Next-Generation Probiotics Targeting \u3ci\u3eClostridium difficile\u3c/i\u3e through Precursor- Directed Antimicrobial Biosynthesis

Integration of antibiotic and probiotic therapy has the potential to lessen the public health burden of antimicrobial-associated diseases. Clostridium difficile infection (CDI) represents an important example where the rational design of next-generation probiotics is being actively pursued to prevent disease recurrence. Because intrinsic resistance to clinically relevant antibiotics used to treat CDI (vancomycin, metronidazole, and fidaxomicin) is a desired trait in such probiotic species, we screened several bacteria and identified Lactobacillus reuteri to be a promising candidate for adjunct therapy. Human-derived L. reuteri bacteria convert glycerol to the broad-spectrum antimicrobial compound reuterin. When supplemented with glycerol, strains carrying the pocR gene locus were potent reuterin producers, with L. reuteri 17938 inhibiting C. difficile growth at a level on par with the level of growth inhibition by vancomycin. Targeted pocR mutations and complementation studies identified reuterin to be the precursor-induced antimicrobial agent. Pathophysiological relevance was demonstrated when the codelivery of L. reuteri with glycerol was effective against C. difficile colonization in complex human fecal microbial communities, whereas treatment with either glycerol or L. reuteri alone was ineffective. A global unbiased microbiome and metabolomics analysis independently confirmed that glycerol precursor delivery with L. reuteri elicited changes in the composition and function of the human microbial community that preferentially targets C. difficile outgrowth and toxicity, a finding consistent with glycerol fermentation and reuterin production. Antimicrobial resistance has thus been successfully exploited in the natural design of human microbiome evasion of C. difficile, and this method may provide a prototypic precursor-directed probiotic approach. Antibiotic resistance and substrate bioavailability may therefore represent critical new determinants of probiotic efficacy in clinical trials

Pathologic Inflammation in Malnutrition Is Driven by Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, and Translocation of Bacterial Lipopolysaccharide

Acute malnutrition, or wasting, is implicated in over half of all deaths in children under five and increases risk of infectious disease. Studies in humans and preclinical models have demonstrated that malnutrition is linked to an immature intestinal microbiota characterized by increased prevalence of Enterobacteriaceae. Observational studies in children with moderate acute malnutrition (MAM) have also observed heightened systemic inflammation and increased circulating bacterial lipopolysaccharides (LPS; endotoxin). However, the mechanisms that underpin the systemic inflammatory state and endotoxemia, and their pathophysiological consequences, remain uncertain. Understanding these pathophysiological mechanisms is necessary to design targeted treatments that will improve the unacceptable rate of failure or relapse that plague current approaches. Here we use a mouse model of MAM to investigate the mechanisms that promote inflammation in the malnourished host. We found that mice with MAM exhibited increased systemic inflammation at baseline, increased translocation of bacteria and bacterial LPS, and an exaggerated response to inflammatory stimuli. An exaggerated response to bacterial LPS was associated with increased acute weight loss. Remarkably, intestinal inflammation and barrier dysfunction was found in the cecum and colon. The cecum showed a dysbiotic microbiota with expansion of Gammaproteobacteria and some Firmicutes, and contraction of Bacteroidetes. These changes were paralleled by an increase in fecal LPS bioactivity. The inflammatory phenotype and weight loss was modulated by oral administration of non-absorbable antibiotics that altered the proportion of cecal Gammaproteobacteria. We propose that the heightened inflammation of acute malnutrition is the result of changes in the intestinal microbiota, intestinal barrier dysfunction in the cecum and colon, and increased systemic exposure to LPS

