Efficacy and mechanism of sub-sensory sacral (optimised) neuromodulation in adults with faecal incontinence:Study protocol for a randomised controlled trial

Background: Faecal incontinence (FI) is a substantial health problem with a prevalence of approximately 8% in community-dwelling populations. Sacral neuromodulation (SNM) is considered the first-line surgical treatment option in adults with FI in whom conservative therapies have failed. The clinical efficacy of SNM has never been rigorously determined in a trial setting and the underlying mechanism of action remains unclear. Methods/design: The design encompasses a multicentre, randomised, double-blind crossover trial and cohort follow-up study. Ninety participants will be randomised to one of two groups (SNM/SHAM or SHAM/SNM) in an allocation ratio of 1:1. The main inclusion criteria will be adults aged 18-75 years meeting Rome III and ICI definitions of FI, who have failed non-surgical treatments to the UK standard, who have a minimum of eight FI episodes in a 4-week screening period, and who are clinically suitable for SNM. The primary objective is to estimate the clinical efficacy of sub-sensory SNM vs. SHAM at 32 weeks based on the primary outcome of frequency of FI episodes using a 4-week paper diary, using mixed Poisson regression analysis on the intention-to-treat principle. The study is powered (0.9) to detect a 30% reduction in frequency of FI episodes between sub-sensory SNM and SHAM stimulation over a 32-week crossover period. Secondary objectives include: measurement of established and new clinical outcomes after 1 year of therapy using new (2017 published) optimised therapy (with standardised SNM-lead placement); validation of new electronic outcome measures (events) and a device to record them, and identification of potential biological effects of SNM on underlying anorectal afferent neuronal pathophysiology (hypothesis: SNM leads to increased frequency of perceived transient anal sphincter relaxations; improved conscious sensation of defaecatory urge and cortical/subcortical changes in afferent responses to anorectal electrical stimulation (main techniques: high-resolution anorectal manometry and magnetoencephalography). Discussion: This trial will determine clinical effect size for sub-sensory chronic electrical stimulation of the sacral innervation. It will provide experimental evidence of modifiable afferent neurophysiology that may aid future patient selection as well as a basic understanding of the pathophysiology of FI

Highly sensitive multipoint real-time kinetic detection of Surface Plasmon bioanalytes with custom CMOS cameras

Phase sensitive Surface Plasmon Resonance (SPR) techniques are a popular means of characterizing biomolecular interactions. However, limitations due to the narrow dynamic range and difficulty in adapting the method for multi-point sensing have restricted its range of applications. This paper presents a compact phase sensitive SPR technology using a custom CMOS camera. The system is exceptionally versatile enabling one to trade dynamic range for sensitivity without altering the optical system. We present results showing sensitivity over the array of better than 10−6 Refractive Index Units (RIU) over a refractive index range of 2×10−2 RIU, with peak sensitivity of 3×10−7 RIU at the center of this range. We also explain how simply altering the settings of polarization components can give sensitivity on the order of 10−8 RIU albeit at the cost of lower dynamic range. The consistent response of the custom CMOS camera in the system also allowed us to demonstrate precise quantitative detection of two Fibrinogen antibody–protein binding sites. Moreover, we use the system to determine reaction kinetics and argue how the multipoint detection gives useful insight into the molecular binding mechanisms

Toward Open and Reproducible Environmental Modeling by Integrating Online Data Repositories, Computational Environments, and Model Application Programming Interfaces

Cyberinfrastructure needs to be advanced to enable open and reproducible environmental modeling research. Recent efforts toward this goal have focused on advancing online repositories for data and model sharing, online computational environments along with containerization technology and notebooks for capturing reproducible computational studies, and Application Programming Interfaces (APIs) for simulation models to foster intuitive programmatic control. The objective of this research is to show how these efforts can be integrated to support reproducible environmental modeling. We present first the high-level concept and general approach for integrating these three components. We then present one possible implementation that integrates HydroShare (an online repository), CUAHSI JupyterHub and CyberGIS-Jupyter for Water (computational environments), and pySUMMA (a model API) to support open and reproducible hydrologic modeling. We apply the example implementation for a hydrologic modeling use case to demonstrate how the approach can advance reproducible environmental modeling through the seamless integration of cyberinfrastructure services

Midgut microbiota of the malaria mosquito vector Anopheles gambiae and Interactions with plasmodium falciparum Infection

The susceptibility of Anopheles mosquitoes to Plasmodium infections relies on complex interactions between the insect vector and the malaria parasite. A number of studies have shown that the mosquito innate immune responses play an important role in controlling the malaria infection and that the strength of parasite clearance is under genetic control, but little is known about the influence of environmental factors on the transmission success. We present here evidence that the composition of the vector gut microbiota is one of the major components that determine the outcome of mosquito infections. A. gambiae mosquitoes collected in natural breeding sites from Cameroon were experimentally challenged with a wild P. falciparum isolate, and their gut bacterial content was submitted for pyrosequencing analysis. The meta-taxogenomic approach revealed a broader richness of the midgut bacterial flora than previously described. Unexpectedly, the majority of bacterial species were found in only a small proportion of mosquitoes, and only 20 genera were shared by 80% of individuals. We show that observed differences in gut bacterial flora of adult mosquitoes is a result of breeding in distinct sites, suggesting that the native aquatic source where larvae were grown determines the composition of the midgut microbiota. Importantly, the abundance of Enterobacteriaceae in the mosquito midgut correlates significantly with the Plasmodium infection status. This striking relationship highlights the role of natural gut environment in parasite transmission. Deciphering microbe-pathogen interactions offers new perspectives to control disease transmission.Institut de Recherche pour le Developpement (IRD); French Agence Nationale pour la Recherche [ANR-11-BSV7-009-01]; European Community [242095, 223601]info:eu-repo/semantics/publishedVersio

Vitamin D Supplementation to Prevent Acute Respiratory Tract Infections: Systematic Review and Meta-Analysis Of Individual Participant Data

OBJECTIVES To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. DESIGN Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. DATA SOURCES Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. ELIGIBILITY CRITERIA FOR STUDY SELECTION Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. RESULTS 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity \u3c0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels \u3c25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality. CONCLUSIONS Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit

Intergenerational Wealth Transmission and the Dynamics of Inequality in Small-Scale Societies

Small-scale human societies range from foraging bands with a strong egalitarian ethos to more economically stratified agrarian and pastoral societies. We explain this variation in inequality using a dynamic model in which a population’s long-run steady-state level of inequality depends on the extent to which its most important forms of wealth are transmitted within families across generations. We estimate the degree of intergenerational transmission of three different types of wealth (material, embodied, and relational), as well as the extent of wealth inequality in 21 historical and contemporary populations. We show that intergenerational transmission of wealth and wealth inequality are substantial among pastoral and small-scale agricultural societies (on a par with or even exceeding the most unequal modern industrial economies) but are limited among horticultural and foraging peoples (equivalent to the most egalitarian of modern industrial populations). Differences in the technology by which a people derive their livelihood and in the institutions and norms making up the economic system jointly contribute to this pattern

Comparative genomics in cyprinids: common carp ESTs help the annotation of the zebrafish genome

BACKGROUND: Automatic annotation of sequenced eukaryotic genomes integrates a combination of methodologies such as ab-initio methods and alignment of homologous genes and/or proteins. For example, annotation of the zebrafish genome within Ensembl relies heavily on available cDNA and protein sequences from two distantly related fish species and other vertebrates that have diverged several hundred million years ago. The scarcity of genomic information from other cyprinids provides the impetus to leverage EST collections to understand gene structures in this diverse teleost group. RESULTS: We have generated 6,050 ESTs from the differentiating testis of common carp (Cyprinus carpio) and clustered them with 9,303 non-gonadal ESTs from CarpBase as well as 1,317 ESTs and 652 common carp mRNAs from GenBank. Over 28% of the resulting 8,663 unique transcripts are exclusively testis-derived ESTs. Moreover, 974 of these transcripts did not match any sequence in the zebrafish or fathead minnow EST collection. A total of 1,843 unique common carp sequences could be stringently mapped to the zebrafish genome (version 5), of which 1,752 matched coding sequences of zebrafish genes with or without potential splice variants. We show that 91 common carp transcripts map to intergenic and intronic regions on the zebrafish genome assembly and regions annotated with non-teleost sequences. Interestingly, an additional 42 common carp transcripts indicate the potential presence of new splicing variants not found in zebrafish databases so far. The fact that common carp transcripts help the identification or confirmation of these coding regions in zebrafish exemplifies the usefulness of sequences from closely related species for the annotation of model genomes. We also demonstrate that 5' UTR sequences of common carp and zebrafish orthologs share a significant level of similarity based on preservation of motif arrangements for as many as 10 ab-initio motifs. CONCLUSION: Our data show that there is sufficient homology between the transcribed sequences of common carp and zebrafish to warrant an even deeper cyprinid transcriptome comparison. On the other hand, the comparative analysis illustrates the value in utilizing partially sequenced transcriptomes to understand gene structure in this diverse teleost group. We highlight the need for integrated resources to leverage the wealth of fragmented genomic data

p73: A Multifunctional Protein in Neurobiology

p73, a transcription factor of the p53 family, plays a key role in many biological processes including neuronal development. Indeed, mice deficient for both TAp73 and ΔNp73 isoforms display neuronal pathologies, including hydrocephalus and hippocampal dysgenesis, with defects in the CA1-CA3 pyramidal cell layers and the dentate gyrus. TAp73 expression increases in parallel with neuronal differentiation and its ectopic expression induces neurite outgrowth and expression of neuronal markers in neuroblastoma cell lines and neural stem cells, suggesting that it has a pro-differentiation role. In contrast, ΔNp73 shows a survival function in mature cortical neurons as selective ΔNp73 null mice have reduced cortical thickness. Recent evidence has also suggested that p73 isoforms are deregulated in neurodegenerative pathologies such as Alzheimer’s disease, with abnormal tau phosphorylation. Thus, in addition to its increasingly accepted contribution to tumorigenesis, the p73 subfamily also plays a role in neuronal development and neurodegeneration

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents