Stillbirths including intrapartum timing: EN-BIRTH multi-country validation study.

BACKGROUND: An estimated >2 million babies stillborn around the world each year lack visibility. Low- and middle-income countries carry 84% of the burden yet have the least data. Most births are now in facilities, hence routine register-recording presents an opportunity to improve counting of stillbirths, but research is limited, particularly regarding accuracy. This paper evaluates register-recorded measurement of hospital stillbirths, classification accuracy, and barriers and enablers to routine recording. METHODS: The EN-BIRTH mixed-methods, observational study took place in five hospitals in Bangladesh, Nepal and Tanzania (2017-2018). Clinical observers collected time-stamped data on perinatal care and birth outcomes as gold standard. To assess accuracy of routine register-recorded stillbirth rates, we compared birth outcomes recorded in labour ward registers to observation data. We calculated absolute rate differences and individual-level validation metrics (sensitivity, specificity, percent agreement). We assessed misclassification of stillbirths with neonatal deaths. To examine stillbirth appearance (fresh/macerated) as a proxy for timing of death, we compared appearance to observed timing of intrauterine death based on heart rate at admission. RESULTS: 23,072 births were observed including 550 stillbirths. Register-recorded completeness of birth outcomes was > 90%. The observed study stillbirth rate ranged from 3.8 (95%CI = 2.0,7.0) to 50.3 (95%CI = 43.6,58.0)/1000 total births and was under-estimated in routine registers by 1.1 to 7.3 /1000 total births (register: observed ratio 0.9-0.7). Specificity of register-recorded birth outcomes was > 99% and sensitivity varied between hospitals, ranging from 77.7-86.1%. Percent agreement between observer-assessed birth outcome and register-recorded birth outcome was very high across all hospitals and all modes of birth (> 98%). Fresh or macerated stillbirth appearance was a poor proxy for timing of stillbirth. While there were similar numbers of stillbirths misclassified as neonatal deaths (17/430) and neonatal deaths misclassified as stillbirths (21/36), neonatal deaths were proportionately more likely to be misclassified as stillbirths (58.3% vs 4.0%). Enablers to more accurate register-recording of birth outcome included supervision and data use. CONCLUSIONS: Our results show these routine registers accurately recorded stillbirths. Fresh/macerated appearance was a poor proxy for intrapartum stillbirths, hence more focus on measuring fetal heart rate is crucial to classification and importantly reduction in these preventable deaths

Neonatal resuscitation: EN-BIRTH multi-country validation study.

BACKGROUND: Annually, 14 million newborns require stimulation to initiate breathing at birth and 6 million require bag-mask-ventilation (BMV). Many countries have invested in facility-based neonatal resuscitation equipment and training. However, there is no consistent tracking for neonatal resuscitation coverage. METHODS: The EN-BIRTH study, in five hospitals in Bangladesh, Nepal, and Tanzania (2017-2018), collected time-stamped data for care around birth, including neonatal resuscitation. Researchers surveyed women and extracted data from routine labour ward registers. To assess accuracy, we compared gold standard observed coverage to survey-reported and register-recorded coverage, using absolute difference, validity ratios, and individual-level validation metrics (sensitivity, specificity, percent agreement). We analysed two resuscitation numerators (stimulation, BMV) and three denominators (live births and fresh stillbirths, non-crying, non-breathing). We also examined timeliness of BMV. Qualitative data were collected from health workers and data collectors regarding barriers and enablers to routine recording of resuscitation. RESULTS: Among 22,752 observed births, 5330 (23.4%) babies did not cry and 3860 (17.0%) did not breathe in the first minute after birth. 16.2% (n = 3688) of babies were stimulated and 4.4% (n = 998) received BMV. Survey-report underestimated coverage of stimulation and BMV. Four of five labour ward registers captured resuscitation numerators. Stimulation had variable accuracy (sensitivity 7.5-40.8%, specificity 66.8-99.5%), BMV accuracy was higher (sensitivity 12.4-48.4%, specificity > 93%), with small absolute differences between observed and recorded BMV. Accuracy did not vary by denominator option. < 1% of BMV was initiated within 1 min of birth. Enablers to register recording included training and data use while barriers included register design, documentation burden, and time pressure. CONCLUSIONS: Population-based surveys are unlikely to be useful for measuring resuscitation coverage given low validity of exit-survey report. Routine labour ward registers have potential to accurately capture BMV as the numerator. Measuring the true denominator for clinical need is complex; newborns may require BMV if breathing ineffectively or experiencing apnoea after initial drying/stimulation or subsequently at any time. Further denominator research is required to evaluate non-crying as a potential alternative in the context of respectful care. Measuring quality gaps, notably timely provision of resuscitation, is crucial for programme improvement and impact, but unlikely to be feasible in routine systems, requiring audits and special studies

Analysis and Prediction of the Metabolic Stability of Proteins Based on Their Sequential Features, Subcellular Locations and Interaction Networks

The metabolic stability is a very important idiosyncracy of proteins that is related to their global flexibility, intramolecular fluctuations, various internal dynamic processes, as well as many marvelous biological functions. Determination of protein's metabolic stability would provide us with useful information for in-depth understanding of the dynamic action mechanisms of proteins. Although several experimental methods have been developed to measure protein's metabolic stability, they are time-consuming and more expensive. Reported in this paper is a computational method, which is featured by (1) integrating various properties of proteins, such as biochemical and physicochemical properties, subcellular locations, network properties and protein complex property, (2) using the mRMR (Maximum Relevance & Minimum Redundancy) principle and the IFS (Incremental Feature Selection) procedure to optimize the prediction engine, and (3) being able to identify proteins among the four types: “short”, “medium”, “long”, and “extra-long” half-life spans. It was revealed through our analysis that the following seven characters played major roles in determining the stability of proteins: (1) KEGG enrichment scores of the protein and its neighbors in network, (2) subcellular locations, (3) polarity, (4) amino acids composition, (5) hydrophobicity, (6) secondary structure propensity, and (7) the number of protein complexes the protein involved. It was observed that there was an intriguing correlation between the predicted metabolic stability of some proteins and the real half-life of the drugs designed to target them. These findings might provide useful insights for designing protein-stability-relevant drugs. The computational method can also be used as a large-scale tool for annotating the metabolic stability for the avalanche of protein sequences generated in the post-genomic age

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe