A Method to Estimate High-Dimensional Synergistic Interactions: A Case Study on Information Technology Business Value

In describing cause and effect relationships, difficulties may arise when two or more factors act as causes of a particular outcome. The complication results from the possibility that any one or more of the factors modify the extent to which others provide an effect. Such complex multi-factor interactions imply that multiple causal chains have at least some part in common; thus the evaluation of the synergistic effect of two or more causes is pertinent to the study of the causal mechanisms involved. The aim of this paper is to propose a new approach to systematically analyse combinations of interacting causal factors that might lead to good outcomes. Our approach was demonstrated on data from a highly complex field; a large dataset about Information Technology impact on business value collected by the Australian Department of Communication, IT and Art. Experimental evaluation confirms that this approach is able to statistically estimate the magnitude of higher-order interactions from multiple causal factors. Hence, synergistic interactions can be hypothesised and tested between any number of factors

Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection

Significance The emergence of multidrug-resistant bacteria, including uropathogenic Escherichia coli (UPEC), makes the development of targeted antivirulence therapeutics a critical focus of research. During urinary tract infections (UTIs), UPEC uses chaperone–usher pathway pili tipped with an array of adhesins that recognize distinct receptors with sterochemical specificity to facilitate persistence in various tissues and habitats. We used an interdisciplinary approach driven by structural biology and synthetic glycoside chemistry to design and optimize glycomimetic inhibitors of the UPEC adhesin FmlH. These inhibitors competitively blocked FmlH in vitro, in in vivo mouse UTI models, and in ex vivo healthy human kidney tissue. This work demonstrates the utility of structure-driven drug design in the effort to develop antivirulence therapeutic compounds. </jats:p

Relationships between sodium, fats and carbohydrates on blood pressure, cholesterol and HbA1c: an umbrella review of systematic reviews

Background The relationship between nutrition and health is complex and the evidence to describe it broad and diffuse. This review brings together evidence for the effect of nutrients on cardiometabolic risk factors. Methods An umbrella review identified systematic reviews of randomised controlled trials and meta-analyses estimating the effects of fats, carbohydrates and sodium on blood pressure, cholesterol and haemoglobin A1c (HbA1c). Medline, Embase, Cochrane Library and Science Citation Index were search through 26 May 2020, with supplementary searches of grey literature and websites. English language systematic reviews and meta-analyses were included that assessed the effect of sodium, carbohydrates or fat on blood pressure, cholesterol and HbA1c. Reviews were purposively selected using a sampling framework matrix. The quality of evidence was assessed with A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2) checklist, evidence synthesised in a narrative review and causal pathways diagram. Results Forty-three systematic reviews were included. Blood pressure was significantly associated with sodium, fibre and fat. Sodium, fats and carbohydrates were significantly associated with cholesterol. Monounsaturated fat, fibre and sugars were associated with HbA1c. Conclusion Multiple relationships between nutrients and cardiometabolic risk factors were identified and summarised in an accessible way for public health researchers. The review identifies associations, inconsistencies and gaps in evidence linking nutrition to cardiometabolic health

Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial

Abstract Introduction Benzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients. Methods In this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis. Results Of the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11). Conclusions In this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results. Trial Registration NCT00095251

Lack of confidence among trainee doctors in the management of diabetes: the Trainees Own Perception of Delivery of Care (TOPDOC) Diabetes Study

Background: There is an increased prevalence of diabetes. Doctors in training, irrespective of specialty, will have patients with diabetes under their care

Reconnaissance Survey of the Irish Continental Shelf/Shelf Edge - Atlantic Irish Regional Survey (AIRS) 1996: A GLORIA Survey of the Irish Continental Margin

The Atlantic Irish Regional Survey (AIRS96) sidescan sonar survey was carried out in August 1996. Covering an area of 200,000 sq.km it represented the largest reconnaissance seabed survey of the Irish Continental Shelf region. It covered both margins, together with much of the basin floor, of the Irish sector of the Rockall Trough and extended into the northern part of the Porcupine Seabight. The objectives of this project were two fold: 1. Strategic: •to undertake, for the first time a preliminary reconnaissance survey of the Irish Continental Shelf/Shelf Edge, •to establish a strategic database on Shelf/Slope Edge conditions, •to provide training and experience to Irish researchers in state of the art marine surveying equipment (GLORIA) and data processing. 2. Scientific: •to document slope stability and mass wasting features on the margins of the Rockall Trough, •to map, where possible, occurrences of deep water carbonate mounds, •to investigate the sediment erosional, transport and depositional mechanisms that have shaped the present morphology of the region. The survey revealed a range of sedimentary features across the steep (i.e. >6º slope) margins and the basin floor in the Rockall Trough. Four classes of sedimentary feature are recognised: (1) mass failure, (2) canyon systems, (3) sediment fans, and (4) sediment drifts. The western margin is characterised by large-scale downslope mass movement features. The western and central parts of the basin floor in the Rockall Trough contain the Feni Sediment Ridge, a large Miocene-Recent contourite sediment accumulation draped by large sediment waves trending sub-parallel to the dominant modern current pattern. A large-scale downslope mass failure feature is recognised across 14,000 sq.km of the northeastern margin of the Rockall Trough. Smaller slides and slumps occur along the eastern margin in association with more prevalent canyon, channel and fan systems. A cluster of carbonate mounds was imaged in the northern part of the Porcupine Seabight. These represent part of one of the most extensive suites of deep-water carbonate mounds in the Atlantic Margin and are currently the subject of a number of new EU-funded research projects. Strong northward-directed bottom currents along the eastern margin are suggested to erode, circulate and re-deposit sediment on the basin floor and on the western margin of the Rockall Trough. The main terrigenous sedimentary input was from the Irish Mainland Shelf. A broad interplay of alongslope and downslope sediment transport processes shaped the morphology of the Rockall Trough, while tectonically-driven basin subsidence, Quaternary glaciations and glacio-eustatic sea-level fluctuations also influenced the overall sedimentation pattern in the Rockall Trough.Funder: Marine Institut

Loss of tolerance to gut immunity protein; glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis

Abstract Glycoprotein 2[GP2] is a specific target of pancreatic autoantibodies[PAbs] in Crohn’s disease(CD) and is involved in gut innate immunity processes. Our aim was to evaluate the prevalence and prognostic potential of PAbs in primary sclerosing cholangitis(PSC). Sixty-five PSC patients were tested for PAbs by indirect immunofluorescence and compared with healthy (n = 100) and chronic liver disease controls(CLD, n = 488). Additionally, a panel of anti-microbial antibodies and secretory (s)IgA levels were measured, as markers of bacterial translocation and immune dysregulation. PAbs were more frequent in PSC(46.2%) compared to controls(healthy:0% and CLD:4.5%), [P < 0.001, for each]. Occurrence of anti-GP2 antibody was 30.8% (20/65) and was exclusively of IgA isotype. Anti-GP2 IgA positive patients had higher sIgA levels (P = 0.021). With flow-cytometry, 68.4% (13/19) of anti-GP2 IgA antibodies were bound with secretory component, suggesting an active retro-transportation of anti-GP2 from the gut lumen to the mucosa. Anti-GP2 IgA was associated with shorter transplant-free survival [PLogRank < 0.01] during the prospective follow-up (median, IQR: 87 [9–99] months) and remained an independent predictor after adjusting for Mayo risk score(HR: 4.69 [1.05–21.04], P = 0.043). These results highlight the significance of gut-liver interactions in PSC. Anti-GP2 IgA might be a valuable tool for risk stratification in PSC and considered as a potential therapeutic target

An RBP4 promoter polymorphism increases risk of type 2 diabetes

Aims/hypothesis: Retinol-binding protein 4 (RBP4), originally known for retinol transport, was recently identified as an adipokine affecting insulin resistance. The RBP4 -803GA promoter polymorphism influences binding of hepatic nuclear factor 1α and is associated with type 2 diabetes in case-control studies. We hypothesised that the RBP4 -803GA polymorphism increases type 2 diabetes risk at a population-based level. In addition, information on retinol intake and plasma vitamin A levels enabled us to explore the possible underlying mechanism. Methods: In the Rotterdam Study, a prospective, population-based, follow-up study, the -803GA polymorphism was genotyped. In Cox proportional hazards models, associations of the -803GA polymorphism and retinol intake with type 2 diabetes risk were examined. Moreover, the interaction of the polymorphism with retinol intake on type 2 diabetes risk was assessed. In a subgroup of participants the association of the polymorphism and vitamin A plasma levels was investigated. Results: Homozygous carriers of the -803A allele had increased risk of type 2 diabetes (HR 1.83; 95% CI 1.26-2.66). Retinol intake was not associated with type 2 diabetes risk and showed no interaction with the RBP4 -803GA polymorphism. Furthermore, there was no significant association of the polymorphism with plasma vitamin A levels. Conclusions/interpretation: Our results provide evidence that homozygosity for the RBP4 -803A allele is associated with increased risk of type 2 diabetes in the Rotterdam population. This relationship was not clearly explained by retinol intake and vitamin A plasma levels. Therefore, we cannot differentiate between a retinol-dependent or -independent mechanism of this RBP4 variant