Beyond Trial Registration: A Global Trial Bank for Clinical Trial Reporting

The prose reporting of trial information could be powerfully augmented by a computable repository of trial information-a global "trial bank.

Succession of embryonic and the intestinal bacterial communities of Atlantic salmon (Salmo salar) reveals stage‐specific microbial signatures

publishedVersio

Sponge Microbiota are a Reservoir of Functional Antibiotic Resistance Genes

Wide application of antibiotics has contributed to the evolution of multi-drug resistant human pathogens, resulting in poorer treatment outcomes for infections. In the marine environment, seawater samples have been investigated as a resistance reservoir; however, no studies have methodically examined sponges as a reservoir of antibiotic resistance. Sponges could be important in this respect because they often contain diverse microbial communities that have the capacity to produce bioactive metabolites. Here, we applied functional metagenomics to study the presence and diversity of functional resistance genes in the sponges Aplysina aerophoba, Petrosia ficiformis and Corticium candelabrum. We obtained 37 insert sequences facilitating resistance to D-cycloserine (n=6), gentamicin (n=1), amikacin (n=7), trimethoprim (n=17), chloramphenicol (n=1), rifampicin (n=2) and ampicillin (n=3). Fifteen of 37 inserts harboured resistance genes that shared <90% amino acid identity with known gene products, whereas on 13 inserts no resistance gene could be identified with high confidence, in which case we predicted resistance to be mainly mediated by antibiotic efflux. One marine-specific ampicillin-resistance-conferring β-lactamase was identified in the genus Pseudovibrio with 41% global amino acid identity to the closest β-lactamase with demonstrated functionality, and subsequently classified into a new family termed PSV. Taken together, our results show that sponge microbiota host diverse and novel resistance genes that may be harnessed by phylogenetically distinct bacteria

Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism

Dangerous damage to mitochondrial DNA (mtDNA) can be ameliorated during mammalian development through a highly debated mechanism called the mtDNA bottleneck. Uncertainty surrounding this process limits our ability to address inherited mtDNA diseases. We produce a new, physically motivated, generalisable theoretical model for mtDNA populations during development, allowing the first statistical comparison of proposed bottleneck mechanisms. Using approximate Bayesian computation and mouse data, we find most statistical support for a combination of binomial partitioning of mtDNAs at cell divisions and random mtDNA turnover, meaning that the debated exact magnitude of mtDNA copy number depletion is flexible. New experimental measurements from a wild-derived mtDNA pairing in mice confirm the theoretical predictions of this model. We analytically solve a mathematical description of this mechanism, computing probabilities of mtDNA disease onset, efficacy of clinical sampling strategies, and effects of potential dynamic interventions, thus developing a quantitative and experimentally-supported stochastic theory of the bottleneck.Comment: Main text: 14 pages, 5 figures; Supplement: 17 pages, 4 figures; Total: 31 pages, 9 figure

T‐cell epitope content comparison (EpiCC) of swine H1 influenza A virus hemagglutinin

Background: Predicting vaccine efficacy against emerging pathogen strains is a significant problem in human and animal vaccine design. T‐cell epitope cross‐conservation may play an important role in cross‐strain vaccine efficacy. While influenza A virus (IAV) hemagglutination inhibition (HI) antibody titers are widely used to predict protective efficacy of 1 IAV vaccine against new strains, no similar correlate of protection has been identified for T‐cell epitopes. Objective: We developed a computational method (EpiCC) that facilitates pairwise comparison of protein sequences based on an immunological property—T‐cell epitope content—rather than sequence identity, and evaluated its ability to classify swine IAV strain relatedness to estimate cross‐protective potential of a vaccine strain for circulating viruses. Methods: T‐cell epitope relatedness scores were assessed for 23 IAV HA sequences representing the major H1 swine IAV phylo‐clusters circulating in North American swine and HA sequences in a commercial inactivated vaccine (FluSure XP®). Scores were compared to experimental data from previous efficacy studies. Results: Higher EpiCC scores were associated with greater protection by the vaccine against strains for 23 field IAV strain vaccine comparisons. A threshold for EpiCC relatedness associated with full or partial protection in the absence of cross‐reactive HI antibodies was identified. EpiCC scores for field strains for which FluSure protective efficacy is not yet available were also calculated. Conclusion: EpiCC thresholds can be evaluated for predictive accuracy of protection in future efficacy studies. EpiCC may also complement HI cross‐reactivity and phylogeny for selection of influenza strains in vaccine development

Tensions and paradoxes in electronic patient record research: a systematic literature review using the meta-narrative method

Background: The extensive and rapidly expanding research literature on electronic patient records (EPRs) presents challenges to systematic reviewers. This literature is heterogeneous and at times conflicting, not least because it covers multiple research traditions with different underlying philosophical assumptions and methodological approaches. Aim: To map, interpret and critique the range of concepts, theories, methods and empirical findings on EPRs, with a particular emphasis on the implementation and use of EPR systems. Method: Using the meta-narrative method of systematic review, and applying search strategies that took us beyond the Medline-indexed literature, we identified over 500 full-text sources. We used ‘conflicting’ findings to address higher-order questions about how the EPR and its implementation were differently conceptualised and studied by different communities of researchers. Main findings: Our final synthesis included 24 previous systematic reviews and 94 additional primary studies, most of the latter from outside the biomedical literature. A number of tensions were evident, particularly in relation to: [1] the EPR (‘container’ or ‘itinerary’); [2] the EPR user (‘information-processer’ or ‘member of socio-technical network’); [3] organizational context (‘the setting within which the EPR is implemented’ or ‘the EPR-in-use’); [4] clinical work (‘decision-making’ or ‘situated practice’); [5] the process of change (‘the logic of determinism’ or ‘the logic of opposition’); [6] implementation success (‘objectively defined’ or ‘socially negotiated’); and [7] complexity and scale (‘the bigger the better’ or ‘small is beautiful’). Findings suggest that integration of EPRs will always require human work to re-contextualize knowledge for different uses; that whilst secondary work (audit, research, billing) may be made more efficient by the EPR, primary clinical work may be made less efficient; that paper, far from being technologically obsolete, currently offers greater ecological flexibility than most forms of electronic record; and that smaller systems may sometimes be more efficient and effective than larger ones. Conclusions: The tensions and paradoxes revealed in this study extend and challenge previous reviews and suggest that the evidence base for some EPR programs is more limited than is often assumed. We offer this paper as a preliminary contribution to a much-needed debate on this evidence and its implications, and suggest avenues for new research

Expressed protein profile of a Tectomicrobium and other microbial symbionts in the marine sponge Aplysina aerophoba as evidenced by metaproteomics.

Aplysina aerophoba is an emerging model marine sponge, with a well-characterized microbial community in terms of diversity and structure. However, little is known about the expressed functional capabilities of its associated microbes. Here, we present the first metaproteomics-based study of the microbiome of A. aerophoba. We found that transport and degradation of halogenated and chloroaromatic compounds are common active processes in the sponge microbiomes. Our data further reveal that the highest number of proteins were affiliated to a sponge-associated Tectomicrobium, presumably from the family Entotheonellaceae, as well as to the well-known symbiont "Candidatus Synechococcus spongiarium", suggesting a high metabolic activity of these two microorganisms in situ. Evidence for nitric oxide (NO) conversion to nitrous oxide was consistently observed for Tectomicrobia across replicates, by production of the NorQ protein. Moreover, we found a potential energy-yielding pathway through CO oxidation by putative Chloroflexi bacteria. Finally, we observed expression of enzymes that may be involved in the transformation of chitin, glycoproteins, glycolipids and glucans into smaller molecules, consistent with glycosyl hydrolases predicted from analyses of the genomes of Poribacteria sponge symbionts. Thus, this study provides crucial links between expressed proteins and specific members of the A. aerophoba microbiome

Does time of surgery influence the rate of false-negative appendectomies?:A retrospective observational study of 274 patients

