Development of a pilot data management infrastructure for biomedical researchers at University of Manchester – approach, findings, challenges and outlook of the MaDAM Project

Management and curation of digital data has been becoming ever more important in a higher education and research environment characterised by large and complex data, demand for more interdisciplinary and collaborative work, extended funder requirements and use of e-infrastructures to facilitate new research methods and paradigms. This paper presents the approach, technical infrastructure, findings, challenges and outlook (including future development within the successor project, MiSS) of the ‘MaDAM: Pilot data management infrastructure for biomedical researchers at University of Manchester’ project funded under the infrastructure strand of the JISC Managing Research Data (JISCMRD) programme. MaDAM developed a pilot research data management solution at the University of Manchester based on biomedical researchers’ requirements, which includes technical and governance components with the flexibility to meet future needs across multiple research groups and disciplines

A comparison of transplant outcomes in peritoneal and hemodialysis patients

A comparison of transplant outcomes in peritoneal and hemodialysis patients.BackgroundStudies examining the effect of pre-transplant dialysis modality on graft and patient survival after kidney transplantation have produced conflicting results. Therefore, we studied the effects of pre-transplant dialysis modality on outcomes in a large United States cohort.MethodsWe compared rates of transplantation between peritoneal dialysis and hemodialysis patients from the years 1995 to 1998 in the United States (N = 252,402) and outcomes after transplantation (N = 22,776), using data from the Centers for Medicare and Medicaid Services.ResultsIn a Cox proportional hazards analysis that was adjusted for multiple patient characteristics, kidney transplantation was 1.39 (95% CI = 1.35 to 1.43) times more likely in peritoneal dialysis vs. hemodialysis patients (P < 0.0001). Over the entire follow-up period, the adjusted risk for death-censored graft failure was 1.15 (1.04 to 1.26) times higher in peritoneal dialysis vs. hemodialysis (P < 0.05), but mortality and overall graft failure rates were not different. Pre-transplant dialysis modality did not affect outcomes for patients who survived with a functioning kidney for at least 3 months. However, in adjusted Cox analyses restricted to the first 3 months, peritoneal dialysis was associated with a 1.23 (1.09 to 1.39) times higher risk for early graft failure (P < 0.001) and a 1.33 (1.16 to 1.53) times higher risk for death-censored graft failure (P < 0.001). Peritoneal dialysis patients, however, were seen to have a lower incidence of delayed graft function. In a smaller sample of patients with data on causes of early graft failure, graft thrombosis was more commonly listed as a cause of graft failure among peritoneal dialysis patients, 41% (64/156), compared to hemodialysis patients, 30% (106/349), P < 0.05.ConclusionsKidney transplantation is more frequent in peritoneal dialysis than in hemodialysis patients, and transplantation in peritoneal dialysis patients is more frequently associated with early, but not late, graft failure. Delayed graft function was less common in peritoneal dialysis patients but this potential benefit appears to be offset by other factors which are associated with early graft loss. Additional studies are needed to determine what factors may help understand this early risk of graft failure

Requirements for Pseudomonas aeruginosa Type I-F CRISPR-Cas Adaptation Determined Using a Biofilm Enrichment Assay

CRISPR (clustered regularly interspaced short palindromic repeat)-Cas (CRISPR-associated protein) systems are diverse and found in many archaea and bacteria. These systems have mainly been characterized as adaptive immune systems able to protect against invading mobile genetic elements, including viruses. The first step in this protection is acquisition of spacer sequences from the invader DNA and incorporation of those sequences into the CRISPR array, termed CRISPR adaptation. Progress in understanding the mechanisms and requirements of CRISPR adaptation has largely been accomplished using overexpression of cas genes or plasmid loss assays; little work has focused on endogenous CRISPR-acquired immunity from viral predation. Here, we developed a new biofilm-based assay system to enrich for Pseudomonas aeruginosa strains with new spacer acquisition. We used this assay to demonstrate that P. aeruginosa rapidly acquires spacers protective against DMS3vir, an engineered lytic variant of the Mu-like bacteriophage DMS3, through primed CRISPR adaptation from spacers present in the native CRISPR2 array. We found that for the P. aeruginosa type I-F system, the cas1 gene is required for CRISPR adaptation, recG contributes to (but is not required for) primed CRISPR adaptation, recD is dispensable for primed CRISPR adaptation, and finally, the ability of a putative priming spacer to prime can vary considerably depending on the specific sequences of the spacer

Phylogenetics of Trachylina (Cnidaria: Hydrozoa) with new insights on the evolution of some problematical taxa

Some of the most interesting and enigmatic cnidarians are classified within the hydrozoan subclass Trachylina. Despite being relatively depauperate in species richness, the clade contains four taxa typically accorded ordinal status: Actinulida, Limnomedusae, Narcomedusae and Trachymedusae. We bring molecular data (mitochondrial 16S and nuclear small and large subunit ribosomal genes) to bear on the question of phylogenetic relationships within Trachylina. Surprisingly, we find that a diminutive polyp form, Microhydrula limopsicola (classified within Limnomedusae) is actually a previously unknown life stage of a species of Stauromedusae. Our data confirm that the interstitial form Halammohydra sp. (Actinulida) is derived from holopelagic direct developing ancestors, likely within the trachymedusan family Rhopalonematidae. Trachymedusae is shown to be diphyletic, suggesting that the polyp stage has been lost independently at least two times within trachyline evolution. Narcomedusae is supported as a monophyletic group likely also arising from trachymedusan ancestors. Finally, some data, albeit limited, suggest that some trachyline species names refer to cryptic species that have yet to be sorted taxonomicall

Phylogenetics of Trachylina (Cnidaria: Hydrozoa) with new insights on the evolution of some problematical taxa

This is the published version, also available here: http://dx.doi.org/10.1017/S0025315408001732.Some of the most interesting and enigmatic cnidarians are classified within the hydrozoan subclass Trachylina. Despite being relatively depauperate in species richness, the clade contains four taxa typically accorded ordinal status: Actinulida, Limnomedusae, Narcomedusae and Trachymedusae. We bring molecular data (mitochondrial 16S and nuclear small and large subunit ribosomal genes) to bear on the question of phylogenetic relationships within Trachylina. Surprisingly, we find that a diminutive polyp form, Microhydrula limopsicola (classified within Limnomedusae) is actually a previously unknown life stage of a species of Stauromedusae. Our data confirm that the interstitial form Halammohydra sp. (Actinulida) is derived from holopelagic direct developing ancestors, likely within the trachymedusan family Rhopalonematidae. Trachymedusae is shown to be diphyletic, suggesting that the polyp stage has been lost independently at least two times within trachyline evolution. Narcomedusae is supported as a monophyletic group likely also arising from trachymedusan ancestors. Finally, some data, albeit limited, suggest that some trachyline species names refer to cryptic species that have yet to be sorted taxonomically

Measuring Parton Densities in the Pomeron

We present a program to measure the parton densities in the pomeron using diffractive deep inelastic scattering and diffractive photoproduction, and to test the resulting parton densities by applying them to other processes such as the diffractive production of jets in hadron-hadron collisions. Since QCD factorization has been predicted NOT to apply to hard diffractive scattering, this program of fitting and using parton densities might be expected to fail. Its success or failure will provide useful information on the space-time structure of the pomeron.Comment: Contains revisions based on Phys. Rev. D referee comments. RevTeX version 3, epsf, 31 pages. Uuencoded compressed postscript figures appended. Uncompressed postscript files available at ftp://ftp.phys.psu.edu/pub/preprint/psuth136

Aphasia: Can it be taught? Can it be caught?