Evaluation of Lay Support in Pregnant women with Social risk (ELSIPS): a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Maternal, neonatal and child health outcomes are worse in families from black and ethnic minority groups and disadvantaged backgrounds. There is little evidence on whether lay support improves maternal and infant outcomes among women with complex social needs within a disadvantaged multi-ethnic population in the United Kingdom (UK).</p> <p>Method/Design</p> <p>The aim of this study is to evaluate a lay Pregnancy Outreach Worker (POW) service for nulliparous women identified as having social risk within a maternity service that is systematically assessing social risks alongside the usual obstetric and medical risks. The study design is a randomised controlled trial (RCT) in nulliparous women assessed as having social risk comparing standard maternity care with the addition of referral to the POW support service.</p> <p>The POWs work alongside community midwifery teams and offer individualised support to women to encourage engagement with services (health and social care) from randomisation (before 28 weeks gestation) until 6 weeks after birth.</p> <p>The primary outcomes have been chosen on the basis that they are linked to maternal and infant health. The two primary outcomes are engagement with antenatal care, assessed by the number of antenatal visits; and maternal depression, assessed using the Edinburgh Postnatal Depression Scale at 8-12 weeks after birth. Secondary outcomes include maternal and neonatal morbidity and mortality, routine child health assessments, including immunisation uptake and breastfeeding at 6 weeks. Other psychological outcomes (self efficacy) and mother-to-infant bonding will also be collected using validated tools.</p> <p>A sample size of 1316 will provide 90% power (at the 5% significance level) to detect increased engagement with antenatal services of 1.5 visits and a reduction of 1.5 in the average EPDS score for women with two or more social risk factors, with power in excess of this for women with any social risk factor. Analysis will be by intention to treat.</p> <p>Qualitative research will explore the POWs' daily work in context. This will complement the findings of the RCT through a triangulation of quantitative and qualitative data on the process of the intervention, and identify other contextual factors that affect the implementation of the intervention.</p> <p>Discussion</p> <p>The trial will provide high quality evidence as to whether or not lay support (POW) offered to women identified with social risk factors improves engagement with maternity services and reduces numbers of women with depression.</p> <p>MREC number</p> <p>10/H1207/23</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN35027323">ISRCTN35027323</a></p

Effects of lay support for pregnant women with social risk factors on infant development and maternal psychological health at 12 months postpartum

Background The ELSIPS (Evaluation of Lay Support in Pregnant Women with Social Risk) RCT showed that lay support for women with social risk had a positive effect on maternal mental health and mother-infant bonding. This exploratory study examined whether these observed benefits would impact infant development at 1 year. Methods A sub-sample of women whose infants were under one year who had participated in the ELSIPS RCT which randomised women to receive either standard care or the services of a Pregnancy Outreach Worker (POW), and who were contactable, were eligible to participate in the follow up. At home visits, the Bayley Scales of Infant Development (3rd Edition) and standardised measures of depression, self efficacy, mind-mindedness and bonding were completed. Results 486 women were eligible for follow up, of whom 154 agreed to participate. 61/273 were successfully followed up in the standard maternity care arm and 51/213 in the POW arm. Women who completed follow up were less depressed and had higher selfefficacy scores at 8–12 weeks postpartum than those who did not complete follow up. There were no significant differences in maternal outcomes, infant cognitive development, receptive communication, expressive communication, fine motor development or social/emotional functioning between groups at 12 month follow up. Infants of mothers who received the POW intervention had significantly better gross motor development than infants whose mothers received standard care (p<0.03)

Measurements of the charge asymmetry in top-quark pair production in the dilepton final state at s √ =8 TeV with the ATLAS detector

Measurements of the top-antitop quark pair production charge asymmetry in the dilepton channel, characterized by two high-pT leptons (electrons or muons), are presented using data corresponding to an integrated luminosity of 20.3  fb−1 from pp collisions at a center-of-mass energy s√=8  TeV collected with the ATLAS detector at the Large Hadron Collider at CERN. Inclusive and differential measurements as a function of the invariant mass, transverse momentum, and longitudinal boost of the tt¯ system are performed both in the full phase space and in a fiducial phase space closely matching the detector acceptance. Two observables are studied: AℓℓC based on the selected leptons and Att¯C based on the reconstructed tt¯ final state. The inclusive asymmetries are measured in the full phase space to be AℓℓC=0.008±0.006 and Att¯C=0.021±0.016, which are in agreement with the Standard Model predictions of AℓℓC=0.0064±0.0003 and Att¯C=0.0111±0.0004