Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo.

Neutral competition, an emerging feature of stem cell homeostasis, posits that individual stem cells can be lost and replaced by their neighbors stochastically, resulting in chance dominance of a clone at the niche. A single stem cell with an oncogenic mutation could bias this process and clonally spread the mutation throughout the stem cell pool. The Drosophila testis provides an ideal system for testing this model. The niche supports two stem cell populations that compete for niche occupancy. Here, we show that cyst stem cells (CySCs) conform to the paradigm of neutral competition and that clonal deregulation of either the Hedgehog (Hh) or Hippo (Hpo) pathway allows a single CySC to colonize the niche. We find that the driving force behind such behavior is accelerated proliferation. Our results demonstrate that a single stem cell colonizes its niche through oncogenic mutation by co-opting an underlying homeostatic process.This is the final version. It was first published by Wiley at http://onlinelibrary.wiley.com/doi/10.15252/embj.201387500/abstract

Impact of gender: Rivaroxaban for patients with atrial fibrillation in the XANTUS real-world prospective study.

BACKGROUND: The XANTUS study (NCT01606995) demonstrated low rates of stroke and major bleeding in patients with atrial fibrillation (AF) receiving rivaroxaban in clinical practice for the prevention of thromboembolic events (N = 6784). HYPOTHESIS: Because previous real-world studies have not reported gender-dependent responses to rivaroxaban treatment, this sub-analysis of the XANTUS study investigated the effect of gender on outcomes. METHODS: The centrally adjudicated outcomes were compared between genders. Primary outcomes were major bleeding and all-cause death. Secondary outcomes included symptomatic thromboembolic events. Multivariable Cox regression analysis was performed to assess the effect of risk factors on outcomes between genders. RESULTS: A total of 2765 female and 4016 male patients were included in the analysis. Baseline characteristics were generally similar. No nominally significant interaction between gender and risk factors for the study outcomes was observed. Rates of major bleeding, all-cause death and symptomatic thromboembolic events in patients with non-valvular AF receiving rivaroxaban for stroke prevention were similar in men and women; no significant differences in risk factors for these outcomes were observed between genders. CONCLUSIONS: Further research is needed to better characterize the relative importance of different risk factors on outcomes in men vs women and to determine whether gender differences exist in patients treated with non-vitamin K antagonist oral anticoagulants

Embodied neurology: an integrative framework for neurological disorders

From a systems biology perspective, the brain and spinal cord are interwoven with the body, through afferent and efferent synaptic connections—they are literally ‘embodied’ (Adams et al., 2013). Neurologists appreciate the embodied nature of neurological disorders in terms of diagnosis, classification and their understanding of the underlying pathophysiology. They routinely use a combination of physical examinations (e.g. scales that test motor, sensory and autonomic function) in conjunction with physiological, biochemical and anatomical measures (e.g. electrophysiology, serum and CSF, and radiology) of the peripheral and central nervous system. These measures often produce combinations of symptoms and signs that translate into conventional nosological classifications. While therapeutics focus on the ‘treatable’ cause of a disorder, it is difficult to separate out the impact on the patient due to the primary effects of a lesion/insult etc. and the effects of (possibly delayed) secondary processes that may be reasonable targets for interventions on their own. Moreover, standard neurological assessments often fail to distinguish between pathogenic and compensatory processes. This state of affairs calls for a better understanding of neurological disease within a formal framework that links pathology to phenomenology (i.e. symptoms, impairment and physical signs). We suggest that such a framework should pay special attention to the embodied nature of the nervous system and the implicit pathophysiological and compensatory processes that can be present throughout the neuroaxis. In particular, we postulate that reciprocal information flows, between the body and the nervous system, are crucial for understanding and treating neurological disorders. This framework aims to link pathology to phenomenology, while respecting the ‘embodied’ nature of the nervous system. If fully realized, the framework of embodied neurology has the potential to improve functional outcome following individualized treatment (i.e. precision neurology), promote successful translation of novel therapeutics into clinical use, and refine nosology in the context of disease heterogeneity.Our description of embodied neurology is largely theoretical and is based on a series of focused workshops. It draws on recent advances in biophysical modelling of functional (Deco et al., 2008) and microstructural processes and neuroimaging (Weiskopf et al., 2015). These advances—together with preclinical research—constitute the three tenets of embodied neurology: biophysical modelling, quantitative physiological measures (with an emphasis on non-invasive neuroimaging) and preclinical research on basic mechanisms. These three have a particular focus on the entire nervous system

Selecting patients for randomized trials: a systematic approach based on risk group

BACKGROUND: A key aspect of randomized trial design is the choice of risk group. Some trials include patients from the entire at-risk population, others accrue only patients deemed to be at increased risk. We present a simple statistical approach for choosing between these approaches. The method is easily adapted to determine which of several competing definitions of high risk is optimal. METHOD: We treat eligibility criteria for a trial, such as a smoking history, as a prediction rule associated with a certain sensitivity (the number of patients who have the event and who are classified as high risk divided by the total number patients who have an event) and specificity (the number of patients who do not have an event and who do not meet criteria for high risk divided by the total number of patients who do not have an event). We then derive simple formulae to determine the proportion of patients receiving intervention, and the proportion who experience an event, where either all patients or only those at high risk are treated. We assume that the relative risk associated with intervention is the same over all choices of risk group. The proportion of events and interventions are combined using a net benefit approach and net benefit compared between strategies. RESULTS: We applied our method to design a trial of adjuvant therapy after prostatectomy. We were able to demonstrate that treating a high risk group was superior to treating all patients; choose the optimal definition of high risk; test the robustness of our results by sensitivity analysis. Our results had a ready clinical interpretation that could immediately aid trial design. CONCLUSION: The choice of risk group in randomized trials is usually based on rather informal methods. Our simple method demonstrates that this decision can be informed by simple statistical analyses

Abdominal functional electrical stimulation to improve respiratory function after spinal cord injury: a systematic review and meta-analysis

Objectives: Abdominal functional electrical stimulation (abdominal FES) is the application of a train of electrical pulses to the abdominal muscles, causing them to contract. Abdominal FES has been used as a neuroprosthesis to acutely augment respiratory function and as a rehabilitation tool to achieve a chronic increase in respiratory function after abdominal FES training, primarily focusing on patients with spinal cord injury (SCI). This study aimed to review the evidence surrounding the use of abdominal FES to improve respiratory function in both an acute and chronic manner after SCI. Settings: A systematic search was performed on PubMed, with studies included if they applied abdominal FES to improve respiratory function in patients with SCI. Methods: Fourteen studies met the inclusion criteria (10 acute and 4 chronic). Low participant numbers and heterogeneity across studies reduced the power of the meta-analysis. Despite this, abdominal FES was found to cause a significant acute improvement in cough peak flow, whereas forced exhaled volume in 1 s approached significance. A significant chronic increase in unassisted vital capacity, forced vital capacity and peak expiratory flow was found after abdominal FES training compared with baseline. Conclusions: This systematic review suggests that abdominal FES is an effective technique for improving respiratory function in both an acute and chronic manner after SCI. However, further randomised controlled trials, with larger participant numbers and standardised protocols, are needed to fully establish the clinical efficacy of this technique

Shallow marine serpentinization-derived fluid seepage in the Upper Cretaceous Qahlah Formation, United Arab Emirates

Serpentinization of ultramafic rocks in the sea and on land leads to the generation of alkaline fluids rich in molecular hydrogen (H2) and methane (CH4) that favour the formation of carbonate mineralization, such as veins in the sub-seafloor, seafloor carbonate chimneys and terrestrial hyperalkaline spring deposits. Examples of this type of seawater–rock interaction and the formation of serpentinization-derived carbonates in a shallow-marine environment are scarce, and almost entirely lacking in the geological record. Here we present evidence for serpentinization-induced fluid seepage in shallow-marine sedimentary rocks from the Upper Cretaceous (upper Campanian to lower Maastrichtian) Qahlah Formation at Jebel Huwayyah, United Arab Emirates. The research object is a metre-scale structure (the Jebel Huwayyah Mound) formed of calcite-cemented sand grains, which formed a positive seafloor feature. The Jebel Huwayyah Mound contains numerous vertically orientated fluid conduits containing two main phases of calcite cement. We use C and O stable isotopes and elemental composition to reconstruct the fluids from which these cements precipitated and infer that the fluids consisted of variable mixtures of seawater and fluids derived from serpentinization of the underlying Semail Ophiolite. Based on their negative δ13C values, hardgrounds in the same section as the Jebel Huwayyah Mound may also have had a similar origin. The Jebel Huwayyah Mound shows that serpentinization of the Semail Ophiolite by seawater occurred very soon after obduction and marine transgression, a process that continued through to the Miocene, and, with interaction of meteoric water, up to the present day

An exploratory randomised controlled trial of a premises-level intervention to reduce alcohol-related harm including violence in the United Kingdom

<b>Background</b><p></p> To assess the feasibility of a randomised controlled trial of a licensed premises intervention to reduce severe intoxication and disorder; to establish effect sizes and identify appropriate approaches to the development and maintenance of a rigorous research design and intervention implementation.<p></p> <b>Methods</b><p></p> An exploratory two-armed parallel randomised controlled trial with a nested process evaluation. An audit of risk factors and a tailored action plan for high risk premises, with three month follow up audit and feedback. Thirty-two premises that had experienced at least one assault in the year prior to the intervention were recruited, match paired and randomly allocated to control or intervention group. Police violence data and data from a street survey of study premises’ customers, including measures of breath alcohol concentration and surveyor rated customer intoxication, were used to assess effect sizes for a future definitive trial. A nested process evaluation explored implementation barriers and the fidelity of the intervention with key stakeholders and senior staff in intervention premises using semi-structured interviews.<p></p> <b>Results</b><p></p> The process evaluation indicated implementation barriers and low fidelity, with a reluctance to implement the intervention and to submit to a formal risk audit. Power calculations suggest the intervention effect on violence and subjective intoxication would be raised to significance with a study size of 517 premises.<p></p> <b>Conclusions</b><p></p> It is methodologically feasible to conduct randomised controlled trials where licensed premises are the unit of allocation. However, lack of enthusiasm in senior premises staff indicates the need for intervention enforcement, rather than voluntary agreements, and on-going strategies to promote sustainability

Spooked

There’s always something a bit scary about a ghost story. Somehow, though, when you read a collection of them you’re expecting to meet a spook or two. It takes a little more effort to frighten the reader. We hope we’ve managed to do just that with this bunch of tales and our striking cover. We hope as well you’ll find the stories as different from each other as they are from the normal ghost story. You’ll come across some old friends amongst the authors in this volume. Bridge House is beginning to es-tablish a brand and we have several writers now who have the measure of what we’re looking for. You’ll also meet some new names and writing styles. We’re sure both will please. And now to the ghosts…. They too have a life of their own … precisely drawn by our authors. It’s that time of year isn’t it? When the nights are getting longer, the days are getting shorter, when strange shadows lurk and you begin to hear noises you don’t understand. We have traditional ghosts, more subtle ghosts, naughty ghosts, nice ghost, nasty ghost and in one or two of our stories it’s a little difficult to work out who is haunting whom. Stoke up the fire, sit back, enjoy and prepare to be: Spooked