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This paper reviews the archival process at the Inter-university Consortium for Political and Social Research (ICPSR), a repository of digital social science data, and maps ICPSR's Ingest and Access operations to the Open Archival Information System (OAIS) Reference Model. The paper also assesses ICPSR's conformance with the archival responsibilities of \"trusted\" OAIS repositories, with the proviso that audit criteria for archival certification are still under development. The ICPSR to OAIS mapping exercise has benefits for the larger social science archiving community because it provides an interpretation of the reference model in the quantitative social science environment and points to preservation-related issues that may be salient for other social science archives. Building on the archives; long tradition of shared norms and cooperation, we may ultimately be able to design a federated system of trusted social science repositories that provides access to the global heritage. [PUBLICATION ABSTRACT]

Human genetic variants causing loss of function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes. Gain of kinase function variants in LRRK2 are known to significantly increase the risk of Parkinsons disease suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

Background Major extremity trauma forms a considerable proportion of combat-related injuries. Coverage of lower limb soft tissue defects utilises the reconstructive ladder. The 72-h target to definitive reconstruction has been proposed in civilian trauma. The primary aim of this study was to determine whether the time to definitive reconstruction and the number of pre-flap debridements have an impact on flap success in lower limb combat injury reconstructions. Methods A literature search was conducted on Pubmed, Prospero, Dynamed, DARE, EMBASE, COCHRANE and BMJ databases. A random effects model was used due to significant heterogeneity between the papers and a meta-regression was implemented for the analysis of outcomes. Results A total of seven studies had fulfilled the inclusion criteria. The cumulative number of flaps performed was 378 (255 free flaps and 123 non-free flaps). The Latissimus Dorsi free flap was the most common flap performed ( n  = 153). The proportion of flap success across the studies was 88% (0.88, 95% CI: 0.77–0.94). There was no statistically significant impact of the number of pre-flap debridements on flap success rates (OR of: 1.23 [95% CI: 0.62 to 2.44], p  > 0.05). Time to reconstruction had no statistically significant impact on flap success rates (OR of: 0.88 [95% CI: 0.77 to 1.00], p  > 0.05). Conclusions The choice of flap used in lower limb combat-related injuries is dependent upon the type, extent and location of injury. Onus should be placed on ensuring the wound is adequately debrided prior to definitive coverage to provide a healthy wound bed for reconstruction. Level of Evidence: Not gradable