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Background: People with MS (PwMS) can experience a number of diverse needs which may be met by community-based services such as those delivered by MS Ireland (MSI), where Community Workers (CWs) provide support to PwMS on an individualised basis. However, while such support may be critical in helping PwMS adapt and cope with the challenges of living with MS, there has been little evaluation of the outcomes and impacts of this service to date. This study aimed to explore the perceived effectiveness and impacts of community work from the perspectives of both PwMS and CWs. Methods: Using stakeholder engagement and public and patient involvement (PPI), two surveys were developed for (1) CWs, and (2) services users of MSI. A series of open and closed questions centred on the effectiveness of community work in meeting twelve distinct categories of needs taken from an adapted framework of rehabili?tation and healthcare needs of PwMS. Both CWs and service users rated the extent to which these various needs were met through community work, as well as describing the mechanisms by which needs were met, and the challenges faced in meeting these needs. Separately, both groups described the perceived impacts of community work using open-text responses. Results: Fifteen CWs and 367 PwMS, 269 (73%) of whom knew their CW, participated. Both groups rated community work positively in meeting the needs for information, emotional/psychological support and coordination of care, with lower perceived capacity for community work to meet needs for employment accommodations, caregiver support and homecare. Mann Whitney U tests did not find any significant difference between groups in the perceived capacity of community work to meet the various needs examined (p>.05). Core mechanisms by which CWs meet needs are by signposting to relevant services, listening, and facilitating peer support. Difficulty accessing external services was the primary challenge identified in meeting needs. Positive impacts of community work included the role that CWs play in fostering confidence and acceptance of MS, and in helping service users overcome the challenges of MS. Conclusion: Results suggest how CWs can help meet the needs of PwMS, while also highlighting the numerous positive impacts that community work has for this group. While it is clear that a number of unmet needs may remain due to a lack of access to other external services, this study shows how community-based services may play an important role in helping PwMS adapt to living with MS.

Head and neck cancers (HNC) are often late stage at diagnosis; stage is a major determinant of prognosis. The urgent cancer referral pathway (two week wait; 2WW) within England’s National Health Service aims to reduce time to diagnosis. We investigated factors associated with HNC route to diagnosis. Data were obtained from the English population-based cancer registry on 66,411 primary invasive HNCs (ICD C01-14 and C31-32) diagnosed 2006–2014. Multivariable logistic regression determined the likelihood of different diagnosis routes by patients’ demographic and clinical characteristics. Significant socio-demographic inequalities were observed. Emergency presentations declined over time and 2WW increased. Significant socio-demographic inequalities were observed. Non-white patients, aged over 65, residing in urban areas with advanced disease, were more likely to have emergency presentations. White males aged 55 and older with an oropharynx cancer were more likely to be diagnosed via 2WW. Higher levels of deprivation were associated with both emergency and 2WW routes. Dental referral was more likely in women, with oral cancers and lower stage disease. Despite the decline over time in emergency presentation and the increased use of 2WW, socio-demographic variation is evident in routes to diagnosis. Further work exploring the reasons for these inequalities, and the consequences for patients’ care and outcomes, is urgently required.

Rural cancer inequalities are evident internationally, with rural cancer patients 5% less likely to survive than their urban counterparts. There is evidence to suggest that diagnostic delays prior to entry into secondary care may be contributing to these poorer rural cancer outcomes. This study explores the symptom appraisal and help-seeking decision-making of people experiencing symptoms of colorectal cancer in rural areas of England. Patients were randomly invited from 4 rural practices, serving diverse communities. Semi-structured interviews were undertaken with 40 people who had experienced symptoms of colorectal cancer in the preceding 8 weeks. Four key themes were identified as influential in participants’ willingness and timeliness of consultation: a desire to rule out cancer (facilitator of help-seeking); stoicism and self-reliance (barrier to help-seeking); time scarcity (barrier to help-seeking); and GP/patient relationship (barrier or facilitator, depending on perceived strength of the relationship). Self-employed, and “native” rural residents most commonly reported experiencing time scarcity and poor GP/patient relationships as a barrier to (re-)consultation. Targeted, active safety-netting approaches, and increased continuity of care, may be particularly beneficial to expedite timely diagnoses and minimise cancer inequalities for rural populations.

Background The interaction between genetic, epigenetic and environmental factors plays an important role in the aetiology of hypertension. GWAS and observational studies link the C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) with hypertension, while riboflavin, the MTHFR cofactor, has been shown to reduce blood pressure and global DNA methylation in homozygous (TT genotype) individuals. It is currently unclear whether riboflavin modulates DNA methylation of other hypertension-related genes. Objectives To compare DNA methylation of hypertension-related genes in adults stratified by MTHFR genotype and effect of riboflavin intervention in adults with the variant MTHFR 677TT genotype. Method Pyrosequencing was carried out for hypertension-related genes (ACE, AGTR1, GCK, GNA12, IGF2, MMP9 and NOS3) in blood samples from participants in previous trials (CC, n = 40; TT, n = 40). The effect of intervention with riboflavin (1.6 mg/d for16 weeks) or placebo on DNA methylation was investigated in adults with the variant MTHFR 677TT genotype (n = 80). Results Individuals with the MTHFR 677TT v CC genotype had significantly higher average DNA methylation at NOS3 (+1.66%, P = 0.044). In response to riboflavin supplementation in TT individuals, there was an increase in average DNA methylation at IGF2 (+1.09%, P = 0.019) and a decrease at ACE (−0.44%, P = 0.021) in females only. Specific CpG sites were hypomethylated in GNA12 and hypermethylated in AGTR1. Conclusion This study provides the first RCT evidence that riboflavin alters DNA methylation of hypertension-related genes in adults with the MTHFR 677TT genotype, providing some insight into mechanisms linking hypertension with the genotype-specific response of BP to riboflavin.

DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (-1.2%, p 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.

Introduction:The C677T polymorphism in the folate metabolising enzyme methylenetetrahydrofolate reductase (MTHFR) is associated with hypertension. Riboflavin acts as a cofactor for MTHFR in one-carbon metabolism which generates methyl groups for utilisation in important biological reactions such as DNA methylation. Supplementation with riboflavin has previously been shown to lower blood pressure in individuals with the MTHFR 677TT genotype. The mechanism regulating this gene-nutrient interaction is currently unknown but may involve aberrant DNA methylation which has been implicated hypertension.Objectives:The aims of this study were to examine DNA methylation of hypertension-related genes in adults stratified by MTHFR C677T genotype and the effect of riboflavin supplementation on DNA methylation of these genes in individuals with the MTHFR 677TT genotype.Materials and Methods:We measured DNA methylation using pyrosequencing in a set of candidate genes associated with hypertension including angiotensin II receptor type 1 (AGTR1), G nucleotide binding protein subunit alpha 12 (GNA12), insulin-like growth factor 2 (IGF2) and nitric oxide synthase 3 (NOS3). Stored peripheral blood leukocyte samples from participants previously screened for the MTHFR C677T genotype who participated in targeted randomised controlled trials (1.6mg/d riboflavin or placebo for 16 weeks) at Ulster University were accessed for this analysis (n = 120).Results:There were significant differences in baseline average methylation between MTHFR CC and TT genotypes at NOS3 (p = 0.026) and AGTR1 (p = 0.045) loci. Riboflavin supplementation in the TT genotype group resulted in altered average methylation at IGF2 (p = 0.025) and CpG site-specific alterations at the AGTR1 and GNA12 loci.Conclusion:DNA methylation at genes related to hypertension were significantly different in individuals stratified by MTHFR genotype group. Furthermore, in MTHFR 677TT genotype individuals, there were concurrent alterations in DNA methylation at genes linked to hypertension in response to riboflavin supplementation. This is the largest study to date to demonstrate an interaction between DNA methylation of hypertension-related genes and riboflavin supplementation in adults with the MTHFR 677TT genotype. Further work using a genome-wide approach is required to better understand the role of riboflavin in altering DNA methylation in these genetically at-risk individuals.

Context Aberrant DNA methylation is linked to various diseases. The supply of methyl groups for methylation reactions is mediated by S-adenosylmethionine, which depends on the availability of folate and related B vitamins. Objectives To investigate the influence of key nutrients involved in 1-carbon metabolism on DNA methylation in adults. Data sources Systematic literature searches were conducted in the Cochrane Library, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, and Web of Science databases. Studies that met the inclusion criteria and were published in English were included. Data extraction The first author, study design, sample size, population characteristics, type and duration of intervention, tissue type or cells analyzed, molecular techniques, and DNA methylation outcomes. Data synthesis A meta-analysis of randomized, controlled trials (RCTs) was conducted to investigate the effect of 1-carbon metabolism nutrients on global DNA methylation. Functional analysis and visualization were performed using BioVenn software. Results From a total of 2620 papers screened by title, 53 studies met the inclusion criteria. Qualitative analysis indicated significant associations between 1-carbon metabolism nutrients and DNA methylation. In meta-analysis of RCTs stratified by method of laboratory analysis, supplementation with folic acid alone or in combination with vitamin B12 significantly increased global DNA methylation in studies using liquid chromatography–mass spectrometry, which had markedly lower heterogeneity (n = 3; Z = 3.31; P = 0.0009; I2 = 0%) in comparison to other methods. Functional analysis highlighted a subset of 12 differentially methylated regions that were significantly related to folate and vitamin B12 biomarkers. Conclusion This study supports significant associations between 1-carbon metabolism nutrients and DNA methylation. However, standardization of DNA methylation techniques is recommended to reduce heterogeneity and facilitate comparison across studies. Systematic Review registration PROSPERO registration number: CRD42018091898.

The number of cancer survivors is growing due to population ageing, earlier detection and more effective therapies. Routinely collected data (RCD), generally cancer registry data, has been used to investigate survivors' needs and outcomes. We reviewed uses of RCD since 2017, identifying novel findings and research directions.Survival is improving internationally but continues to vary between subgroups. Longitudinal survivor surveys suggest malignancy-specific temporal patterns in unmet needs and health-related quality-of-life (HRQoL). Unmet needs are a risk factor for future depression and depression predicts poorer HRQoL in all domains. Emerging evidence suggests links between posttraumatic stress and poor HRQoL and posttraumatic growth and improved HRQoL. Evidence for a link between cancer-related financial hardship and poor HRQoL is accumulating. Surveys and linkage studies continue to show poorer work outcomes in survivors. Among survivors of childhood and young adult cancers, large linkage studies demonstrate significant risk of late effects, including hospitalization, pregnancy and labour complications, and cardiac death.RCD plays a significant role in understanding survivors' needs and outcomes. New approaches which overlay different types of data - including detailed clinical and treatment data, biomarker data and nonhealth administrative data - have the potential to generate considerable new knowledge.

Ziele: Mehr als zwei Millionen Menschen in Großbritannien und Nordirland leben mit einer Krebserkrankung oder haben diese überlebt. Ein Drittel von ihnen berichtet über eine verminderte Lebensqualität. Design: Review der veröffentlichten systematischen Übersichtsarbeiten zur Identifizierung wirksamer, nicht medikamentöser Interventionen zur Verbesserung der Lebensqualität von Krebsüberlebenden. Datenquellen: Folgende Datenbanken wurden bis Mai 2017 durchsucht: PubMed, Cochrane Central, EMBASE, MEDLINE, Web of Science, Cumulative Index to Nursing and Allied Health Literature sowie PsycINFO. Studienauswahl: Eingeschlossen wurden veröffentlichte systematische Übersichtsarbeiten über randomisierte Studien zu nicht medikamentösen Interventionen bei Patienten mit oder nach einer Krebserkrankung, die mindestens 18 Jahre alt waren. Bei allen Teilnehmern war bereits eine Krebserkrankung diagnostiziert worden. Die Interventionen wurden unabhängig vom Setting, d.h. unabhängig davon, ob sie in einer Gesundheitseinrichtung, im häuslichen Umfeld oder internetbasiert durchgeführt wurden, eingeschlossen. Ausgeschlossen waren Übersichtsarbeiten zu alternativen Therapien oder nicht auf Englisch verfasste Berichte. Zwei Wissenschaftler bewerteten unabhängig voneinander Titel, Abstract und den vollständigen Text der Veröffentlichungen und nahmen eine unabhängige Datenextraktion vor. Outcomes: Das primär interessierende Outcome waren alle Maße der globalen (Gesamt-)Lebensqualität. Analysemethoden: Bewertung der Qualität gemäß AMSTAR (Assessment of Multiple Systematic Reviews) und narrative Synthese zur Beurteilung der Wirksamkeit nicht medikamentöser Interventionen und ihrer Komponenten. Ergebnisse: Von 14 430 eindeutigen Titeln wurden 21 in das Review der Übersichtsarbeiten einbezogen. Zwischen den Übersichtsarbeiten bestanden wenige Überschneidungen hinsichtlich der eingeschlossenen Primärveröffentlichungen. 13 Übersichtsarbeiten behandelten unterschiedliche Tumorgruppen, in 7 lag der Schwerpunkt auf Brustkrebs und in einer ging es um Prostatakrebs. Häufig wurden persönliche Interventionen mit internetbasierten oder telefonischen Ansätzen und gedruckten Informationen kombiniert. Die Interventionen umfassten körperliche, psychologische oder verhaltensorientierte, multidimensionale Rehabilitations- und Online-Ansätze. Vorteile hinsichtlich der Lebensqualität zeigten insbesondere Yoga, körperliche Bewegung allgemein, kognitive Verhaltenstherapie (CBT) und Programme zur achtsamkeitsbasierten Stressreduktion (MBSR). Schlussfolgerungen: Bewegungsbasierte Interventionen waren kurzfristig (weniger als 3 bis 8 Monate) und langfristig wirksam. CBT und MBSR waren, insbesondere kurzfristig, ebenfalls mit Vorteilen verbunden. Die Evidenzlage für multidisziplinäre, internetbasierte und edukative Interventionen fiel uneinheitlich aus. Übersetzung aus Duncan M, et al.: BMJ Open 2017;7:e015860 (DOI: 10.1136/bmjopen-2017-015860)

International audience; The biological significance of Archaea in the human gut microbiota is largely unclear. We recently reported genomic and biochemical analyses of the Methanomassiliicoccales, a novel order of methanogenic Archaea dwelling in soil and the animal digestive tract. We now show that these Methanomassiliicoccales are present in published microbiome data sets from eight countries. They are represented by five Operational Taxonomic Units present in at least four cohorts and phylogenetically distributed into two clades. Genes for utilizing trimethylamine (TMA), a bacterial precursor to an atherosclerogenic human metabolite, were present in four of the six novel Methanomassiliicoccales genomes assembled from ELDERMET metagenomes. In addition to increased microbiota TMA production capacity in long-term residential care subjects, abundance of TMA-utilizing Methanomassiliicoccales correlated positively with bacterial gene count for TMA production and negatively with fecal TMA concentrations. The two large Methanomassiliicoccales clades have opposite correlations with host health status in the ELDERMET cohort and putative distinct genomic signatures for gut adaptation.

Purpose Clostridium difficile has been reported to occur in the gastrointestinal tract of 50% of Cystic Fibrosis (CF) subjects, however, clinical C. difficile infection (CDI) is a rare occurrence in this cohort despite the presence of toxigenic and hypervirulent ribotypes. Here, we present the first longitudinal, multicentre analysis of C. difficile prevalence among adult CF subjects. Methodology Faecal samples were collected from adults with CF (selected based on confirmed Pseudomonas aeruginosa pulmonary colonisation) from Ireland, UK and Belgium as part of the CFMATTERS clinical research trial (grant No. 603038) and from non-CF controls. Faecal samples were collected on enrolment, at three monthly intervals, during pulmonary exacerbation and three months post exacerbation. C. difficile was isolated from faecal samples by ethanol shocking followed by culturing on cycloserine cefoxitin egg yolk agar. Isolates were characterised in terms of ribotype, toxin type and antibiotic susceptibility to antibiotics routinely used in the treatment of CDI (metronidazole and vancomycin) and those implicated in induction of CDI (ciprofloxacin and moxifloxacin). Results Prevalence of C. difficile among CF subjects in the three sites was similar ranging from 47% to 50% at baseline, while the healthy control cohort had a carriage rate of 7.1%. Including subjects who were positive for C. difficile at any time point there was a higher carriage rate of 71.4%, 66.7% and 63.2% in Ireland, UK, and Belgium, respectively. Ribotyping of 80 isolates from 45 CF persons, over multiple time points revealed 23 distinct ribotypes with two ribotypes (046 and 078) shared by all centres. The proportion of toxigenic isolates varied across the sites, ranging from 66.7% in Ireland to 52.9% in Belgium and 100% in the UK. Antibiotic susceptibility rates to vancomycin, metronidazole, ciprofloxacin and moxifloxacin was 100%, 97.5%, 1.3% and 63.8%, respectively. Conclusions This study demonstrates the highest carriage rate of C. difficile to date in a CF cohort. Longitudinal data show that C. difficile can be a transient inhabitant of the CF gut, changing both in terms of strain and excretion rates.

The gut microbiota interacts with the host via neuroimmune, neuroendocrine and neural pathways. These pathways are components of the brain-gut-microbiota axis and preclinical evidence suggests that the microbiota can recruit this bidirectional communication system to modulate brain development, function and behaviour. The pathophysiology of depression involves neuroimmune-neuroendocrine dysregulation. However, the extent to which changes in gut microbiota composition and function mediate the dysregulation of these pathways is unknown. Thirty four patients with major depression and 33 matched healthy controls were recruited. Cytokines, CRP, Salivary Cortisol and plasma Lipopolysaccharide binding protein were determined by ELISA. Plasma tryptophan and kynurenine were determined by HPLC. Fecal samples were collected for 16s rRNA sequencing. A Fecal Microbiota transplantation was prepared from a sub group of depressed patients and controls and transferred by oral gavage to a microbiota-deficient rat model. We demonstrate that depression is associated with decreased gut microbiota richness and diversity. Fecal microbiota transplantation from depressed patients to microbiota-depleted rats can induce behavioural and physiological features characteristic of depression in the recipient animals, including anhedonia and anxiety-like behaviours, as well as alterations in tryptophan metabolism. This suggests that the gut microbiota may play a causal role in the development of features of depression and may provide a tractable target in the treatment and prevention of this disorder.

Test parameter variations were evaluated for their effects on surotomycin MICs. Calcium concentration was the only variable that influenced MICs; therefore, 50 μg/ml (standard for lipopeptide testing) is recommended. Quality control ranges for Clostridium difficile (0.12 to 1 μg/ml) and Eggerthella lenta (broth, 1 to 4 μg/ml; agar, 1 to 8 μg/ml) were approved by the Clinical and Laboratory Standards Institute based on these data.

