Omadacycline gut microbiome exposure does not induce Clostridium difficile proliferation or toxin production in a model that simulates the proximal, medial and distal human colon

A clinically reflective model of the human colon was used to investigate the effects of the broad-spectrum antibiotic omadacycline on the gut microbiome, and subsequent potential to induce simulated Clostridium difficile infection (CDI). Triple stage chemostat gut models were inoculated with pooled human faecal slurry from healthy volunteers (age ≥60 years). Models were challenged twice with 107 cfu C. difficile spores (PCR ribotype 027). Omadacycline effects were assessed in a single gut model. Observations were confirmed in a parallel study with omadacycline and moxifloxacin. Antibiotic instillation was performed once daily for 7 days. The models were observed for 3 weeks post-antibiotic challenge. Gut microbiota populations and C. difficile total viable and spore counts were enumerated daily by culture. Cytotoxin titres and antibiotic concentrations were also measured. Gut microbiota populations were stable before antibiotic challenge. Moxifloxacin instillation caused a ∼4 log10 cfu/mL decline in enterococci and Bacteroides fragilis group populations, and a ∼3 log10 cfu/mL decline in bifidobacteria and lactobacilli, followed by simulated CDI (vegetative cell proliferation and detectable toxin). In both models, omadacycline instillation decreased populations of bifidobacteria (∼8 log10 cfu/mL), B. fragilis group populations (7-8 log10 cfu/mL), lactobacilli (2-6 log10 cfu/mL), and enterococci (4-6 log10 cfu/mL). Despite these microbial shifts, there was no evidence of C. difficile germination or toxin production. In contrast to moxifloxacin, omadacycline exposure did not facilitate simulated CDI, suggesting this antibiotic may have a low propensity to induce CDI in the clinical setting

A Novel, Orally Delivered Antibody Therapy and Its Potential to Prevent Clostridioides difficile Infection in Pre-clinical Models

Clostridioides difficile infection (CDI) is a toxin-mediated infection in the gut and a major burden on healthcare facilities worldwide. We rationalized that it would be beneficial to design an antibody therapy that is delivered to, and is active at the site of toxin production, rather than neutralizing the circulating and luminal toxins after significant damage of the layers of the intestines has occurred. Here we describe a highly potent therapeutic, OraCAb, with high antibody titers and a formulation that protects the antibodies from digestion/inactivation in the gastrointestinal tract. The potential of OraCAb to prevent CDI in an in vivo hamster model and an in vitro human colon model was assessed. In the hamster model we optimized the ratio of the antibodies against each of the toxins produced by C. difficile (Toxins A and B). The concentration of immunoglobulins that is effective in a hamster model of CDI was determined. A highly significant difference in animal survival for those given an optimized OraCAb formulation versus an untreated control group was observed. This is the first study testing the effect of oral antibodies for treatment of CDI in an in vitro gut model seeded with a human fecal inoculum. Treatment with OraCAb successfully neutralized toxin production and did not interfere with the colonic microbiota in this model. Also, treatment with a combination of vancomycin and OraCAb prevented simulated CDI recurrence, unlike vancomycin therapy alone. These data demonstrate the efficacy of OraCAb formulation for the treatment of CDI in pre-clinical models

Profiling the Effects of Systemic Antibiotics for Acne, Including the Narrow-Spectrum Antibiotic Sarecycline, on the Human Gut Microbiota

Treatment for moderate-to-severe acne vulgaris relies on prolonged use of oral tetracycline-class antibiotics; however, these broad-spectrum antibiotics are often associated with off-target effects and negative gastrointestinal sequelae. Sarecycline is a narrow-spectrum antibiotic treatment option. Here, we investigated the effect of prolonged sarecycline exposure, compared with broad-spectrum tetracyclines (doxycycline and minocycline) upon the colonic microbiota. Three in vitro models of the human colon were instilled with either minocycline, doxycycline or sarecycline, and we measured microbiota abundance and diversity changes during and after antibiotic exposure. Significant reductions in microbial diversity were observed following minocycline and doxycycline exposure, which failed to recover post antibiotic withdrawal. Specifically, minocycline caused a ~10% decline in Lactobacillaceae and Bifidobacteriaceae abundances, while doxycycline caused a ~7% decline in Lactobacillaceae and Bacteroidaceae abundances. Both minocycline and doxycycline were associated with a large expansion (>10%) of Enterobacteriaceae. Sarecycline caused a slight decline in bacterial diversity at the start of treatment, but abundances of most families remained stable during treatment. Ruminococcaceae and Desulfovibrionaceae decreased 9% and 4%, respectively, and a transient increased in Enterobacteriaceae abundance was observed during sarecycline administration. All populations recovered to pre-antibiotic levels after sarecycline exposure. Overall, sarecycline had minimal and transient impact on the gut microbiota composition and diversity, when compared to minocycline and doxycycline

Intervention planning and modification of the BUMP intervention: a digital intervention for the early detection of raised blood pressure in pregnancy

Background: Hypertensive disorders in pregnancy, particularly pre-eclampsia, pose a substantial health risk for both maternal and foetal outcomes. The BUMP (Blood Pressure Self-Monitoring in Pregnancy) interventions are being tested in a trial. They aim to facilitate the early detection of raised blood pressure through self-monitoring. This article outlines how the self-monitoring interventions in the BUMP trial were developed and modified using the person-based approach to promote engagement and adherence. Methods: Key behavioural challenges associated with blood pressure self-monitoring in pregnancy were identified through synthesising qualitative pilot data and existing evidence, which informed guiding principles for the development process. Social cognitive theory was identified as an appropriate theoretical framework. A testable logic model was developed to illustrate the hypothesised processes of change associated with the intervention. Iterative qualitative feedback from women and staff informed modifications to the participant materials. Results: The evidence synthesis suggested women face challenges integrating self-monitoring into their lives and that adherence is challenging at certain time points in pregnancy (for example, starting maternity leave). Intervention modification included strategies to address adherence but also focussed on modifying outcome expectancies, by providing messages explaining pre-eclampsia and outlining the potential benefits of self-monitoring. Conclusions: With an in-depth understanding of the target population, several methods and approaches to plan and develop interventions specifically relevant to pregnant women were successfully integrated, to address barriers to behaviour change while ensuring they are easy to engage with, persuasive and acceptable

Progesterone reduces erectile dysfunction in sleep-deprived spontaneously hypertensive rats

BACKGROUND: Paradoxical sleep deprivation (PSD) associated with cocaine has been shown to enhance genital reflexes (penile erection-PE and ejaculation-EJ) in Wistar rats. Since hypertension predisposes males to erectile dysfunction, the aim of the present study was to investigate the effects of PSD on genital reflexes in the spontaneously hypertensive rat (SHR) compared to the Wistar strain. We also extended our study to examine how PSD affect steroid hormone concentrations involved in genital events in both experimental models. METHODS: The first experiment investigated the effects of PSD on genital reflexes of Wistar and SHR rats challenged by saline and cocaine (n = 10/group). To further examine the impact of the PSD on concentrations of sexual hormones, we performed a hormonal analysis of testosterone and progesterone in the Wistar and in SHR strains. Since after PSD progesterone concentrations decreased in the SHR compared to the Wistar PSD group we extended our study by investigating whether progesterone (25 mg/kg or 50 mg/kg) or testosterone (0.5 mg/kg or 1.0 mg/kg) administration during PSD would have a facilitator effect on the occurrence of genital reflexes in this hypertensive strain. RESULTS: A 4-day period of PSD induced PE in 50% of the Wistar rats against 10% for the SHR. These genital reflexes was potentiated by cocaine in Wistar rats whereas this scenario did not promote significant enhancement in PE and EJ in hypertensive rats, and the percentage of SHR displaying genital reflexes still figured significantly lower than that of the Wistar strain. As for hormone concentrations, both sleep-deprived Wistar and SHR showed lower testosterone concentrations than their respective controls. Sleep deprivation promoted an increase in concentrations of progesterone in Wistar rats, whereas no significant alterations were found after PSD in the SHR strain, which did not present enhancement in erectile responses. In order to explore the role of progesterone in the occurrence of genital reflexes, SHR were treated daily during the sleep deprivation period with progesterone; after the administration of this hormone and challenge with cocaine, we observed a significant increase in erectile events compared with the vehicle PSD SHR+cocaine group. CONCLUSION: Our data showed that the low frequency of genital reflexes found in SHR sleep deprived rats may be attributed to the lower concentrations of progesterone in these rats, based on the observation that progesterone replacement increased genital reflexes in this strain

Understanding high pressure hydrogen with a hierarchical machine-learned potential

The hydrogen phase diagram has a number of unusual features which are generally well reproduced by density functional calculations. Unfortunately, these calculations fail to provide good physical insights into why those features occur. In this paper, we parameterize a model potential for molecular hydrogen which permits long and large simulations. The model shows excellent reproduction of the phase diagram, including the broken-symmetry Phase II, an efficiently-packed phase III and the maximum in the melt curve. It also gives an excellent reproduction of the vibrational frequencies, including the maximum in the vibrational frequency $\nu(P)$ and negative thermal expansion. By detailed study of lengthy molecular dynamics, we give intuitive explanations for observed and calculated properties. All solid structures approximate to hexagonal close packed, with symmetry broken by molecular orientation. At high pressure, Phase I shows significant short-ranged correlations between molecular orientations. The turnover in Raman frequency is due to increased coupling between neighboring molecules, rather than weakening of the bond. The liquid is denser than the close-packed solid because, at molecular separations below 2.3\AA, the favoured relative orientation switches from quadrupole-energy-minimising to steric-repulsion-minimising. The latter allows molecules to get closer together, without atoms getting closer but this cannot be achieved within the constraints of a close-packed layer

Willingness to act upon beliefs about 'treatment as prevention' among Australian gay and bisexual men

HIV 'treatment as prevention' (TasP) is highly effective in reducing HIV transmission in serodiscordant couples. There has been little examination of gay and bisexual men's attitudes towards TasP, particularly regarding men's willingness to act on beliefs about TasP. We conducted an online cross-sectional survey of Australian men in late 2012 to investigate knowledge and beliefs about new developments in HIV prevention. Amongst 839 men (mean age 39.5 years), men tended to disagree that TasP was sufficiently effective to justify reduced condom use, although HIV-positive men had more favourable attitudes. Only a minority of men were aware of any evidence for TasP; and one-quarter incorrectly believed that evidence for the effectiveness of TasP already existed for the homosexual population. One-fifth (20.5%) of men reported that they would be willing to have condomless anal intercourse with an opposite-status sexual partner when the HIV-positive partner was taking HIV treatments. Factors independently associated with such willingness were: HIV-positive serostatus, reporting any serodiscordant or serononconcordant condomless anal intercourse with a regular male partner in the previous six months, reporting any condomless anal intercourse with a casual male partner in the previous six months, and having greater beliefs in the effectiveness of TasP. This indicated that the men most willing to rely on TasP to prevent transmission were already engaging in higher risk practices. Biomedical HIV prevention represents a rapidly changing environment with new research as well as community and policy responses emerging at a fast pace. For men with serodiscordant sexual partners to successfully apply TasP to reducing transmission risk, more support and education is needed to enable better utilisation of TasP in specific relational and sexual contexts

Trehalose-Induced Remodelling of the Human Microbiota Affects Clostridioides difficile Infection Outcome in an In Vitro Colonic Model: A Pilot Study

Within the human intestinal tract, dietary, microbial- and host-derived compounds are used as signals by many pathogenic organisms, including Clostridioides difficile. Trehalose has been reported to enhance virulence of certain C. difficile ribotypes; however, such variants are widespread and not correlated with clinical outcomes for patients suffering from C. difficile infection (CDI). Here, we make preliminary observations on how trehalose supplementation affects the microbiota in an in vitro model and show that trehalose-induced changes can reduce the outgrowth of C. difficile, preventing simulated CDI. Three clinically reflective human gut models simulated the effects of sugar (trehalose or glucose) or saline ingestion on the microbiota. Models were instilled with sugar or saline and further exposed to C. difficile spores. The recovery of the microbiota following antibiotic treatment and CDI induction was monitored in each model. The human microbiota remodelled to utilise the bioavailable trehalose. Clindamycin induction caused simulated CDI in models supplemented with either glucose or saline; however, trehalose supplementation did not result in CDI, although limited spore germination did occur. The absence of CDI in trehalose model was associated with enhanced abundances of Finegoldia, Faecalibacterium and Oscillospira, and reduced abundances of Klebsiella and Clostridium spp., compared with the other models. Functional analysis of the microbiota in the trehalose model revealed differences in the metabolic pathways, such as amino acid metabolism, which could be attributed to prevention of CDI. Our data show that trehalose supplementation remodelled the microbiota, which prevented simulated CDI, potentially due to enhanced recovery of nutritionally competitive microbiota against C. difficile

Child abuse inventory at emergency rooms: CHAIN-ER rationale and design

<p>Abstract</p> <p>Background</p> <p>Child abuse and neglect is an important international health problem with unacceptable levels of morbidity and mortality. Although maltreatment as a cause of injury is estimated to be only 1% or less of the injured children attending the emergency room, the consequences of both missed child abuse cases and wrong suspicions are substantial. Therefore, the accuracy of ongoing detection at emergency rooms by health care professionals is highly important. Internationally, several diagnostic instruments or strategies for child abuse detection are used at emergency rooms, but their diagnostic value is still unknown. The aim of the study 'Child Abuse Inventory at Emergency Rooms' (CHAIN-ER) is to assess if active structured inquiry by emergency room staff can accurately detect physical maltreatment in children presenting at emergency rooms with physical injury.</p> <p>Methods/design</p> <p>CHAIN-ER is a multi-centre, cross-sectional study with 6 months diagnostic follow-up. Five thousand children aged 0-7 presenting with injury at an emergency room will be included. The index test - the SPUTOVAMO-R questionnaire- is to be tested for its diagnostic value against the decision of an expert panel. All SPUTOVAMO-R positives and a 15% random sample of the SPUTOVAMO-R negatives will undergo the same systematic diagnostic work up, which consists of an adequate history being taken by a pediatrician, inquiry with other health care providers by structured questionnaires in order to obtain child abuse predictors, and by additional follow-up information. Eventually, an expert panel (reference test) determines the <it>true </it>presence or absence of child abuse.</p> <p>Discussion</p> <p>CHAIN-ER will determine both positive and negative predictive value of a child abuse detection instrument used in the emergency room. We mention a benefit of the use of an expert panel and of the use of complete data. Conducting a diagnostic accuracy study on a child abuse detection instrument is also accompanied by scientific hurdles, such as the lack of an accepted reference standard and potential (non-) response. Notwithstanding these scientific challenges, CHAIN-ER will provide accurate data on the predictive value of SPUTOVAMO-R.</p

The relationship between gambling event frequency, motor response inhibition, arousal, and dissociative experience

Speed of play has been identified as a key structural characteristic in gambling behaviour, where games involving higher playing speeds enhance the experience of gambling. Of interest in the present study is the consistent finding that games with higher event frequencies are preferred by problem gamblers and are associated with more negative gambling outcomes, such as difficulty quitting the game and increased monetary loss. The present study investigated the impact of gambling speed of play on executive control functioning, focusing on how increased speeds of play impact motor response inhibition, and the potential mediating role arousal and dissociative experience play in this relationship. Fifty regular non-problem gamblers took part in a repeated-measures experiment where they gambled with real money on a simulated slot machine across five speed of play conditions. Response inhibition was measured using an embedded Go/No-Go task, where participants had to withhold motor responses, rather than operating the spin button on the slot machine when a specific colour cue was present. Results indicated that response inhibition performance was significantly worse during faster speeds of play, and that the role of arousal in this relationship was independent of any motor priming affect. The implications of these findings for gambling legislation and gambling harm-minimisation approaches are discussed