KELVIN: A Software Package for Rigorous Measurement of Statistical Evidence in Human Genetics

This paper describes the software package KELVIN, which supports the PPL (posterior probability of linkage) framework for the measurement of statistical evidence in human (or more generally, diploid) genetic studies. In terms of scope, KELVIN supports two-point (trait-marker or marker-marker) and multipoint linkage analysis, based on either sex-averaged or sex-specific genetic maps, with an option to allow for imprinting; trait-marker linkage disequilibrium (LD), or association analysis, in case-control data, trio data, and/or multiplex family data, with options for joint linkage and trait-marker LD or conditional LD given linkage; dichotomous trait, quantitative trait and quantitative trait threshold models; and certain types of gene-gene interactions and covariate effects. Features and data (pedigree) structures can be freely mixed and matched within analyses. The statistical framework is specifically tailored to accumulate evidence in a mathematically rigorous way across multiple data sets or data subsets while allowing for multiple sources of heterogeneity, and KELVIN itself utilizes sophisticated software engineering to provide a powerful and robust platform for studying the genetics of complex disorders

Reflective Journaling: A Theoretical Model and Digital Prototype for Developing Resilience and Creativity

Reflection is commonly discussed as a tool for personal and professional development that is becoming increasingly important in today’s global and digital world. In this paper, we propose a model that suggests ways in which reflection, in the form of Reflective Journaling, can support the development of creativity and resilience, which are needed to enable individuals to function effectively in a fast-changing environment. In addition, the model proposes ways in which external support and progress monitoring can be used in conjunction with skills in adaptive resilience and structured creativity, to support the maintenance of reflective journaling as a habit, in the longer term, thus creating virtuous cycles of skills and behaviours that can reinforce each other. Based on our model, and additional user research, we describe the design of a first digital prototype that aims to support the use of Reflective Journaling and to develop creativity and resilience through suggested mechanisms. Initial evaluations of our prototype are positive. It has been well-received by early test users, and has the potential to address all the connections defined. We therefore suggest that the theoretical model can be used to develop digital tools, such as the one included, to help those who wish to develop the habit of reflective journaling, and through that a range of other skills associated with resilience and creative thinking. We see this as a starting point for investigating this potential in more depth

The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains

We have investigated the contribution to ionic selectivity of residues in the selectivity filter and pore helices of the P1 and P2 domains in the acid sensitive potassium channel TASK-1. We used site directed mutagenesis and electrophysiological studies, assisted by structural models built through computational methods. We have measured selectivity in channels expressed in Xenopus oocytes, using voltage clamp to measure shifts in reversal potential and current amplitudes when Rb+ or Na+ replaced extracellular K+. Both P1 and P2 contribute to selectivity, and most mutations, including mutation of residues in the triplets GYG and GFG in P1 and P2, made channels nonselective. We interpret the effects of these—and of other mutations—in terms of the way the pore is likely to be stabilised structurally. We show also that residues in the outer pore mouth contribute to selectivity in TASK-1. Mutations resulting in loss of selectivity (e.g. I94S, G95A) were associated with slowing of the response of channels to depolarisation. More important physiologically, pH sensitivity is also lost or altered by such mutations. Mutations that retained selectivity (e.g. I94L, I94V) also retained their response to acidification. It is likely that responses both to voltage and pH changes involve gating at the selectivity filter

Multi-parallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming

BACKGROUND: Although chronic morbidity in humans from soil transmitted helminth (STH) infections can be reduced by anthelmintic treatment, inconsistent diagnostic tools make it difficult to reliably measure the impact of deworming programs and often miss light helminth infections. METHODS: Cryopreserved stool samples from 796 people (aged 2-81 years) in four villages in Bungoma County, western Kenya, were assessed using multi-parallel qPCR for 8 parasites and compared to point-of-contact assessments of the same stools by the 2-stool 2-slide Kato-Katz (KK) method. All subjects were treated with albendazole and all Ascaris lumbricoides expelled post-treatment were collected. Three months later, samples from 633 of these people were re-assessed by both qPCR and KK, re-treated with albendazole and the expelled worms collected. RESULTS: Baseline prevalence by qPCR (n = 796) was 17 % for A. lumbricoides, 18 % for Necator americanus, 41 % for Giardia lamblia and 15% for Entamoeba histolytica. The prevalence was <1% for Trichuris trichiura, Ancylostoma duodenale, Strongyloides stercoralis and Cryptosporidium parvum. The sensitivity of qPCR was 98% for A. lumbricoides and N. americanus, whereas KK sensitivity was 70% and 32%, respectively. Furthermore, qPCR detected infections with T. trichiura and S. stercoralis that were missed by KK, and infections with G. lamblia and E. histolytica that cannot be detected by KK. Infection intensities measured by qPCR and by KK were correlated for A. lumbricoides (r = 0.83, p < 0.0001) and N. americanus (r = 0.55, p < 0.0001). The number of A. lumbricoides worms expelled was correlated (p < 0.0001) with both the KK (r = 0.63) and qPCR intensity measurements (r = 0.60). CONCLUSIONS: KK may be an inadequate tool for stool-based surveillance in areas where hookworm or Strongyloides are common or where intensity of helminth infection is low after repeated rounds of chemotherapy. Because deworming programs need to distinguish between populations where parasitic infection is controlled and those where further treatment is required, multi-parallel qPCR (or similar high throughput molecular diagnostics) may provide new and important diagnostic information

The Minimal Scale Invariant Extension of the Standard Model

We perform a systematic analysis of an extension of the Standard Model that includes a complex singlet scalar field and is scale invariant at the tree level. We call such a model the Minimal Scale Invariant extension of the Standard Model (MSISM). The tree-level scale invariance of the model is explicitly broken by quantum corrections, which can trigger electroweak symmetry breaking and potentially provide a mechanism for solving the gauge hierarchy problem. Even though the scale invariant Standard Model is not a realistic scenario, the addition of a complex singlet scalar field may result in a perturbative and phenomenologically viable theory. We present a complete classification of the flat directions which may occur in the classical scalar potential of the MSISM. After calculating the one-loop effective potential of the MSISM, we investigate a number of representative scenarios and determine their scalar boson mass spectra, as well as their perturbatively allowed parameter space compatible with electroweak precision data. We discuss the phenomenological implications of these scenarios, in particular, whether they realize explicit or spontaneous CP violation, neutrino masses or provide dark matter candidates. In particular, we find a new minimal scale-invariant model of maximal spontaneous CP violation which can stay perturbative up to Planck-mass energy scales, without introducing an unnaturally large hierarchy in the scalar-potential couplings.Comment: 71 pages, 34 eps figures, numerical error corrected, clarifying comments adde

CoRoT 105906206: a short-period and totally eclipsing binary with a Delta Scuti type pulsator

Eclipsing binary systems with pulsating components allow the determination of several physical parameters of the stars, such as mass and radius, that, when combined with the pulsation properties, can be used to constrain the modeling of stellar interiors and evolution. Hereby, we present the results of the study of CoRoT 105906206, an eclipsing binary system with a pulsating component located in the CoRoT LRc02 field. The analysis of the CoRoT light curve was complemented by high-resolution spectra from the Sandiford at McDonald Observatory and FEROS at ESO spectrographs, which revealed a double-lined spectroscopic binary. We used an iterative procedure to separate the pulsation-induced photometric variations from the eclipse signals. First, a Fourier analysis was used to identify the significant frequencies and amplitudes due to pulsations. Second, after removing the contribution of the pulsations from the light curve we applied the PIKAIA genetic-algorithm approach to derive the best parameters that describe the orbital properties of the system. The light curve cleaned for pulsations contains the partial eclipse of the primary and the total eclipse of the secondary. The system has an orbital period of about 3.694 days and is formed by a primary star with mass M1 = 2.25 +/- 0.04 solar masses, radius R1 = 4.24 +/- 0.02 solar radii, and effective temperature Teff1 = 6750 +/- 150 K, and a secondary with M2 = 1.29 +/- 0.03 solar masses, R2 = 1.34 +/- 0.01 solar radii, and Teff2 = 6152 +/- 162 K. The best solution for the parameters was obtained by taking into account the asymmetric modulation observed in the light curve, known as the O'Connell effect, presumably caused by Doppler beaming. The analysis of the Fourier spectrum revealed that the primary component has p-mode pulsations in the range 5-13 c/d, which are typical of Delta Scuti type stars.Comment: 11 pages, 8 figures, 3 table

Professionalism and Evolving Concepts of Quality

For much of the twentieth century, quality of care was defined specifically in terms of physician characteristics and behaviors. High-quality physicians were well trained, knowledgeable, skillful, and compassionate. More recently, quality of care has been defined in terms of systems of care. High-quality organizations develop and adopt practices to reduce adverse events and optimize outcomes. This essay discusses this transformation from physician-based to organization-based concepts of quality and the consequences for patient care and medical professionalism