Symptom Domain Groups of the Patient-Reported Outcomes Measurement Information System Tools Independently Predict Hospitalizations and Re-hospitalizations in Cirrhosis

Background Patient-Reported Outcomes Measurement Information System (PROMIS) tools can identify health-related quality of life (HRQOL) domains that could differentially affect disease progression. Cirrhotics are highly prone to hospitalizations and re-hospitalizations, but the current clinical prognostic models may be insufficient, and thus studying the contribution of individual HRQOL domains could improve prognostication. Aim Analyze the impact of individual HRQOL PROMIS domains in predicting time to all non-elective hospitalizations and re-hospitalizations in cirrhosis. Methods Outpatient cirrhotics were administered PROMIS computerized tools. The first non-elective hospitalization and subsequent re-hospitalizations after enrollment were recorded. Individual PROMIS domains significantly contributing toward these outcomes were generated using principal component analysis. Factor analysis revealed three major PROMIS domain groups: daily function (fatigue, physical function, social roles/activities and sleep issues), mood (anxiety, anger, and depression), and pain (pain behavior/impact) accounted for 77% of the variability. Cox proportional hazards regression modeling was used for these groups to evaluate time to first hospitalization and re-hospitalization. Results A total of 286 patients [57 years, MELD 13, 67% men, 40% hepatic encephalopathy (HE)] were enrolled. Patients were followed at 6-month (mth) intervals for a median of 38 mths (IQR 22–47), during which 31% were hospitalized [median IQR mths 12.5 (3–27)] and 12% were re-hospitalized [10.5 mths (3–28)]. Time to first hospitalization was predicted by HE, HR 1.5 (CI 1.01–2.5, p = 0.04) and daily function PROMIS group HR 1.4 (CI 1.1–1.8, p = 0.01), independently. In contrast, the pain PROMIS group were predictive of the time to re-hospitalization HR 1.6 (CI 1.1–2.3, p = 0.03) as was HE, HR 2.1 (CI 1.1–4.3, p = 0.03). Conclusions Daily function and pain HRQOL domain groups using PROMIS tools independently predict hospitalizations and re-hospitalizations in cirrhotic patients

Modulation of the Metabiome by Rifaximin in Patients with Cirrhosis and Minimal Hepatic Encephalopathy

Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. Methods Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. Results There was a significant improvement in cognition(six of seven tests improved,pVeillonellaceaeand increase inEubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered onEnterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. Conclusions Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. Trial Registration ClinicalTrials.gov NCT0106913

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases

A hypothetico-deductive approach to assessing the social function of chemical signalling in a non-territorial solitary carnivore

The function of chemical signalling in non-territorial solitary carnivores is still relatively unclear. Studies on territorial solitary and social carnivores have highlighted odour capability and utility, however the social function of chemical signalling in wild carnivore populations operating dominance hierarchy social systems has received little attention. We monitored scent marking and investigatory behaviour of wild brown bears Ursus arctos, to test multiple hypotheses relating to the social function of chemical signalling. Camera traps were stationed facing bear ‘marking trees’ to document behaviour by different age sex classes in different seasons. We found evidence to support the hypothesis that adult males utilise chemical signalling to communicate dominance to other males throughout the non-denning period. Adult females did not appear to utilise marking trees to advertise oestrous state during the breeding season. The function of marking by subadult bears is somewhat unclear, but may be related to the behaviour of adult males. Subadults investigated trees more often than they scent marked during the breeding season, which could be a result of an increased risk from adult males. Females with young showed an increase in marking and investigation of trees outside of the breeding season. We propose the hypothesis that females engage their dependent young with marking trees from a young age, at a relatively ‘safe’ time of year. Memory, experience, and learning at a young age, may all contribute towards odour capabilities in adult bears

A data-driven, meaningful, easy to interpret, standardised accelerometer outcome variable for global surveillance

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Objectives: Our aim is to demonstrate how a data-driven accelerometer metric, the acceleration above which a person’s most active minutes are accumulated, can a) quantify the prevalence of meeting current physical activity guidelines for global surveillance and b) moving forward, could inform accelerometer-driven physical activity guidelines. Unlike cut-point methods, the metric is population-independent (e.g. age) and potentially comparable across datasets. Design: Cross-sectional, secondary data analysis. Methods: Analyses were carried out on five datasets using wrist-worn accelerometers: children (N=145), adolescent girls (N=1669), office workers (N=114), pre- (N=1218) and post- (N=1316) menopausal women, and adults with type 2 diabetes (N=475). Open-source software (GGIR) was used to generate the magnitude of acceleration above which a person’s most active 60, 30 and 2 minutes are accumulated: M60ACC; M30ACC and M2ACC, respectively. Results: The proportion of participants with M60ACC (children) and M30ACC (adults) values higher than accelerations representative of brisk walking (i.e., moderate-to-vigorous physical activity) ranged from 17-68% in children and 15%-81% in adults, tending to decline with age. The proportion of pre-and postmenopausal women with M2ACC values meeting thresholds for bone health ranged from 6-13%. Conclusions: These metrics can be used for global surveillance of physical activity, including assessing prevalence of meeting current physical activity guidelines. As accelerometer and corresponding health data accumulate it will be possible to interpret the metrics relative to age- and sex- specific norms and derive evidence-based physical activity guidelines directly from accelerometer data for use in future global surveillance. This is where the potential advantages of these metrics lie

