Statistical methods for automated drug susceptibility testing: Bayesian minimum inhibitory concentration prediction from growth curves

Determination of the minimum inhibitory concentration (MIC) of a drug that prevents microbial growth is an important step for managing patients with infections. In this paper we present a novel probabilistic approach that accurately estimates MICs based on a panel of multiple curves reflecting features of bacterial growth. We develop a probabilistic model for determining whether a given dilution of an antimicrobial agent is the MIC given features of the growth curves over time. Because of the potentially large collection of features, we utilize Bayesian model selection to narrow the collection of predictors to the most important variables. In addition to point estimates of MICs, we are able to provide posterior probabilities that each dilution is the MIC based on the observed growth curves. The methods are easily automated and have been incorporated into the Becton--Dickinson PHOENIX automated susceptibility system that rapidly and accurately classifies the resistance of a large number of microorganisms in clinical samples. Over seventy-five studies to date have shown this new method provides improved estimation of MICs over existing approaches.Comment: Published in at http://dx.doi.org/10.1214/08-AOAS217 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Challenging perspectives on the cellular origins of lymphoma.

Both B and T lymphocytes have signature traits that set them apart from other cell types. They actively and repeatedly rearrange their DNA in order to produce a unique and functional antigen receptor, they have potential for massive clonal expansion upon encountering antigen via this receptor or its precursor, and they have the capacity to be extremely long lived as 'memory' cells. All three of these traits are fundamental to their ability to function as the adaptive immune response to infectious agents, but concurrently render these cells vulnerable to transformation. Thus, it is classically considered that lymphomas arise at a relatively late stage in a lymphocyte's development during the process of modifying diversity within antigen receptors, and when the cell is capable of responding to stimulus via its receptor. Attempts to understand the aetiology of lymphoma have reinforced this notion, as the most notable advances to date have shown chronic stimulation of the antigen receptor by infectious agents or self-antigens to be key drivers of these diseases. Despite this, there is still uncertainty about the cell of origin in some lymphomas, and increasing evidence that a subset arises in a more immature cell. Specifically, a recent study indicates that T-cell lymphoma, in particular nucleophosmin-anaplastic lymphoma kinase-driven anaplastic large cell lymphoma, may originate in T-cell progenitors in the thymus.T.I.M.M. was supported by a Bloodwise Gordon Piller Studentship.This is the final version of the article. It first appeared from The Royal Society via https://doi.org/10.1098/rsob.16023

Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial

Background: Cognitive behavioural therapy (CBT) is an effective treatment for people whose depression has not responded to antidepressants. However, the long-term outcome is unknown. In a long-term follow-up of the CoBalT trial, we examined the clinical and cost-effectiveness of cognitive behavioural therapy as an adjunct to usual care that included medication over 3–5 years in primary care patients with treatment-resistant depression. Methods: CoBalT was a randomised controlled trial done across 73 general practices in three UK centres. CoBalT recruited patients aged 18–75 years who had adhered to antidepressants for at least 6 weeks and had substantial depressive symptoms (Beck Depression Inventory [BDI-II] score ≥14 and met ICD-10 depression criteria). Participants were randomly assigned using a computer generated code, to receive either usual care or CBT in addition to usual care. Patients eligible for the long-term follow-up were those who had not withdrawn by the 12 month follow-up and had given their consent to being re-contacted. Those willing to participate were asked to return the postal questionnaire to the research team. One postal reminder was sent and non-responders were contacted by telephone to complete a brief questionnaire. Data were also collected from general practitioner notes. Follow-up took place at a variable interval after randomisation (3–5 years). The primary outcome was self-report of depressive symptoms assessed by BDI-II score (range 0–63), analysed by intention to treat. Cost-utility analysis compared health and social care costs with quality-adjusted life-years (QALYs). This study is registered with isrctn.com, number ISRCTN38231611. Findings: Between Nov 4, 2008, and Sept 30, 2010, 469 eligible participants were randomised into the CoBalT study. Of these, 248 individuals completed a long-term follow-up questionnaire and provided data for the primary outcome (136 in the intervention group vs 112 in the usual care group). At follow-up (median 45·5 months [IQR 42·5–51·1]), the intervention group had a mean BDI-II score of 19·2 (SD 13·8) compared with a mean BDI-II score of 23·4 (SD 13·2) for the usual care group (repeated measures analysis over the 46 months: difference in means −4·7 [95% CI −6·4 to −3·0, p<0·001]). Follow-up was, on average, 40 months after therapy ended. The average annual cost of trial CBT per participant was £343 (SD 129). The incremental cost-effectiveness ratio was £5374 per QALY gain. This represented a 92% probability of being cost effective at the National Institute for Health and Care Excellence QALY threshold of £20 000. Interpretation: CBT as an adjunct to usual care that includes antidepressants is clinically effective and cost effective over the long-term for individuals whose depression has not responded to pharmacotherapy. In view of this robust evidence of long-term effectiveness and the fact that the intervention represented good value-for-money, clinicians should discuss referral for CBT with all those for whom antidepressants are not effective

An algorithm for Monte-Carlo time-dependent radiation transfer

A new Monte-Carlo algorithm for calculating time-dependent radiative-transfer under the assumption of LTE is presented. Unlike flux-limited diffusion the method is polychromatic, includes scattering, and is able to treat the optically thick and free-streaming regimes simultaneously. The algorithm is tested on a variety of 1-d and 2-d problems, and good agreement with benchmark solutions is found. The method is used to calculate the time-varying spectral energy distribution from a circumstellar disc illuminated by a protostar whose accretion luminosity is varying. It is shown that the time lag between the optical variability and the infrared variability results from a combination of the photon travel time and the thermal response in the disc, and that the lag is an approximately linear function of wavelength.Comment: 10 pages, 10 figures, accepted for publication by MNRA

Architecture of North Atlantic Contourite Drifts Modified by Transient Circulation of the Icelandic Mantle Plume

Overflow of Northern Component Water, the precursor of North Atlantic Deep Water, appears to have varied during Neogene times. It has been suggested that this variation is moderated by transient behavior of the Icelandic mantle plume, which has influenced North Atlantic bathymetry through time. Thus pathways and intensities of bottom currents that control deposition of contourite drifts could be affected by mantle processes. Here, we present regional seismic reflection profiles that cross sedimentary accumulations (Björn, Gardar, Eirik and Hatton Drifts). Prominent reflections were mapped and calibrated using a combination of boreholes and legacy seismic profiles. Interpreted seismic profiles were used to reconstruct solid sedimentation rates. Björn Drift began to accumulate in late Miocene times. Its average sedimentation rate decreased at ∼2.5 Ma and increased again at ∼0.75 Ma. In contrast, Eirik Drift started to accumulate in early Miocene times. Its average sedimentation rate increased at ∼5.5 Ma and decreased at ∼2.2 Ma. In both cases, there is a good correlation between sedimentation rates, inferred Northern Component Water overflow, and the variation of Icelandic plume temperature independently obtained from the geometry of diachronous V-shaped ridges. Between 5.5 and 2.5 Ma, the plume cooled, which probably caused subsidence of the Greenland-Iceland-Scotland Ridge, allowing drift accumulation to increase. When the plume became hotter at 2.5 Ma, drift accumulation rate fell. We infer that deep-water current strength is modulated by fluctuating dynamic support of the Greenland-Scotland Ridge. Our results highlight the potential link between mantle convective processes and ocean circulation

Intergroup Contact, Social Dominance and Environmental Concern: A Test of the Cognitive-Liberalization Hypothesis

Intergroup contact is among the most effective ways to improve intergroup attitudes. While it is now beyond any doubt that contact can reduce prejudice, in this paper we provide evidence that its benefits can extend beyond intergroup relations – a process referred to as cognitive liberalization (Hodson, Crisp, Meleady & Earle, 2018). We focus specifically on the impact of intergroup contact on environmentally-relevant attitudes and behavior. Recent studies suggest that support for an inequality-based ideology (Social Dominance Orientation) can predict both intergroup attitudes and broader environmental conduct. Individuals higher in SDO are more willing to exploit the environment in unsustainable ways because doing so aids the production and maintenance of hierarchical social structures. In four studies conducted with British adults we show that by promoting less hierarchical and more egalitarian viewpoints (reduced SDO), intergroup contact encourages more environmentally responsible attitudes and behavior. Both cross-sectional and longitudinal data support this model. Effects are more strongly explained by reductions in an anti-egalitarian motive (SDO-E) than a dominance motive (SDO-D). We discuss how these findings help define an expanded vision for intergroup contact theory that moves beyond traditional conflict-related outcomes

Microbial responses to warming enhance soil carbon loss following translocation across a tropical forest elevation gradient

Tropical soils contain huge carbon stocks, which climate warming is projected to reduce by stimulating organic matter decomposition, creating a positive feedback that will promote further warming. Models predict that the loss of carbon from warming soils will be mediated by microbial physiology, but no empirical data are available on the response of soil carbon and microbial physiology to warming in tropical forests, which dominate the terrestrial carbon cycle. Here we show that warming caused a considerable loss of soil carbon that was enhanced by associated changes in microbial physiology. By translocating soils across a 3000 m elevation gradient in tropical forest, equivalent to a temperature change of ± 15 °C, we found that soil carbon declined over 5 years by 4% in response to each 1 °C increase in temperature. The total loss of carbon was related to its original quantity and lability, and was enhanced by changes in microbial physiology including increased microbial carbon‐use‐efficiency, shifts in community composition towards microbial taxa associated with warmer temperatures, and increased activity of hydrolytic enzymes. These findings suggest that microbial feedbacks will cause considerable loss of carbon from tropical forest soils in response to predicted climatic warming this century

Impact of opioid substitution therapy on antiretroviral therapy outcomes:a systematic review and meta-analysis

BACKGROUND: Human immunodeficiency virus (HIV)-infected people who inject drugs (PWID) frequently encounter barriers accessing and remaining on antiretroviral therapy (ART). Some studies have suggested that opioid substitution therapy (OST) could facilitate PWID's engagement with HIV services. We conducted a systematic review and meta-analysis to evaluate the impact of concurrent OST use on ART-related outcomes among HIV-infected PWID. METHODS: We searched Medline, PsycInfo, Embase, Global Health, Cochrane, Web of Science, and Social Policy and Practice databases for studies between 1996 to November 2014 documenting the impact of OST, compared to no OST, on ART outcomes. Outcomes considered were coverage and recruitment onto ART, adherence, viral suppression, attrition from ART, and mortality. Meta-analyses were conducted using random-effects modeling, and heterogeneity assessed using Cochran Q test and I2 statistic. RESULTS: We identified 4685 articles, and 32 studies conducted in North America, Europe, Indonesia, and China were included. OST was associated with a 69% increase in recruitment onto ART (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.32-2.15), a 54% increase in ART coverage (odds ratio [OR], 1.54; 95% CI, 1.17-2.03), a 2-fold increase in adherence (OR, 2.14; 95% CI, 1.41-3.26), and a 23% decrease in the odds of attrition (OR, 0.77; 95% CI, .63-.95). OST was associated with a 45% increase in odds of viral suppression (OR, 1.45; 95% CI, 1.21-1.73), but there was limited evidence from 6 studies for OST decreasing mortality for PWID on ART (HR, 0.91; 95% CI, .65-1.25). CONCLUSIONS: These findings support the use of OST, and its integration with HIV services, to improve the HIV treatment and care continuum among HIV-infected PWID

Addressing uncertainty in marine resource management; combining community engagement and tracking technology to characterize human behavior

This study was approved by the University of Exeter Ethics committee and the Ministry of Scientific Research and Technological Innovation in Congo (Permit: No. 023/MRSIT/DGRST/DMAST); and supported by funding from the Darwin Initiative (Projects 20-009 and 23-011) and the Wildlife Conservation Society.Small-scale fisheries provide an essential source of food and employment for coastal communities, yet the availability of detailed information on the spatiotemporal distribution of fishing effort to support resource management at a country level is scarce. Here, using a national-scale study in the Republic of Congo, we engaged with fishers from 23 of 28 small-scale fisheries landing sites along the coast to demonstrate how combining community engagement and relatively low cost Global Positioning System (GPS) trackers can rapidly provide fine-scale information on: (1) the behavioral dynamics of the fishers and fleets that operate within this sector; and (2) the location, size and attributes of important fishing grounds upon which communities are dependent. This multi-disciplinary approach should be considered within a global context where uncertainty over the behavior of marine and terrestrial resource-users can lead to management decisions that potentially compromise local livelihoods, conservation, and resource sustainability goals.Publisher PDFPeer reviewe