Background Multiple disciplines have described an “after-hours effect” relating to worsened mortality and morbidity outside regular working hours. This retrospective observational study aimed to evaluate whether diagnostic accuracy of a common surgical condition worsened after regular hours. Methods Electronic operative records for all non-infant patients (age > 4 years) operated on at a single centre for presumed acute appendicitis were retrospectively reviewed over a 56-month period (06/17/2012–02/01/2017). The primary outcome measure of unknown diagnosis was compared between those performed in regular hours (08:00–17:00) or off hours (17:01–07:59). Pre-clinical biochemistry and pre-morbid status were recorded to determine case heterogeneity between the two groups, along with secondary outcomes of length of stay and complication rate. Results Out of 289 procedures, 274 cases were deemed eligible for inclusion. Of the 133 performed in regular hours, 79% were appendicitis, compared to 74% of the 141 procedures performed off hours. The percentage of patients with an unknown diagnosis was 6% in regular hours compared to 15% off hours (RR 2.48; 95% CI 1.14–5.39). This was accompanied by increased numbers of registrars (residents in training) leading procedures off hours (37% compared to 24% in regular hours). Pre-morbid status, biochemistry, length of stay and post-operative complication rate showed no significant difference. Conclusions This retrospective study suggests that the rate of unknown diagnoses for acute appendicitis increases overnight, potentially reflecting increased numbers of unnecessary procedures being performed off hours due to poorer diagnostic accuracy. Reduced levels of staffing, availability of diagnostic modalities and changes to workforce training may explain this, but further prospective work is required. Potential solutions may include protocolizing the management of common acute surgical conditions and making more use of non-resident on call senior colleagues

Host immunity in the protective response to nasal immunization with a pneumococcal antigen associated to live and heat-killed Lactobacillus casei

Background: At present, available pneumococcal vaccines have failed to eradicate infections caused by S. pneumoniae. Search for effective vaccine continues and some serotype independent pneumococcal proteins are considered as candidates for the design of new vaccines, especially a mucosal vaccine, since pneumococci enter the body through mucosal surfaces. Selection of the appropriate adjuvant is important for mucosal vaccines, and lactic acid bacteria (LAB) with immunostimulant properties are promissory candidates. In this work, we assessed the adjuvant effect of a probiotic strain, Lactobacillus casei (L. casei), when nasally administered with a pneumococcal antigen (pneumococcal protective protein A: PppA) for the prevention of pneumococcal infection. Adjuvanticity of both live (LcV) and heat-killed (LcM) was evaluated and humoral and cellular antigen-specific immune response was assessed in mucosal and systemic compartments. The potential mechanisms induced by nasal immunization were discussed.Results: Nasal immunization of young mice with PppA+LcV and PppA+LcM induced anti-PppA IgA and IgG antibodies in mucosal and systemic compartments and levels of these specific antibodies remained high even at day 45 after the 3rd Immunization (3rd I). These results were correlated with IL-4 induction by the mixture of antigen plus LcV and LcM. Also, PppA+Lc (V and M) induced stimulation of Th1 and Th17 cells involved in the defence against pneumococci. The protection against pneumococcal respiratory challenge at day 30 after the 3rd I showed that PppA+LcV and PppA+LcM immunizations significantly reduced pathogen counts in nasal lavages while prventing their passage into lung and blood. Survival of mice immunized with the co-application of PppA plus LcV and LcM was significantly higher than in mice immunized with PppA alone and control mice when intraperitoneal challenge was performed. No significant differences between the treatments involving LcV and LcM were found.Conclusions: Live and heat-killed L. casei enhanced the antigen-specific immune response when administered nasally with a pneumococcal antigen. Considering the potential risk associated with live bacteria, the design of a nasal vaccine based on pneumococcal antigens and heat-killed L. casei emerges as a safe and effective strategy for the prevention of pneumococcal infections and opens new possibilities of application of dead LAB as adjuvants in vaccine formulations against other pathogens.Fil: Vintiñi, Elisa Ofelia. Universidad Nacional de Tucumán. Facultad de Agronomía y Zootecnia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; ArgentinaFil: Medina, Marcela Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentin