, and (3) safety-net community clinic. Results and Conclusions: The thematic analysis yielded 5 themes that enable physicians to establish connections with patients: Respect for the Patient, Engaged Curiosity, Focused Listening, Mutual Participation, and Self-Awareness. Underlying all of these themes was a quality of authenticity, or a state of symmetry between one’s internal experience and external words and actions. Adopting these communication techniques while allowing for adaptability in order to remain authentic in one’s interactions with patients may facilitate improved connection and trust with patients. Encouraging physician authenticity in the patient-physician relationship supports a shift toward relationship-centered care. Additional medical education training is needed to facilitate authentic connection between physicians and patients.

Cover crop residues and animal waste products can be important sources of N in cropping systems. The objectives of this research were to determine, under field conditions, the effects of hairy vetch (legume; Vicia villosa Roth)/cereal rye (grass; Secale cereale L.) proportion and pelletized poultry litter (PPL) management (no PPL, subsurface banded, broadcast, or incorporated with tillage) on the extent and rate of cover crop residue mass loss and N release during a subsequent growing season. Measuring cover crop residues placed in mesh litter bags, or residues+PPL in litter bags for the broadcast treatment, we found that increasing hairy vetch proportion led to greater proportional mass loss and N release (cumulative mass loss ranged from 40 to 80% and N release ranged from 0–90% of initial), as well as greater rates of mass loss in all PPL treatments. Nitrogen release rates were generally unaffected by species proportions; however, N release rates for pure cereal rye residue in all PPL treatments except broadcast could not be estimated due to minimal N release. Incorporation of residues and PPL increased the rates of mass loss and N release for pure hairy vetch and hairy vetch–cereal rye mixtures. Although broadcast PPL application and incorporation affected decomposition patterns, subsurface banded PPL application did not. Results suggest that cereal rye provides the greatest mulch persistence, hairy vetch provides the greatest N release, and mixtures provide moderate delivery of these two services. Subsurface banding is the recommended PPL application method to conserve surface residues.

Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was −3·9 mm Hg (Bayesian 95% credible interval −6·2 to −1·6) and for office systolic blood pressure the difference was −6·5 mm Hg (−9·6 to −3·5). No major device-related or procedural-related safety events occurred up to 3 months. SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. Medtronic.

The performance of legume–grass cover crop mixtures may be influenced by the species proportions in mixture. The objectives of this study were to: (i) evaluate total aboveground biomass and species biomass proportions resulting from different hairy vetch (legume; Vicia villosa Roth)/cereal rye (grass; Secale cereale L.) sown proportions, (ii) characterize aboveground N content and C/N ratios in response to species biomass proportions, and (iii) quantify biologically fixed nitrogen (BFN) in hairy vetch and the potential transfer of BFN to associated cereal rye. A gradient of six sown proportions ranging from 100% cereal rye to 100% hairy vetch was drilled in fall 2011 and 2012 at two sites in Beltsville, MD, and sampled for biomass, C and N content, and BFN the following spring. Hairy vetch monocultures produced less biomass than cereal rye monocultures, but biomass levels were similar between cereal rye monocultures and mixtures. Cereal rye was usually the dominant species in mixtures. Nitrogen content increased from 64 to 181 kg ha−1 and C/N ratio decreased from 83 to 16 as hairy vetch biomass increased from 0 to 100%. Nitrogen content was estimated to plateau when hairy vetch reached approximately 50% of the total biomass. Averaged across site‐years, BFN made up 63 and 86% of hairy vetch N in monoculture and mixture, respectively. For mixtures, a wide range of sown proportions produced >8 Mg ha−1 biomass, but achieving maximum N content and low C/N ratios required a hairy vetch/cereal rye seeding rate of 27:34 kg ha−1.

Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2-3 days of age with a retroviral vector (RV) expressing canine β-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5-60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6-17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal.

Biotechnological approaches to reduce or modify lignin in biomass crops are predicated on the assumption that it is the principal determinant of the recalcitrance of biomass to enzymatic digestion for biofuels production. We defined quantitative trait loci (QTL) in the Intermated B73 × Mo17 recombinant inbred maize (Zea mays) population using pyrolysis molecular-beam mass spectrometry to establish stem lignin content and an enzymatic hydrolysis assay to measure glucose and xylose yield. Among five multiyear QTL for lignin abundance, two for 4-vinylphenol abundance, and four for glucose and/or xylose yield, not a single QTL for aromatic abundance and sugar yield was shared. A genome-wide association study for lignin abundance and sugar yield of the 282-member maize association panel provided candidate genes in the 11 QTL of the B73 and Mo17 parents but showed that many other alíeles impacting these traits exist among this broader pool of maize genetic diversity. B73 and Mo17 genotypes exhibited large differences in gene expression in developing stem tissues independent of allelic variation. Combining these complementary genetic approaches provides a narrowed list of candidate genes. A cluster of SCARECROW-LIKE9 and SCAKECROW-LIKE14 transcription factor genes provides exceptionally strong candidate genes emerging from the genome-wide association study. In addition to these and genes associated with cell wall metabolism, candidates include several other transcription factors associated with vascularization and fiber formation and components of cellular signaling pathways. These results provide new insights and strategies beyond the modification of lignin to enhance yields of biofuels from genetically modified biomass.