TB

Crystal structure of the PXR–T1317 complex provides a scaffold to examine the potential for receptor antagonism

The human pregnane X receptor (PXR) recognizes a range of structurally- and chemically-distinct ligands and plays a key role in regulating the expression of protective gene products involved in the metabolism and excretion of potentially harmful compounds. The identification and development of PXR antagonists is desirable as a potential way to control the up-regulation of drug metabolism pathways during the therapeutic treatment of disease. We present the 2.8 Å resolution crystal structure of the PXR ligand binding domain (LBD) in complex with T0901317 (T1317), which is also an agonist of another member of the orphan class of the nuclear receptor superfamily, the liver X receptor (LXR). In spite of differences in the size and shape of the receptors' ligand binding pockets, key interactions with this ligand are conserved between human PXR and human LXR. Based on the PXR-T1317 structure, analogues of T1317 were generated with the goal of designing an PXR antagonist effective via the receptor's ligand binding pocket. We find that selectivity in activating PXR vs. LXR was achieved; such compounds may be useful in addressing neurodegenerative diseases like Niemann-Pick C. We were not successful, however, in producing a PXR antagonist. Based on these observations, we conclude that the generation of PXR antagonists targeted to the ligand binding pocket may be difficult due to the promiscuity and structural conformability of this xenobiotic sensor

On Fair Selection in the Presence of Implicit Variance

Quota-based fairness mechanisms like the so-called Rooney rule or four-fifths rule are used in selection problems such as hiring or college admission to reduce inequalities based on sensitive demographic attributes. These mechanisms are often viewed as introducing a trade-off between selection fairness and utility. In recent work, however, Kleinberg and Raghavan showed that, in the presence of implicit bias in estimating candidates' quality, the Rooney rule can increase the utility of the selection process. We argue that even in the absence of implicit bias, the estimates of candidates' quality from different groups may differ in another fundamental way, namely, in their variance. We term this phenomenon implicit variance and we ask: can fairness mechanisms be beneficial to the utility of a selection process in the presence of implicit variance (even in the absence of implicit bias)? To answer this question, we propose a simple model in which candidates have a true latent quality that is drawn from a group-independent normal distribution. To make the selection, a decision maker receives an unbiased estimate of the quality of each candidate, with normal noise, but whose variance depends on the candidate's group. We then compare the utility obtained by imposing a fairness mechanism that we term $\gamma$-rule (it includes demographic parity and the four-fifths rule as special cases), to that of a group-oblivious selection algorithm that picks the candidates with the highest estimated quality independently of their group. Our main result shows that the demographic parity mechanism always increases the selection utility, while any $\gamma$-rule weakly increases it. We extend our model to a two-stage selection process where the true quality is observed at the second stage. We discuss multiple extensions of our results, in particular to different distributions of the true latent quality.Comment: 27 pages, 10 figures, Economics and Computation (EC'20

iPrevent®: a tailored, web-based, decision support tool for breast cancer risk assessment and management

We aimed to develop a user-centered, web-based, decision support tool for breast cancer risk assessment and personalized risk management. Using a novel model choice algorithm, iPrevent&reg; selects one of two validated breast cancer risk estimation models (IBIS or BOADICEA), based on risk factor data entered by the user. Resulting risk estimates are presented in simple language and graphic formats for easy comprehension. iPrevent&reg; then presents risk-adapted, evidence-based, guideline-endorsed management options. Development was an iterative process with regular feedback from multidisciplinary experts and consumers. To verify iPrevent&reg;, risk factor data for 127 cases derived from the Australian Breast Cancer Family Study were entered into iPrevent&reg;, IBIS (v7.02), and BOADICEA (v3.0). Consistency of the model chosen by iPrevent&reg; (i.e., IBIS or BOADICEA) with the programmed iPrevent&reg; model choice algorithm was assessed. Estimated breast cancer risks from iPrevent&reg; were compared with those attained directly from the chosen risk assessment model (IBIS or BOADICEA). Risk management interventions displayed by iPrevent&reg; were assessed for appropriateness. Risk estimation model choice was 100% consistent with the programmed iPrevent&reg;logic. Discrepant 10-year and residual lifetime risk estimates of &gt;1% were found for 1 and 4 cases, respectively, none was clinically significant (maximal variation 1.4%). Risk management interventions suggested by iPrevent&reg; were 100% appropriate. iPrevent&reg; successfully integrates the IBIS and BOADICEA risk assessment models into a decision support tool that provides evidence-based, risk-adapted risk management advice. This may help to facilitate precision breast cancer prevention discussions between women and their healthcare providers