SNS programming environment user's guide

The computing environment is briefly described for the Supercomputing Network Subsystem (SNS) of the Central Scientific Computing Complex of NASA Langley. The major SNS computers are a CRAY-2, a CRAY Y-MP, a CONVEX C-210, and a CONVEX C-220. The software is described that is common to all of these computers, including: the UNIX operating system, computer graphics, networking utilities, mass storage, and mathematical libraries. Also described is file management, validation, SNS configuration, documentation, and customer services

Selection by a panel of clinicians and family representatives of important early morbidities associated with paediatric cardiac surgery suitable for routine monitoring using the nominal group technique and a robust voting process

OBJECTIVE: With survival following paediatric cardiac surgery improving, the attention of quality assurance and improvement initiatives is shifting to long-term outcomes and early surgical morbidities. We wanted to involve family representatives and a range of clinicians in selecting the morbidities to be measured in a major UK study. SETTING: Paediatric cardiac surgery services in the UK. PARTICIPANTS: We convened a panel comprising family representatives, paediatricians from referring centres, and surgeons and other clinicians from surgical centres. PRIMARY AND SECONDARY OUTCOME MEASURES: Using the nominal group technique augmented by a robust voting process to identify group preferences, suggestions for candidate morbidities were elicited, discussed, ranked and then shortlisted. The shortlist was passed to a clinical group that provided a view on the feasibility of monitoring each shortlisted morbidity in routine practice. The panel then met again to select a prioritised list of morbidities for further study, with the list finalised by the clinical group and chief investigators. RESULTS: At the first panel meeting, 66 initial suggestions were made, with this reduced to a shortlist of 24 after two rounds of discussion, consolidation and voting. At the second meeting, this shortlist was reduced to 10 candidate morbidities. Two were dropped on grounds of feasibility and replaced by another the panel considered important. The final list of nine morbidities included indicators of organ damage, acute events and feeding problems. Family representatives and clinicians from outside tertiary centres brought some issues to greater prominence than if the panel had consisted solely of tertiary clinicians or study investigators. CONCLUSION: The inclusion of patient and family perspectives in identifying metrics for use in monitoring a specialised clinical service is challenging but feasible and can broaden notions of quality and how to measure it

Improving Risk Adjustment for Mortality After Pediatric Cardiac Surgery: The UK PRAiS2 Model

BACKGROUND: Partial Risk Adjustment in Surgery (PRAiS), a risk model for 30-day mortality after children's heart surgery, has been used by the UK National Congenital Heart Disease Audit to report expected risk-adjusted survival since 2013. This study aimed to improve the model by incorporating additional comorbidity and diagnostic information. METHODS: The model development dataset was all procedures performed between 2009 and 2014 in all UK and Ireland congenital cardiac centers. The outcome measure was death within each 30-day surgical episode. Model development followed an iterative process of clinical discussion and development and assessment of models using logistic regression under 25 × 5 cross-validation. Performance was measured using Akaike information criterion, the area under the receiver-operating characteristic curve (AUC), and calibration. The final model was assessed in an external 2014 to 2015 validation dataset. RESULTS: The development dataset comprised 21,838 30-day surgical episodes, with 539 deaths (mortality, 2.5%). The validation dataset comprised 4,207 episodes, with 97 deaths (mortality, 2.3%). The updated risk model included 15 procedural, 11 diagnostic, and 4 comorbidity groupings, and nonlinear functions of age and weight. Performance under cross-validation was: median AUC of 0.83 (range, 0.82 to 0.83), median calibration slope and intercept of 0.92 (range, 0.64 to 1.25) and -0.23 (range, -1.08 to 0.85) respectively. In the validation dataset, the AUC was 0.86 (95% confidence interval [CI], 0.82 to 0.89), and the calibration slope and intercept were 1.01 (95% CI, 0.83 to 1.18) and 0.11 (95% CI, -0.45 to 0.67), respectively, showing excellent performance. CONCLUSIONS: A more sophisticated PRAiS2 risk model for UK use was developed with additional comorbidity and diagnostic information, alongside age and weight as nonlinear variables

Discovery, Characterization, and Structure–Activity Relationships of an Inhibitor of Inward Rectifier Potassium (Kir) Channels with Preference for Kir2.3, Kir3.X, and Kir7.1

The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels

Cancer prevalence in the United Kingdom: estimates for 2008

BACKGROUND: Identifying and addressing the requirements of cancer survivors is currently a high priority for the NHS, yet little is known about the population of cancer survivors in the United Kingdom. METHODS: Data from cancer registries in England, Northern Ireland, Scotland and Wales were analysed to provide limited-duration prevalence estimates for 2004. Log-linear regression models were used to extend these to complete prevalence estimates. Trends in prevalence from 2000 to 2004 were used to project complete prevalence estimates forward from 2004 to 2008. RESULTS: We estimated that in total, there were 2 million cancer survivors in the United Kingdom at the end of 2008, approximately 3% of the population overall and 1 in 8 of those aged 65 years and more. Prostate and female breast cancers were the most prevalent. The number of cancer survivors is increasing by approximately 3% each year. Estimates are also provided by time since diagnosis. CONCLUSION: These estimates are the most up-to-date available, and as such will be useful for statutory and voluntary sector organisations that are responsible for planning and providing treatment and support to cancer survivors in the United Kingdom

Strike-slip influenced stratigraphic and structural development of the Foula Sandstone Group, Shetland: implications for offshore Devonian basin development on the northern UK continental shelf

The island of Foula, located 25 km SW of Shetland, preserves a gently folded, 1.6 km thick sequence of Middle Devonian sandstones spectacularly exposed in kilometre-long cliff sections >350 m high. These rocks unconformably overlie likely Precambrian-age amphibolite facies basement rocks that are intruded by sheeted granites. The onshore succession is similar in age to the nearby Lower Clair Group offshore to the west. New mapping, incorporating the use of drone imagery in the inaccessible cliff sections, uses down-plunge projections to show that growth folding and faulting on Foula were contemporaneous with sedimentation during basin filling. The large-scale structural geometry is consistent with the regional constrictional strain due to the sinistral transtension associated with movements along the Walls Boundary–Great Glen fault zone system during the Mid-Devonian. Detrital zircon provenance studies indicate that the Devonian sequences of Foula (and nearby Melby in western Shetland) show similarities with the Clair Group and Orkney successions. We suggest that NE–SW transtensional fold development contemporaneous with regional subsidence in the Devonian basins of Scotland may be more widespread than previously realized. Large, kilometre-scale folds previously interpreted to be related to Permo-Carboniferous inversion may therefore have initiated earlier in the basin evolution sequence than previously realized

Real time monitoring of risk-adjusted paediatric cardiac surgery outcomes using variable life-adjusted display: implementation in three UK centres

To implement routine in-house monitoring of risk-adjusted 30-day mortality following paediatric cardiac surgery