The aim of this pilot study was to assess the benefits of using a brief mindfulness meditation approach to weight loss. Twenty participants (21 per cent men, mean age 31 years) with a BMI between 25 and 39.9 kg/m2were randomly assigned to one of three groups: mindfulness; healthy eating; or weigh–in only. Weight, BMI, self–esteem and mindfulness measures were taken on three occasions (pre– mid– and postintervention). Reductions in weight and BMI were found across all three groups, as were increases in participant’s self–esteem and mindfulness scores. No significant group differences were found. It is likely that this is a result of the small sample size and brevity of the intervention, therefore longer lasting interventions with a larger sample need to be trialled.

The in vitro activity and spectrum of tedizolid and comparators were analyzed against 6884 Gram-positive clinical isolates collected from multiple US and European sites as part of the Surveillance of Tedizolid Activity and Resistance Program in 2011 and 2012. Organisms included 4499 Staphylococcus aureus, 537 coagulase-negative staphylococci (CoNS), 873 enterococci, and 975 β-hemolytic streptococci. The MIC values that inhibited 90% of the isolates within each group (MIC90) were 0.25 μg/mL for Staphylococcus epidermidis and β-hemolytic streptococci and 0.5 μg/mL for S. aureus, other CoNS, and enterococci. Of 16 isolates with elevated tedizolid or linezolid MIC values (intermediate or resistant isolates), 10 had mutations in the genes encoding 23S rRNA (primarily G2576T), 5 had mutations in the genes encoding ribosomal proteins L3 or L4, and 5 carried the cfr multidrug resistance gene. Overall, tedizolid showed excellent activity against Gram-positive bacteria and was at least 4-fold more potent than linezolid against wild-type and linezolid-resistant isolates. Given the low overall frequency of isolates that would be resistant to tedizolid at the proposed break point of 0.5 μg/mL (0.19%) and potent activity against contemporary US and European isolates, tedizolid has the potential to serve as a valuable therapeutic option in the treatment of infections caused by Gram-positive pathogens.

The cfr gene was identified in three linezolid-resistant USA300 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected over a 3-day period at a New York City medical center in 2011 as part of a routine surveillance program. Each isolate possessed a plasmid containing a pSCFS3-like cfr gene environment. Transformation of the cfr -bearing plasmids into the S. aureus ATCC 29213 background recapitulated the expected Cfr antibiogram, including resistance to linezolid, tiamulin, clindamycin, and florfenicol and susceptibility to tedizolid.

Antimicrobial susceptibilities of contemporary Pseudomonas aeruginosa clinical isolates were determined from the CAPITAL 2010 surveillance program. Isolates were collected from 100 sites throughout the USA and Puerto Rico, and included isolates representing a range of patient demographics and infection types. A total of 2722 isolates were tested for susceptibility to a broad spectrum of agents, with susceptibilities ranging from 98.8% for colistin to 74% for levofloxacin. Doripenem was the most active carbapenem agent, with 88.6% of isolates susceptible, in comparison with 78.1% and 84.6% for imipenem and meropenem, respectively. Lower respiratory tract isolates and isolates from the intensive care unit setting were the least susceptible overall. Resistance rates were typically highest in lower respiratory tract isolates, with the exception of urinary tract isolates, which displayed the highest resistance for levofloxacin. Overall, multidrug-resistant isolates comprised 14.8% of the total sample population.

Cell envelope-active agents, particularly β-lactams, play a pivotal role in the treatment of bacterial infections and the extent to which their activity is affected by the emergence of multidrug-resistant organisms is of concern. We analyzed the Surveillance Network (TSN) database to evaluate resistant trends for key cell envelope-active drugs among ESKAPE pathogens. Analysis demonstrated that the activity of these drugs has been notably influenced by the emergence of multidrug resistance; this was especially evident for the β-lactam drugs. For example, Acinetobacter baumannii resistance to imipenem increased from 23.9% to 34.3%, and resistance to piperacillin-tazobactam increased from 37.0% to 49.7% between 2007 and 2011. During the same time period Klebsiella pneumoniae resistance to imipenem increased from 0.8% to 3.8%. As β-lactams are a cornerstone of anti-infective therapy, it is important to closely monitor the activity of the agents being used today and to aggressively pursue new strategies that can augment current drugs and thwart ever-emerging β-lactam resistance mechanisms that are continuously encountered.

Since the commercialization of antibiotics in the 1940s, life expectancy has increased in parallel with their discovery. However, concerns regarding the collateral effects of antibiotic therapy on gut microbiota composition and functionality within the host have come to the fore. Antibiotic therapy disrupts the normal ecology of the gut microbiome, resulting in altered composition, and in some cases function. Cystic fibrosis (CF) is an ideal candidate group in which to examine antibiotic effects on the gut microbiota. Chronic antibiotic use, along with the typical high-fat CF diet, cystic fibrosis transmembrane conductance regulator malfunction itself, pancreatic enzyme supplementation, and suppression of gastric acid, play a key role in defining the unique composition of the CF intestinal microbiota. Most available studies focus on the short-term effects of an antibiotic course of limited duration (eg, 7 days) and the pattern of recovery after such treatments. Here we discuss the specific effects of different antibiotic families on the gut microbiota. We examine the multidrug-resistant, Clostridium difficile, and antibiotic-associated diarrhea risk and prevalence associated with chronic antibiotic use. We review the success to date of probiotics to ameliorate CF symptomology. Finally, we explore alternative therapies for infection control currently under research.

Background and aims Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder that may be triggered by enteric pathogens and has also been linked to alterations in the microbiota and the host immune response. The authors performed a detailed analysis of the faecal microbiota in IBS and control subjects and correlated the findings with key clinical and physiological parameters. Design The authors used pyrosequencing to determine faecal microbiota composition in 37 IBS patients (mean age 37 years; 26 female subjects; 15 diarrhoea-predominant IBS, 10 constipation-predominant IBS and 12 alternating-type IBS) and 20 age- and gender-matched controls. Gastrointestinal and psychological symptom severity and quality of life were evaluated with validated questionnaires and colonic transit time and rectal sensitivity were measured. Results Associations detected between microbiota composition and clinical or physiological phenotypes included microbial signatures associated with colonic transit and levels of clinically significant depression in the disease. Clustering by microbiota composition revealed subgroups of IBS patients, one of which (n=15) showed normal-like microbiota composition compared with healthy controls. The other IBS samples (n=22) were defined by large microbiota-wide changes characterised by an increase of Firmicutes -associated taxa and a depletion of Bacteroidetes -related taxa. Conclusions Detailed microbiota analysis of a well-characterised cohort of IBS patients identified several clear associations with clinical data and a distinct subset of IBS patients with alterations in their microbiota that did not correspond to IBS subtypes, as defined by the Rome II criteria.

Private sector involvement in desalination projects in the Mediterranean Middle East (Algeria, Egypt, Israel, Jordan, Lebanon, Libya, Morocco, Syria and Tunisia) has in the main been limited to the provision of facilities under turnkey type contracts — with the exception of Israel which has recently embarked on a series of BOO/BOT type projects. The first part of this paper outlines the principal types of private sector involvement employed on infrastructure projects globally today — from management contracts to concessions to full-scale privatisations. Each of the MME countries is then reviewed in turn to identify the forms of private sector involvement experienced to date on infrastructure projects, with particular emphasis on desalination projects. The second part of the paper sets out the general drivers and constraints behind private sector involvement on desalination projects from both public and private sector perspectives. Drivers include: need (either to replace or supplement existing supplies); lack of alternative supplies; desire for private sector expertise, lack of public sector funding; and availability of IPP's. Constraints include: political opposition; lack of appropriate regulatory/legal frameworks; inability to pay for services; high country risk; and lack of track record of completed PSP projects. The application of these drivers and constraints to each country in the MME is then undertaken, and the results help inform the likely future prospects for private sector involvement on desalination projects in the foreseeable future.

Over the past decade, excessive sleepiness among children and adolescents has been identified as a major societal concern. Professionals working with pediatric groups must increasingly factor sleepiness into assessments of waking function. We define and discuss excessive sleepiness in children and adolescents and review available evidence regarding effects on behavior, mood, and performance. Findings for daytime sleepiness and subsequent impairment in these domains are classified as robust to unknown. Empirical evidence clearly indicates that children and adolescents experience significant daytime sleepiness as a result of inadequate or disturbed sleep. The specific effect of sleepiness on functional domains in pediatric groups are less well-studied, but existing data suggests that children are likely to experience impairment in behavioral, mood, and performance domains. However, such variables as developmental differences in the type and degree of impairment, the degree of sleep disturbance required to produce impairments, and potential risk and protective factors for the effects of sleepiness in children have yet to be described. Further research is clearly warranted, and we discuss important questions and methodological concerns to encourage inquiry in both clinical and experimental settings. Advice is offered with regard to screening for sleep problems and associated sleepiness with children and adolescents.

ObjectivesOver two million people in the UK are living with and beyond cancer. A third report diminished quality of life.DesignA review of published systematic reviews to identify effective non-pharmacological interventions to improve the quality of life of cancer survivors.Data sourcesDatabases searched until May 2017 included PubMed, Cochrane Central, EMBASE, MEDLINE, Web of Science, the Cumulative Index to Nursing and Allied Health Literature, and PsycINFO.Study selectionPublished systematic reviews of randomised trials of non-pharmacological interventions for people living with and beyond cancer were included; included reviews targeted patients aged over 18. All participants had already received a cancer diagnosis. Interventions located in any healthcare setting, home or online were included. Reviews of alternative therapies or those non-English reports were excluded. Two researchers independently assessed titles, abstracts and the full text of papers, and independently extracted the data.OutcomesThe primary outcome of interest was any measure of global (overall) quality of life.Analytical methodsQuality assessment assessing methdological quality of systematic reviews (AMSTAR) and narrative synthesis, evaluating effectiveness of non-pharmacological interventions and their components.ResultsOf 14 430 unique titles, 21 were included in the review of reviews. There was little overlap in the primary papers across these reviews. Thirteen reviews covered mixed tumour groups, seven focused on breast cancer and one focused on prostate cancer. Face-to-face interventions were often combined with online, telephone and paper-based reading materials. Interventions included physical, psychological or behavioural, multidimensional rehabilitation and online approaches. Yoga specifically, physical exercise more generally, cognitive behavioural therapy (CBT) and mindfulness-based stress reduction (MBSR) programmes showed benefit in terms of quality of life.ConclusionsExercise-based interventions were effective in the short (less than 3–8 months) and long term. CBT and MBSR also showed benefits, especially in the short term. The evidence for multidisciplinary, online and educational interventions was equivocal.

The Cfr methyltransferase confers resistance to six classes of drugs which target the peptidyl transferase center of the 50S ribosomal subunit, including some oxazolidinones, such as linezolid (LZD). The mobile cfr gene was identified in European veterinary isolates from the late 1990s, although the earliest report of a clinical cfr -positive strain was the 2005 Colombian methicillin-resistant Staphylococcus aureus (MRSA) isolate CM05. Here, through retrospective analysis of LZD r clinical strains from a U.S. surveillance program, we identified a cfr -positive MRSA isolate, 1128105, from January 2005, predating CM05 by 5 months. Molecular typing of 1128105 revealed a unique pulsed-field gel electrophoresis (PFGE) profile most similar to that of USA100, spa type t002, and multilocus sequence type 5 (ST5). In addition to cfr , LZD resistance in 1128105 is partially attributed to the presence of a single copy of the 23S rRNA gene mutation T2500A. Transformation of the ∼37-kb conjugative p1128105 cfr -bearing plasmid from 1128105 into S. aureus ATCC 29213 background strains was successful in recapitulating the Cfr antibiogram, as well as resistance to aminoglycosides and trimethoprim. A 7-kb cfr -containing region of p1128105 possessed sequence nearly identical to that found in the Chinese veterinary Proteus vulgaris isolate PV-01 and in U.S. clinical S. aureus isolate 1900, although the presence of IS 431 -like sequences is unique to p1128105. The cfr gene environment in this early clinical cfr -positive isolate has now been identified in Gram-positive and Gram-negative strains of clinical and veterinary origin and has been associated with multiple mobile elements, highlighting the versatility of this multidrug resistance gene and its potential for further dissemination.

The onset of flowering, the change from vegetative to reproductive development, is a major life history transition in flowering plants. Recent work suggests that mutations in cis-regulatory mutations should play critical roles in the evolution of this (as well as other) important adaptive traits, but thus far there has been little evidence that directly links regulatory mutations to evolutionary change at the species level. While several genes have previously been shown to affect natural variation in flowering time in Arabidopsis thaliana, most either show protein-coding changes and/or are found at low frequency (, The transcription factor CONSTANS regulates the timing of flowering in Arabidopsis. Rosas et al. report that genetic variation in the cis-regulatory regions of this gene contributes to natural phenotypic variation in flowering time.

“ Candidatus Methanomassiliicoccus intestinalis” Issoire-Mx1 is a methanogenic archaeon found in the human gut and is a representative of the novel order of methanogens related to Thermoplasmatales . Its complete genome sequence is presented here.

Clinical development of CEM-102 (fusidic acid) has recently begun in the United States for chronic oral treatment of prosthetic joint infections. To support this development, the in vitro activity of fusidic acid against important Staphylococcus aureus clones and resistance phenotypes was determined. Against 51 such isolates, the modal fusidic acid MIC was 0.12 μg/ml (range, 0.06 to 0.25 μg/ml for 49 isolates). This level of in vitro fusidic acid activity underscores the potential clinical utility of this compound in the United States.

Cell envelope-active agents, particularly β-lactams, play a pivotal role in the treatment of bacterial infections and the extent to which their activity is affected by the emergence of multidrug-resistant organisms is of concern. We analyzed the Surveillance Network (TSN) database to evaluate resistant trends for key cell envelope-active drugs among ESKAPE pathogens. Analysis demonstrated that the activity of these drugs has been notably influenced by the emergence of multidrug resistance; this was especially evident for the β-lactam drugs. For example, Acinetobacter baumannii resistance to imipenem increased from 23.9% to 34.3%, and resistance to piperacillin-tazobactam increased from 37.0% to 49.7% between 2007 and 2011. During the same time period Klebsiella pneumoniae resistance to imipenem increased from 0.8% to 3.8%. As β-lactams are a cornerstone of anti-infective therapy, it is important to closely monitor the activity of the agents being used today and to aggressively pursue new strategies that can augment current drugs and thwart ever-emerging β-lactam resistance mechanisms that are continuously encountered.

Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.

Multidrug resistance among Acinetobacter spp. leaves few effective antibiotic options for treatment. To monitor antibiotic resistance in Acinetobacter spp., the US CAPITAL 2010 Surveillance data were evaluated by patient demographics, specimen source, and hospital ward. Isolates (N=514) were collected from 65 sites across the USA and Puerto Rico. Isolates were centrally tested for susceptibility to carbapenems and key antimicrobials by broth microdilution. Colistin was the most effective agent tested, with 95% susceptibility. The overall susceptibility of Acinetobacter spp. was low (39% for piperacillin/tazobactam, 41% for levofloxacin, 45% for ceftazidime, 47-51% for the carbapenems, and 58% for tobramycin). Multidrug resistance (MDR), defined as resistance to ≥3 antimicrobial agent groups, was detected in 54% of the isolates. MDR isolates were most common among elderly patients (65%), lower respiratory tract isolates (62%), and inpatient/intensive care unit isolates (54-58%). These data update trends in the distribution and prevalence of the MDR phenotype in Acinetobacter spp.

Objectives Ivacaftor is effective in the treatment of patients with CF and the G551D gating mutation. We present faecal analysis results of the CORK cohort, a single-centre, adult (n = 20), prospective, longitudinal study of G551D clinical responders (median follow-up 12 months), examining the gut microbiota, exocrine pancreatic function and intestinal inflammation on a 3 monthly basis after commencing treatment. Methods Stool samples pre- and 3 monthly post commencement of ivacaftor in 20 adult patients underwent metagenomic profiling of faecal microbiota. Faecal elastase-1 (FE-1), faecal calprotectin (FC) and faecal lactoferrin (FL) were measured using commercially available ELISA kits. Results Ivacaftor did not significantly alter gut microbial diversity, as measured by chao1 (p = 0.886). At phylum, family and genus levels significant increases were observed in Bacteroidetes (p = 0.044), Bacteroidaceae (p = 0.021) and Bacteroides (p = 0.021). Significant decreases were observed in Microbacteriaceae (p = 0.003) and Eubacteriaceae (p = 0.014). A significant positive correlation was seen between FEV1 and gut microbiota diversity following treatment (r = 0.4, p=0.002). No significant difference was measured in levels of FE-1 (p = 0.267), FC (p = 0.406) or FL (p = 0.779). Conclusion Ivacaftor therapy has a normalisation effect on the gut microbiota, directing the microbiota towards a non-CF profile. Despite this elevated intestinal inflammation was sustained. Lack of exocrine pancreatic recovery may reflect established exocrine pancreatic dysfunction in an adult cohort. On-going longitudinal prospective data may demonstrate further improvements in the gut health of this cohort.

peer-reviewed Background High-throughput sequencing has enabled detailed insights into complex microbial environments, including the human gut microbiota. The accuracy of the sequencing data however, is reliant upon appropriate storage of the samples prior to DNA extraction. The aim of this study was to conduct the first MiSeq sequencing investigation into the effects of faecal storage on the microbiota, compared to fresh samples. Culture-based analysis was also completed. Methods Seven faecal samples were collected from healthy adults. Samples were separated into fresh (DNA extracted immediately), snap frozen on dry ice and frozen for 7 days at -80°C prior to DNA extraction or samples frozen at -80°C for 7 days before DNA extraction. Sequencing was completed on the Illumina MiSeq platform. Culturing of total aerobes, anaerobes and bifidobacteria was also completed. Results No significant differences at phylum or family levels between the treatment groups occurred. At genus level only Faecalibacterium and Leuconostoc were significantly different in the fresh samples compared to the snap frozen group (p = 0.0298; p = 0.0330 respectively). Diversity analysis indicated that samples clustered based on the individual donor, rather than by storage group. No significant differences occurred in the culture-based analysis between the fresh, snap or -80°C frozen samples. Conclusions Using the MiSeq platform coupled with culture-based analysis, this study highlighted that limited significant changes in microbiota occur following rapid freezing of faecal samples prior to DNA extraction. Thus, rapid freezing of samples prior to DNA extraction and culturing, preserves the integrity of the microbiota. Jennifer Deane is in receipt of a Teagasc Walsh Fellowship. The authors and their work were supported by the Science Foundation Ireland and funded by the Centre for Science, Engineering and Technology (SFI-CSET) grant 02/CE/B124 and by FP7 funded CFMATTERS (Cystic Fibrosis Microbiome-determined Antibiotic Therapy Trial in Exacerbations: Results Stratified, Grant Agreement no. 603038). The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI). This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2273.