Complex c-di-GMP Signaling Networks Mediate Transition between Virulence Properties and Biofilm Formation in Salmonella enterica Serovar Typhimurium

Upon Salmonella enterica serovar Typhimurium infection of the gut, an early line of defense is the gastrointestinal epithelium which senses the pathogen and intrusion along the epithelial barrier is one of the first events towards disease. Recently, we showed that high intracellular amounts of the secondary messenger c-di-GMP in S. typhimurium inhibited invasion and abolished induction of a pro-inflammatory immune response in the colonic epithelial cell line HT-29 suggesting regulation of transition between biofilm formation and virulence by c-di-GMP in the intestine. Here we show that highly complex c-di-GMP signaling networks consisting of distinct groups of c-di-GMP synthesizing and degrading proteins modulate the virulence phenotypes invasion, IL-8 production and in vivo colonization in the streptomycin-treated mouse model implying a spatial and timely modulation of virulence properties in S. typhimurium by c-di-GMP signaling. Inhibition of the invasion and IL-8 induction phenotype by c-di-GMP (partially) requires the major biofilm activator CsgD and/or BcsA, the synthase for the extracellular matrix component cellulose. Inhibition of the invasion phenotype is associated with inhibition of secretion of the type three secretion system effector protein SipA, which requires c-di-GMP metabolizing proteins, but not their catalytic activity. Our findings show that c-di-GMP signaling is at least equally important in the regulation of Salmonella-host interaction as in the regulation of biofilm formation at ambient temperature

A PSTOL-like gene, TaPSTOL, controls a number of agronomically important traits in wheat

Background Phosphorus (P) is an essential macronutrient for plant growth, and is required in large quantities by elite varieties of crops to maintain yields. Approximately 70% of global cultivated land suffers from P deficiency, and it has recently been estimated that worldwide P resources will be exhausted by the end of this century, increasing the demand for crops more efficient in their P usage. A greater understanding of how plants are able to maintain yield with lower P inputs is, therefore, highly desirable to both breeders and farmers. Here, we clone the wheat (Triticum aestivum L.) homologue of the rice PSTOL gene (OsPSTOL), and characterize its role in phosphate nutrition plus other agronomically important traits. Results TaPSTOL is a single copy gene located on the short arm of chromosome 5A, encoding a putative kinase protein, and shares a high level of sequence similarity to OsPSTOL. We re-sequenced TaPSTOL from 24 different wheat accessions and (3) three T. durum varieties. No sequence differences were detected in 26 of the accessions, whereas two indels were identified in the promoter region of one of the durum wheats. We characterised the expression of TaPSTOL under different P concentrations and demonstrated that the promoter was induced in root tips and hairs under P limiting conditions. Overexpression and RNAi silencing of TaPSTOL in transgenic wheat lines showed that there was a significant effect upon root biomass, flowering time independent of P treatment, tiller number and seed yield, correlating with the expression of TaPSTOL. However this did not increase PUE as elevated P concentration in the grain did not correspond to increased yields. Conclusions Manipulation of TaPSTOL expression in wheat shows it is responsible for many of the previously described phenotypic advantages as OsPSTOL except yield. Furthermore, we show TaPSTOL contributes to additional agronomically important traits including flowering time and grain size. Analysis of TaPSTOL sequences from a broad selection of wheat varieties, encompassing 91% of the genetic diversity in UK bread wheat, showed that there is very little genetic variation in this gene, which would suggest that this locus may have been under high selection pressure

Similar exemplar pooling processes underlie the learning of facial identity and handwriting style: Evidence from typical observers and individuals with Autism

Considerable research has addressed whether the cognitive and neural representations recruited by faces are similar to those engaged by other types of visual stimuli. For example, research has examined the extent to which objects of expertise recruit holistic representation and engage the fusiform face area. Little is known, however, about the domain-specificity of the exemplar pooling processes thought to underlie the acquisition of familiarity with particular facial identities. In the present study we sought to compare observers’ ability to learn facial identities and handwriting styles from exposure to multiple exemplars. Crucially, while handwritten words and faces differ considerably in their topographic form, both learning tasks share a common exemplar pooling component. In our first experiment, we find that typical observers’ ability to learn facial identities and handwriting styles from exposure to multiple exemplars correlates closely. In our second experiment, we show that observers with autism spectrum disorder (ASD) are impaired at both learning tasks. Our findings suggest that similar exemplar pooling processes are recruited when learning facial identities and handwriting styles. Models of exemplar pooling originally developed to explain face learning, may therefore offer valuable insights into exemplar pooling across a range of domains, extending beyond faces. Aberrant exemplar pooling, possibly resulting from structural differences in the inferior longitudinal fasciculus, may underlie difficulties recognising familiar faces often experienced by individuals with ASD, and leave observers overly reliant on local details present in particular exemplars