Antibody-resistant mutants of Borrelia burgdorferi: in vitro selection and characterization.

We used polyclonal antisera and monoclonal antibodies (mAbs) to inhibit the growth of clonal populations of two strains of Borrelia burgdorferi, the Lyme disease agent, and thereby select for antibody-resistant mutants. mAbs were directed at the outer membrane proteins, OspA or OspB. Mutants resistant to the growth-inhibiting properties of the antibodies were present in the populations at frequencies ranging from 10(-5) to 10(-2). The several escape variants that were examined were of four classes. Class I mutants were resistant to all mAbs; they lacked OspA and OspB and the linear plasmid that encodes them. Two other proteins were expressed in larger amounts in class I mutants; mAbs to these proteins inhibited the mutant but not the wild-type cells. Class II mutants were resistant to some but not all mAbs; they had truncated OspA and/or OspB proteins. Class III mutants were resistant only to the selecting mAb; they had full-length Osp proteins that were not bound by the selecting antibody in Western blots. In two class III mutants resistant to different anti-OspA mAbs, missense mutations were demonstrated in the ospA genes. Class IV mutants were likewise resistant only to selecting antibody, but in this case the selecting antibody still bound in Western blots

V-ROOM: a virtual meeting system with intelligent structured summarisation

With the growth of virtual organisations and multinational companies, virtual collaboration tasks are becoming more important for employees. This paper describes the development of a virtual meeting system, called V-ROOM. An exploration of facilities required in such a system has been conducted. The findings highlighted that intelligent systems are needed, especially since information that individuals have to know and process, is vast. The survey results showed that meeting summarisation is one of the most important new features that should be added to virtual meeting systems for enterprises. This paper highlights the innovative methods employed in V-ROOM to produce relevant meeting summaries. V- ROOM's approach is compared to other methods from the literature and it is shown how the use of meta-data provided by parts of the V-ROOM system can improve the quality of summaries produced

Sample-Efficient Model-Free Reinforcement Learning with Off-Policy Critics

Value-based reinforcement-learning algorithms provide state-of-the-art results in model-free discrete-action settings, and tend to outperform actor-critic algorithms. We argue that actor-critic algorithms are limited by their need for an on-policy critic. We propose Bootstrapped Dual Policy Iteration (BDPI), a novel model-free reinforcement-learning algorithm for continuous states and discrete actions, with an actor and several off-policy critics. Off-policy critics are compatible with experience replay, ensuring high sample-efficiency, without the need for off-policy corrections. The actor, by slowly imitating the average greedy policy of the critics, leads to high-quality and state-specific exploration, which we compare to Thompson sampling. Because the actor and critics are fully decoupled, BDPI is remarkably stable, and unusually robust to its hyper-parameters. BDPI is significantly more sample-efficient than Bootstrapped DQN, PPO, and ACKTR, on discrete, continuous and pixel-based tasks. Source code: https://github.com/vub-ai-lab/bdpi.Comment: Accepted at the European Conference on Machine Learning 2019 (ECML

Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves

Who teaches medical billing? A national cross-sectional survey of Australian medical education stakeholders

© 2018 Author(s). Importance Billing errors and healthcare fraud have been described by the WHO as the last great unreduced health-care cost'. Estimates suggest that 7% of global health expenditure (US$487 billion) is wasted from this phenomenon. Irrespective of different payment models, challenges exist at the interface of medical billing and medical practice across the globe. Medical billing education has been cited as an effective preventative strategy, with targeted education saving$A250 million in Australia in 1 year from an estimated $A1-3 billion of waste. Objective This study attempts to systematically map all avenues of medical practitioner education on medical billing in Australia and explores the perceptions of medical education stakeholders on this topic. Design National cross-sectional survey between April 2014 and June 2015. No patient or public involvement. Data analysis-descriptive statistics via frequency distributions. Participants All stakeholders who educate medical practitioners regarding clinical practice (n=66). 86% responded. Results There is little medical billing education occurring in Australia. The majority of stakeholders (70%, n=40) did not offer/have never offered a medical billing course. 89% thought medical billing should be taught, including 30% (n=17) who were already teaching it. There was no consensus on when medical billing education should occur. Conclusions To our knowledge, this is the first attempt of any country to map the ways doctors learn the complex legal and administrative infrastructure in which they work. Consistent with US findings, Australian doctors may not have expected legal and administrative literacy. Rather than reliance on ad hoc training, development of an Australian medical billing curriculum should be encouraged to improve compliance, expedite judicial processes and reduce waste. In the absence of adequate education, disciplinary bodies in all countries must consider pleas of ignorance by doctors under investigation, where appropriate, for incorrect medical billing

Intestinal transplantation in composite visceral grafts or alone

Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft- versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection

Intestinal transplantation in composite visceral grafts or alone

Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft- versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection

Do Children With Attention-Deficit/Hyperactivity Disorder Symptoms Become Socially Isolated? Longitudinal Within-Person Associations in a Nationally Representative Cohort.

OBJECTIVE: This study examined longitudinal associations between attention-deficit/hyperactivity disorder (ADHD) symptoms and social isolation across childhood. The study tested the direction of this association across time, while accounting for preexisting characteristics, and assessed whether this association varied by ADHD presentation, informant, sex, and socioeconomic status. METHOD: Participants included 2,232 children from the Environmental Risk (E-Risk) Longitudinal Twin Study. ADHD symptoms and social isolation were measured at ages 5, 7, 10, and 12. Random-intercept cross-lagged panel models were used to assess the directionality of the association across childhood. RESULTS: Children with increased ADHD symptoms were consistently at increased risk of becoming socially isolated later in childhood, over and above stable characteristics (β = .05-.08). These longitudinal associations were not bidirectional; isolated children were not at risk of worsening ADHD symptoms later on. Children with hyperactive ADHD presentation were more likely to become isolated, compared with inattentive presentation. This was evident in the school setting, as observed by teachers, but not by mothers at home. CONCLUSION: The study findings highlight the importance of enhancing peer social support and inclusion for children with ADHD, particularly in school settings. This study adds explanatory value beyond traditional longitudinal methods, as the results represent how individual children change over time, relative to their own preexisting characteristics. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work

T cell lineage choice and differentiation in the absence of the RNase III enzyme dicer

The ribonuclease III enzyme Dicer is essential for the processing of micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) from double-stranded RNA precursors. miRNAs and siRNAs regulate chromatin structure, gene transcription, mRNA stability, and translation in a wide range of organisms. To provide a model system to explore the role of Dicer-generated RNAs in the differentiation of mammalian cells in vivo, we have generated a conditional Dicer allele. Deletion of Dicer at an early stage of T cell development compromised the survival of alphabeta lineage cells, whereas the numbers of gammadelta-expressing thymocytes were not affected. In developing thymocytes, Dicer was not required for the maintenance of transcriptional silencing at pericentromeric satellite sequences (constitutive heterochromatin), the maintenance of DNA methylation and X chromosome inactivation in female cells (facultative heterochromatin), and the stable shutdown of a developmentally regulated gene (developmentally regulated gene silencing). Most remarkably, given that one third of mammalian mRNAs are putative miRNA targets, Dicer seems to be dispensable for CD4/8 lineage commitment, a process in which epigenetic regulation of lineage choice has been well documented. Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs

Chemotaxis When Bacteria Remember: Drift versus Diffusion

{\sl Escherichia coli} ({\sl E. coli}) bacteria govern their trajectories by switching between running and tumbling modes as a function of the nutrient concentration they experienced in the past. At short time one observes a drift of the bacterial population, while at long time one observes accumulation in high-nutrient regions. Recent work has viewed chemotaxis as a compromise between drift toward favorable regions and accumulation in favorable regions. A number of earlier studies assume that a bacterium resets its memory at tumbles -- a fact not borne out by experiment -- and make use of approximate coarse-grained descriptions. Here, we revisit the problem of chemotaxis without resorting to any memory resets. We find that when bacteria respond to the environment in a non-adaptive manner, chemotaxis is generally dominated by diffusion, whereas when bacteria respond in an adaptive manner, chemotaxis is dominated by a bias in the motion. In the adaptive case, favorable drift occurs together with favorable accumulation. We derive our results from detailed simulations and a variety of analytical arguments. In particular, we introduce a new coarse-grained description of chemotaxis as biased diffusion, and we discuss the way it departs from older coarse-grained descriptions.Comment: Revised version, journal reference adde