Decision Models and Technology Can Help Psychiatry Develop Biomarkers

Why is psychiatry unable to define clinically useful biomarkers? We explore this question from the vantage of data and decision science and consider biomarkers as a form of phenotypic data that resolves a well-defined clinical decision. We introduce a framework that systematizes different forms of phenotypic data and further introduce the concept of decision model to describe the strategies a clinician uses to seek out, combine, and act on clinical data. Though many medical specialties rely on quantitative clinical data and operationalized decision models, we observe that, in psychiatry, clinical data are gathered and used in idiosyncratic decision models that exist solely in the clinician's mind and therefore are outside empirical evaluation. This, we argue, is a fundamental reason why psychiatry is unable to define clinically useful biomarkers: because psychiatry does not currently quantify clinical data, decision models cannot be operationalized and, in the absence of an operationalized decision model, it is impossible to define how a biomarker might be of use. Here, psychiatry might benefit from digital technologies that have recently emerged specifically to quantify clinically relevant facets of human behavior. We propose that digital tools might help psychiatry in two ways: first, by quantifying data already present in the standard clinical interaction and by allowing decision models to be operationalized and evaluated; second, by testing whether new forms of data might have value within an operationalized decision model. We reference successes from other medical specialties to illustrate how quantitative data and operationalized decision models improve patient care

Systematic review of antiepileptic drugs’ safety and effectiveness in feline epilepsy

Understanding the efficacy and safety profile of antiepileptic drugs (AEDs) in feline epilepsy is a crucial consideration for managing this important brain disease. However, there is a lack of information about the treatment of feline epilepsy and therefore a systematic review was constructed to assess current evidence for the AEDs’ efficacy and tolerability in cats. The methods and materials of our former systematic reviews in canine epilepsy were mostly mirrored for the current systematic review in cats. Databases of PubMed, CAB Direct and Google scholar were searched to detect peer-reviewed studies reporting efficacy and/or adverse effects of AEDs in cats. The studies were assessed with regards to their quality of evidence, i.e. study design, study population, diagnostic criteria and overall risk of bias and the outcome measures reported, i.e. prevalence and 95% confidence interval of the successful and affected population in each study and in total

Achimota Pararubulavirus 3: A New Bat-Derived Paramyxovirus of the Genus Pararubulavirus

Bats are an important source of viral zoonoses, including paramyxoviruses. The paramyxoviral Pararubulavirus genus contains viruses mostly derived from bats that are common, diverse, distributed throughout the Old World, and known to be zoonotic. Here, we describe a new member of the genus Achimota pararubulavirus 3 (AchPV3) and its isolation from the urine of African straw-coloured fruit bats on primary bat kidneys cells. We sequenced and analysed the genome of AchPV3 relative to other Paramyxoviridae, revealing it to be similar to known pararubulaviruses. Phylogenetic analysis of AchPV3 revealed the failure of molecular detection in the urine sample from which AchPV3 was derived and an attachment protein most closely related with AchPV2—a pararubulavirus known to cause cross-species transmission. Together these findings add to the picture of pararubulaviruses, their sources, and variable zoonotic potential, which is key to our understanding of host restriction and spillover of bat-derived paramyxoviruses. AchPV3 represents a novel candidate zoonosis and an important tool for further study

Accurate reconstruction of insertion-deletion histories by statistical phylogenetics

The Multiple Sequence Alignment (MSA) is a computational abstraction that represents a partial summary either of indel history, or of structural similarity. Taking the former view (indel history), it is possible to use formal automata theory to generalize the phylogenetic likelihood framework for finite substitution models (Dayhoff's probability matrices and Felsenstein's pruning algorithm) to arbitrary-length sequences. In this paper, we report results of a simulation-based benchmark of several methods for reconstruction of indel history. The methods tested include a relatively new algorithm for statistical marginalization of MSAs that sums over a stochastically-sampled ensemble of the most probable evolutionary histories. For mammalian evolutionary parameters on several different trees, the single most likely history sampled by our algorithm appears less biased than histories reconstructed by other MSA methods. The algorithm can also be used for alignment-free inference, where the MSA is explicitly summed out of the analysis. As an illustration of our method, we discuss reconstruction of the evolutionary histories of human protein-coding genes.Comment: 28 pages, 15 figures. arXiv admin note: text overlap with arXiv:1103.434

Consultancy-Based Projects

This chapter will:; ; ; Show how consultancy work can inform business discourse teaching;; ; ; Discuss how needs analysis and communication audits can be used to generate recommendations for teaching and training;; ; ; Profile a number of consultancy-based business discourse projects and show how they have informed training and course development;; ; ; Provide a case study, together with a set of tasks appropriate for the business discourse classroom, and a set of further readings

Deliquescence of NaCl–NaNO(3), KNO(3)–NaNO(3), and NaCl–KNO(3 )salt mixtures from 90 to 120°C

We conducted reversed deliquescence experiments in saturated NaCl–NaNO(3)–H(2)O, KNO(3)–NaNO(3)–H(2)O, and NaCl–KNO(3)–H(2)O systems from 90 to 120°C as a function of relative humidity and solution composition. NaCl, NaNO(3), and KNO(3 )represent members of dust salt assemblages that are likely to deliquesce and form concentrated brines on high-level radioactive waste package surfaces in a repository environment at Yucca Mountain, NV. Discrepancy between model prediction and experiment can be as high as 8% for relative humidity and 50% for dissolved ion concentration. The discrepancy is attributed primarily to the use of 25°C models for Cl–NO(3 )and K–NO(3 )ion interactions in the current Yucca Mountain Project high-temperature Pitzer model to describe the nonideal behavior of these highly concentrated solutions

Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment

Background Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. Methods/design Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to ~25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. Discussion This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives

Turnip mosaic potyvirus probably first spread to Eurasian brassica crops from wild orchids about 1000 years ago

Turnip mosaic potyvirus (TuMV) is probably the most widespread and damaging virus that infects cultivated brassicas worldwide. Previous work has indicated that the virus originated in western Eurasia, with all of its closest relatives being viruses of monocotyledonous plants. Here we report that we have identified a sister lineage of TuMV-like potyviruses (TuMV-OM) from European orchids. The isolates of TuMV-OM form a monophyletic sister lineage to the brassica-infecting TuMVs (TuMV-BIs), and are nested within a clade of monocotyledon-infecting viruses. Extensive host-range tests showed that all of the TuMV-OMs are biologically similar to, but distinct from, TuMV-BIs and do not readily infect brassicas. We conclude that it is more likely that TuMV evolved from a TuMV-OM-like ancestor than the reverse. We did Bayesian coalescent analyses using a combination of novel and published sequence data from four TuMV genes [helper component-proteinase protein (HC-Pro), protein 3(P3), nuclear inclusion b protein (NIb), and coat protein (CP)]. Three genes (HC-Pro, P3, and NIb), but not the CP gene, gave results indicating that the TuMV-BI viruses diverged from TuMV-OMs around 1000 years ago. Only 150 years later, the four lineages of the present global population of TuMV-BIs diverged from one another. These dates are congruent with historical records of the spread of agriculture in Western Europe. From about 1200 years ago, there was a warming of the climate, and agriculture and the human population of the region greatly increased. Farming replaced woodlands, fostering viruses and aphid vectors that could invade the crops, which included several brassica cultivars and weeds. Later, starting 500 years ago, inter-continental maritime trade probably spread the TuMV-BIs to the remainder of the world

Ultraviolet and visible reflectance spectra of Phobos and Deimos as measured by the ExoMars-TGO/Nomad-UVIS spectrometer

Spectroscopic measurements are a powerful tool to investigate the surface composition of airless bodies and provide clues of their origin. The composition and origin of Phobos and Deimos are still unknown and are currently widely debated. We present spectroscopic measurements of Phobos and Deimos at ultraviolet and visible wavelengths (250–650 nm) made by the NOMAD-Ultraviolet and Visible Spectrometer (UVIS) on the ExoMars TGO mission. These new spectra cover multiple areas on Phobos and Deimos, and are of generally higher spectral resolution and signal-to-noise than previous spectra, and extend to lower wavelengths than most previous measurements. The UVIS spectra confirm a red-sloped spectrum lacking any strong absorption features; however, we confirm the presence of a previously identified absorption feature near 0.65 μm and tentative absorption near 0.45 μm. The observed Phobos and Deimos spectra are similar to D- and T-type asteroids, adding weight to the captured asteroid hypothesis for the moons' origins. We also find, however, that the UVIS Phobos reflectance spectra of Phobos' red unit is a relatively close match to the olivine-rich, highly shocked Mars meteorite NWA 2737, with a low overall reflectance, a red-sloped spectrum, and lack of olivine-associated absorption bands in the UVIS spectral range. This meteorite, however, exhibits spectral features at longer wavelengths that not observed in the Martian moon spectra, indicating a need for further investigation at longer wavelengths to interpret whether this material could inform our understanding of Phobos' origin

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention