Modelling microbiome recovery after antibiotics using a stability landscape framework

Treatment with antibiotics is one of the most extreme perturbations to the human microbiome. Even standard courses of antibiotics dramatically reduce the microbiome’s diversity and can cause transitions to dysbiotic states. Conceptually, this is often described as a ‘stability landscape’: the microbiome sits in a landscape with multiple stable equilibria, and sufficiently strong perturbations can shift the microbiome from its normal equilibrium to another state. However, this picture is only qualitative and has not been incorporated in previous mathematical models of the effects of antibiotics. Here, we outline a simple quantitative model based on the stability landscape concept and demonstrate its success on real data. Our analytical impulse-response model has minimal assumptions with three parameters. We fit this model in a Bayesian framework to data from a previous study of the year-long effects of short courses of four common antibiotics on the gut and oral microbiomes, allowing us to compare parameters between antibiotics and microbiomes, and further validate our model using data from another study looking at the impact of a combination of last-resort antibiotics on the gut microbiome. Using Bayesian model selection we find support for a long-term transition to an alternative microbiome state after courses of certain antibiotics in both the gut and oral microbiomes. Quantitative stability landscape frameworks are an exciting avenue for future microbiome modelling

Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

Cell walls of the dimorphic fungal pathogens Sporothrix schenckii and Sporothrix brasiliensis exhibit bilaminate structures and sloughing of extensive and intact layers

This work was supported by the Fundação Carlos Chagas de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), grants E-26/202.974/2015 and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), grants 229755/2013-5, Brazil. LMLB is a senior research fellow of CNPq and Faperj. NG acknowledged support from the Wellcome Trust (Trust (097377, 101873, 200208) and MRC Centre for Medical Mycology (MR/N006364/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The RR Lyrae Distance Scale

We review seven methods of measuring the absolute magnitude M_V of RR Lyrae stars in light of the Hipparcos mission and other recent developments. We focus on identifying possible systematic errors and rank the methods by relative immunity to such errors. For the three most robust methods, statistical parallax, trigonometric parallax, and cluster kinematics, we find M_V (at [Fe/H] = -1.6) of 0.77 +/- 0.13, 0.71 +/- 0.15, 0.67 +/- 0.10. These methods cluster consistently around 0.71 +/- 0.07. We find that Baade-Wesselink and theoretical models both yield a broad range of possible values (0.45-0.70 and 0.45-0.65) due to systematic uncertainties in the temperature scale and input physics. Main-sequence fitting gives a much brighter M_V = 0.45 +/- 0.04 but this may be due to a difference in the metallicity scales of the cluster giants and the calibrating subdwarfs. White-dwarf cooling-sequence fitting gives 0.67 +/- 0.13 and is potentially very robust, but at present is too new to be fully tested for systematics. If the three most robust methods are combined with Walker's mean measurement for 6 LMC clusters, V_{0,LMC} = 18.98 +/- 0.03 at [Fe/H] = -1.9, then mu_{LMC} = 18.33 +/- 0.08.Comment: Invited review article to appear in: `Post-Hipparcos Cosmic Candles', A. Heck & F. Caputo (Eds), Kluwer Academic Publ., Dordrecht, in press. 21 pages including 1 table; uses Kluwer's crckapb.sty LaTeX style file, enclose

The HTA risk analysis chart: visualising the need for and potential value of managed entry agreements in health technology assessment

Background Recent changes to the regulatory landscape of pharmaceuticals may sometimes require reimbursement authorities to issue guidance on technologies that have a less mature evidence base. Decision makers need to be aware of risks associated with such health technology assessment (HTA) decisions and the potential to manage this risk through managed entry agreements (MEAs). Objective This work develops methods for quantifying risk associated with specific MEAs and for clearly communicating this to decision makers. Methods We develop the ‘HTA risk analysis chart’, in which we present the payer strategy and uncertainty burden (P-SUB) as a measure of overall risk. The P-SUB consists of the payer uncertainty burden (PUB), the risk stemming from decision uncertainty as to which is the truly optimal technology from the relevant set of technologies, and the payer strategy burden (PSB), the additional risk of approving a technology that is not expected to be optimal. We demonstrate the approach using three recent technology appraisals from the UK National Institute for Health and Clinical Excellence (NICE), each of which considered a price-based MEA. Results The HTA risk analysis chart was calculated using results from standard probabilistic sensitivity analyses. In all three HTAs, the new interventions were associated with substantial risk as measured by the P-SUB. For one of these technologies, the P-SUB was reduced to zero with the proposed price reduction, making this intervention cost effective with near complete certainty. For the other two, the risk reduced substantially with a much reduced PSB and a slightly increased PUB. Conclusions The HTA risk analysis chart shows the risk that the healthcare payer incurs under unresolved decision uncertainty and when considering recommending a technology that is not expected to be optimal given current evidence. This allows the simultaneous consideration of financial and data-collection MEA schemes in an easily understood format. The use of HTA risk analysis charts will help to ensure that MEAs are considered within a standard utility-maximising health economic decision-making framework

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

The psychometric properties of three self-report screening instruments for identifying frail older people in the community

Background: Frailty is highly prevalent in older people. Its serious adverse consequences, such as disability, are considered to be a public health problem. Therefore, disability prevention in community-dwelling frail older people is considered to be a priority for research and clinical practice in geriatric care. With regard to disability prevention, valid screening instruments are needed to identify frail older people in time. The aim of this study was to evaluate and compare the psychometric properties of three screening instruments: the Groningen Frailty Indicator (GFI), the Tilburg Frailty Indicator (TFI) and the Sherbrooke Postal Questionnaire (SPQ). For validation purposes the Groningen Activity Restriction Scale (GARS) was added. Methods: A questionnaire was sent to 687 community-dwelling older people (>= 70 years). Agreement between instruments, internal consistency, and construct validity of instruments were evaluated and compared. Results: The response rate was 77%. Prevalence estimates of frailty ranged from 40% to 59%. The highest agreement was found between the GFI and the TFI (Cohen's kappa = 0.74). Cronbach's alpha for the GFI, the TFI and the SPQ was 0.73, 0.79 and 0.26, respectively. Scores on the three instruments correlated significantly with each other (GFI - TFI, r = 0.87; GFI - SPQ, r = 0.47; TFI - SPQ, r = 0.42) and with the GARS (GFI - GARS, r = 0.57; TFI - GARS, r = 0.61; SPQ - GARS, r = 0.46). The GFI and the TFI scores were, as expected, significantly related to age, sex, education and income. Conclusions: The GFI and the TFI showed high internal consistency and construct validity in contrast to the SPQ. Based on these findings it is not yet possible to conclude whether the GFI or the TFI should be preferred; data on the predictive values of both instruments are needed. The SPQ seems less appropriate for postal screening of frailty among community-dwelling older peopl

Adolescents' reactions to participating in ethically sensitive research: A prospective self-report study

Background: Conducting psychological research with adolescents is imperative for better understanding, prevention and treatment of mental illness. However there is concern that research addressing topics such as mental illness, substance use and suicidality has potential to distress participants, particularly youth. Method: We administered a questionnaire to 1973 adolescents (13-18 years) at two time points, one year apart. Participants responded to items regarding nonsuicidal self-injury, psychological distress, history of physical and/or sexual abuse, adverse life events, alcohol use, suicidal behaviour, self-efficacy, and coping skills as well as two open-ended questions regarding whether they enjoyed participating in the research and whether participation worried or upset them. Results: Most youth (74 %) enjoyed participation and cited altruistic reasons and a greater self-awareness as reasons. Those reporting being upset by the questionnaire (15 %) reported poorer psychological functioning than their peers. Youth who were upset by their participation at baseline, but who reported enjoying the questionnaire at follow-up reported improved psychosocial functioning over time, while the reverse was true for those who initially enjoyed participation but later reported the questionnaire upset them. Conclusions: Results suggest researchers acknowledge benefits for young people who participate in research, but also be mindful of the potential for distress among the most at risk youth