Same Exposure but Two Radically Different Responses to Antibiotics: Resilience of the Salivary Microbiome versus Long-Term Microbial Shifts in Feces

Due to the spread of resistance, antibiotic exposure receives increasing attention. Ecological consequences for the different niches of individual microbiomes are, however, largely ignored. Here, we report the effects of widely used antibiotics (clindamycin, ciprofloxacin, amoxicillin, and minocycline) with different modes of action on the ecology of both the gut and the oral microbiomes in 66 healthy adults from the United Kingdom and Sweden in a two-center randomized placebo-controlled clinical trial. Feces and saliva were collected at baseline, immediately after exposure, and 1, 2, 4, and 12 months after administration of antibiotics or placebo. Sequences of 16S rRNA gene amplicons from all samples and metagenomic shotgun sequences from selected baseline and post-antibiotic-treatment sample pairs were analyzed. Additionally, metagenomic predictions based on 16S rRNA gene amplicon data were performed using PICRUSt. The salivary microbiome was found to be significantly more robust, whereas the antibiotics negatively affected the fecal microbiome: in particular, health-associated butyrate-producing species became strongly underrepresented. Additionally, exposure to different antibiotics enriched genes associated with antibiotic resistance. In conclusion, healthy individuals, exposed to a single antibiotic treatment, undergo considerable microbial shifts and enrichment in antibiotic resistance in their feces, while their salivary microbiome composition remains unexpectedly stable. The health-related consequences for the gut microbiome should increase the awareness of the individual risks involved with antibiotic use, especially in a (diseased) population with an already dysregulated microbiome. On the other hand, understanding the mechanisms behind the resilience of the oral microbiome toward ecological collapse might prove useful in combating microbial dysbiosis elsewhere in the body. IMPORTANCE Many health care professionals use antibiotic prophylaxis strategies to prevent infection after surgery. This practice is under debate since it enhances the spread of antibiotic resistance. Another important reason to avoid nonessential use of antibiotics, the impact on our microbiome, has hardly received attention. In this study, we assessed the impact of antibiotics on the human microbial ecology at two niches. We followed the oral and gut microbiomes in 66 individuals from before, immediately after, and up to 12 months after exposure to different antibiotic classes. The salivary microbiome recovered quickly and was surprisingly robust toward antibiotic-induced disturbance. The fecal microbiome was severely affected by most antibiotics: for months, health-associated butyrate-producing species became strongly underrepresented. Additionally, there was an enrichment of genes associated with antibiotic resistance. Clearly, even a single antibiotic treatment in healthy individuals contributes to the risk of resistance development and leads to long-lasting detrimental shifts in the gut microbiome

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

Development and evaluation of a quality score for abstracts

BACKGROUND: The evaluation of abstracts for scientific meetings has been shown to suffer from poor inter observer reliability. A measure was developed to assess the formal quality of abstract submissions in a standardized way. METHODS: Item selection was based on scoring systems for full reports, taking into account published guidelines for structured abstracts. Interrater agreement was examined using a random sample of submissions to the American Gastroenterological Association, stratified for research type (n = 100, 1992–1995). For construct validity, the association of formal quality with acceptance for presentation was examined. A questionnaire to expert reviewers evaluated sensibility items, such as ease of use and comprehensiveness. RESULTS: The index comprised 19 items. The summary quality scores showed good interrater agreement (intra class coefficient 0.60 – 0.81). Good abstract quality was associated with abstract acceptance for presentation at the meeting. The instrument was found to be acceptable by expert reviewers. CONCLUSION: A quality index was developed for the evaluation of scientific meeting abstracts which was shown to be reliable, valid and useful

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma

Background: The seroprevalence of IgG antibodies of Streptococcus gallolyticus subspecies gallolyticus, CIP 105428, was evaluated to investigate the controversial association of S. gallolyticus with colorectal carcinoma and adenoma in attempt to investigate the nature of such association if any, by exploring the mRNA expression of NF-κB and IL-8. Moreover, the serological behavior of S. gallolyticus IgG antibodies was compared to that of an indicator bacterium of bowel, Bacteroides fragilis. Methods: ELISA was used to measure IgG antibodies of S. gallolyticus and B. fragilis in sera of 50 colorectal cancer, 14 colorectal adenoma patients, 30 age- and sex- matched apparently healthy volunteers (HV) and 30 age- and sex- matched colonoscopically-proven tumor-free control subjects. NF-κB and IL-8 mRNA expression was evaluated in tumorous and non-tumorous tissue sections of carcinoma and adenoma patients in comparison with that of control subjects by using in situ hybridization assay. Results: Colorectal cancer and adenoma patients were associated with higher levels of serum S. Gallolyticus IgG antibodies in comparison with HV and control subjects (P 0.05). ELISA cutoff value for the seropositivity of S. gallolyticus IgG was calculated from tumor-free control group. The expression of NF-κB mRNA was higher in tumorous than non-tumorous tissue sections of adenoma and carcinoma, higher in carcinoma/adenoma sections than in control subjects, higher in tumorous sections of carcinoma than in adenoma patients, and higher in S. gallolyticus IgG seropositive than in seronegative groups in both tumorous and non-tumorous sections (P < 0.05). IL-8 mRNA expression in tumorous sections of adenoma and carcinoma was higher than in non-tumorous sections, higher in carcinoma/adenoma than in control subjects, and higher in S. gallolyticus IgG seropositive than in seronegative groups in tumorous rather than non-tumorous sections (P < 0.05). Conclusion: S. gallolyticus most likely plays an essential role in the oncogenic progression of normal colorectal mucosa to adenoma and to CRC. This promoting/propagating role of S. gallolyticus might take place by utilizing certain inflammatory, anti-apoptotic, and angiogenic factors of transformation including NF-κB and IL-8.Ahmed S Abdulamir, Rand R Hafidh, Layla K Mahdi, Tarik Al-jeboori and Fatimah Abubake

High rate of in-stent restenosis after coronary intervention in carriers of the mutant mannose-binding lectin allele

BACKGROUND: In-stent restenosis occurs in 10-30% of patients following bare metal stent (BMS) implantation and has various risk factors. Mannose-binding lectin (MBL) is known to have effect on the progression of atherosclerosis. Single nucleotide polymorphisms (SNP) of the MBL2 gene intron 1 (codon 52, 54, 57) are known to modulate the bioavailability of the MBL protein. Our aim was to identify the association of these polymorphisms of the MBL gene in the occurrence of in-stent restenosis after coronary artery bare metal stent implantation. METHODS: In a non-randomized prospective study venous blood samples were collected after recoronarography from 225 patients with prior BMS implantation. Patients were assigned to diffuse restenosis group and control group based on the result of the coronarography. MBL genotypes were determined using quantitative real-time PCR. Proportion of different genotypes was compared and adjusted with traditional risk factors using multivariate logistic regression. RESULTS: Average follow-up time was 1.0 (+ - 1.4) year in the diffuse restenosis group (N = 117) and 2.7 (+ - 2.5) years in the control group (N = 108). The age, gender distribution and risk status was not different between study groups. Proportion of the MBL variant genotype was 26.8% (29 vs. 79 normal homozygous) in the control group and 39.3% (46 vs. 71 normal homozygous) in the restenosis group (p = 0.04). In multivariate analysis the mutant allele was an independent risk factor (OR = 1.96, p = 0.03) of in-stent restenosis. CONCLUSIONS: MBL polymorphisms are associated with higher incidence of development of coronary in-stent restenosis. The attenuated protein function in the mutant allelic genotype may represent the underlying mechanism

Study design and rationale of "Synergistic Effect of Combination Therapy with Cilostazol and ProbUcol on Plaque Stabilization and Lesion REgression (SECURE)" study: a double-blind randomised controlled multicenter clinical trial

<p>Abstract</p> <p>Background</p> <p>Probucol, a cholesterol-lowering agent that paradoxically also lowers high-density lipoprotein cholesterol has been shown to prevent progression of atherosclerosis. The antiplatelet agent cilostazol, which has diverse antiatherogenic properties, has also been shown to reduce restenosis in previous clinical trials. Recent experimental studies have suggested potential synergy between probucol and cilostazol in preventing atherosclerosis, possibly by suppressing inflammatory reactions and promoting cholesterol efflux.</p> <p>Methods/design</p> <p>The Synergistic Effect of combination therapy with Cilostazol and probUcol on plaque stabilization and lesion REgression (SECURE) study is designed as a double-blind, randomised, controlled, multicenter clinical trial to investigate the effect of cilostazol and probucol combination therapy on plaque volume and composition in comparison with cilostazol monotherapy using intravascular ultrasound and Virtual Histology. The primary end point is the change in the plaque volume of index intermediate lesions between baseline and 9-month follow-up. Secondary endpoints include change in plaque composition, neointimal growth after implantation of stents at percutaneous coronary intervention target lesions, and serum levels of lipid components and biomarkers related to atherosclerosis and inflammation. A total of 118 patients will be included in the study.</p> <p>Discussion</p> <p>The SECURE study will deliver important information on the effects of combination therapy on lipid composition and biomarkers related to atherosclerosis, thereby providing insight into the mechanisms underlying the prevention of atherosclerosis progression by cilostazol and probucol.</p> <p>Trial registration number</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT01031667">NCT01031667</a></p

Modelling Visual Neglect: Computational Insights into Conscious Perception

Background: Visual neglect is an attentional deficit typically resulting from parietal cortex lesion and sometimes frontal lesion. Patients fail to attend to objects and events in the visual hemifield contralateral to their lesion during visual search. Methodology/Principal Finding: The aim of this work was to examine the effects of parietal and frontal lesion in an existing computational model of visual attention and search and simulate visual search behaviour under lesion conditions. We find that unilateral parietal lesion in this model leads to symptoms of visual neglect in simulated search scan paths, including an inhibition of return (IOR) deficit, while frontal lesion leads to milder neglect and to more severe deficits in IOR and perseveration in the scan path. During simulations of search under unilateral parietal lesion, the model’s extrastriate ventral stream area exhibits lower activity for stimuli in the neglected hemifield compared to that for stimuli in the normally perceived hemifield. This could represent a computational correlate of differences observed in neuroimaging for unconscious versus conscious perception following parietal lesion. Conclusions/Significance: Our results lead to the prediction, supported by effective connectivity evidence, that connections between the dorsal and ventral visual streams may be an important factor in the explanation of perceptua

Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry.

BACKGROUND: The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries. OBJECTIVES: The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data. METHODS: Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis. RESULTS: A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion. CONCLUSIONS: The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers