Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparative Effectiveness of Exercise Electrocardiography With or Without Myocardial Perfusion Single Photon Emission Computed Tomography in Women With Suspected Coronary Artery Disease: Results From the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) Trial

Background— There is a paucity of randomized trials regarding diagnostic testing in women with suspected coronary artery disease (CAD). It remains unclear whether the addition of myocardial perfusion imaging (MPI) to the standard ECG exercise treadmill test (ETT) provides incremental information to improve clinical decision making in women with suspected CAD. Methods and Results— We randomized symptomatic women with suspected CAD, an interpretable ECG, and ≥5 metabolic equivalents on the Duke Activity Status Index to 1 of 2 diagnostic strategies: ETT or exercise MPI. The primary end point was 2-year incidence of major adverse cardiac events, defined as CAD death or hospitalization for an acute coronary syndrome or heart failure. A total of 824 women were randomized to ETT or exercise MPI. For women randomized to ETT, ECG results were normal in 64%, indeterminate in 16%, and abnormal in 20%. By comparison, the exercise MPI results were normal in 91%, mildly abnormal in 3%, and moderate to severely abnormal in 6%. At 2 years, there was no difference in major adverse cardiac events (98.0% for ETT and 97.7% for MPI; P=0.59). Compared with ETT, index testing costs were higher for exercise MPI (P<0.001), whereas downstream procedural costs were slightly lower (P=0.0008). Overall, the cumulative diagnostic cost savings was 48% for ETT compared with exercise MPI (P<0.001). Conclusions— In low-risk, exercising women, a diagnostic strategy that uses ETT versus exercise MPI yields similar 2-year posttest outcomes while providing significant diagnostic cost savings. The ETT with selective follow-up testing should be considered as the initial diagnostic strategy in symptomatic women with suspected CAD. Clinical Trial Registration— http://www.clinicaltrials. gov. Unique identifier: NCT00282711.
A two-dimensional signal space for bandlimited optical intensity channels

Bandlimited optical intensity channels, such as visible light communication (VLC) systems, require that all signals satisfy a bandwidth constraint as well as average and non-negativity amplitude constraints. In this paper, a two-dimensional signal space for optical intensity channels is presented in which all signals are strictly bandlimited. A novel feature of this model is that the strict non-negativity constraint is relaxed and the signal space parameterizes the probability that the resulting output amplitude is negative. The motivation for this relaxation is that even though the optical intensity channel only supports non-negative amplitudes, if the likelihood of a negative amplitude excursion is small enough the impact of clipping or biasing on system performance will be negligible. For a given signal space, the probability that the output signal assumes a negative amplitude is rigorously upperbounded and also numerically found with a tractable and tight approximation. The uncoded power and spectral efficiencies are computed for two-dimensional hexagonal lattice constellations. For a given optical power, constellations developed with the new signal space have larger spectral efficiencies over M-PAM using the minimum bandwidth optical intensity Nyquist pulse.
Decompressive craniectomy following traumatic brain injury: developing the evidence base

Abstract In the context of traumatic brain injury (TBI), decompressive craniectomy (DC) is used as part of tiered therapeutic protocols for patients with intracranial hypertension (secondary or protocol-driven DC). In addition, the bone flap can be left out when evacuating a mass lesion, usually an acute subdural haematoma (ASDH), in the acute phase (primary DC). Even though, the principle of “opening the skull” in order to control brain oedema and raised intracranial pressure has been practised since the beginning of the 20th century, the last 20 years have been marked by efforts to develop the evidence base with the conduct of randomised trials. This article discusses the merits and challenges of this approach and provides an overview of randomised trials of DC following TBI. An update on the RESCUEicp study, a randomised trial of DC versus advanced medical management (including barbiturates) for severe and refractory post-traumatic intracranial hypertension is provided. In addition, the rationale for the RESCUE-ASDH study, the first randomised trial of primary DC versus craniotomy for adult head-injured patients with an ASDH, is presented.
Identification of a Mutation Associated with Fatal Foal Immunodeficiency Syndrome in the Fell and Dales Pony

The Fell and Dales are rare native UK pony breeds at risk due to falling numbers, in-breeding, and inherited disease. Specifically, the lethal Mendelian recessive disease Foal Immunodeficiency Syndrome (FIS), which manifests as B-lymphocyte immunodeficiency and progressive anemia, is a substantial threat. A significant percentage (∼10%) of the Fell ponies born each year dies from FIS, compromising the long-term survival of this breed. Moreover, the likely spread of FIS into other breeds is of major concern. Indeed, FIS was identified in the Dales pony, a related breed, during the course of this work. Using a stepwise approach comprising linkage and homozygosity mapping followed by haplotype analysis, we mapped the mutation using 14 FIS–affected, 17 obligate carriers, and 10 adults of unknown carrier status to a ∼1 Mb region (29.8 – 30.8 Mb) on chromosome (ECA) 26. A subsequent genome-wide association study identified two SNPs on ECA26 that showed genome-wide significance after Bonferroni correction for multiple testing: BIEC2-692674 at 29.804 Mb and BIEC2-693138 at 32.19 Mb. The associated region spanned 2.6 Mb from ∼29.6 Mb to 32.2 Mb on ECA26. Re-sequencing of this region identified a mutation in the sodium/myo-inositol cotransporter gene (SLC5A3); this causes a P446L substitution in the protein. This gene plays a crucial role in the regulatory response to osmotic stress that is essential in many tissues including lymphoid tissues and during early embryonic development. We propose that the amino acid substitution we identify here alters the function of SLC5A3, leading to erythropoiesis failure and compromise of the immune system. FIS is of significant biological interest as it is unique and is caused by a gene not previously associated with a mammalian disease. Having identified the associated gene, we are now able to eradicate FIS from equine populations by informed selective breeding.
Predicting post-traumatic stress and health anxiety following a venous thrombotic embolism

This research identified psychosocial factors associated with post-traumatic stress and health anxiety following a venous thrombotic embolism. In all, 158 participants, largely registered with a venous thrombotic embolism information website (Lifeblood: The Thrombosis Charity), completed an online survey. Post-traumatic symptom scores were linked to health threat, and not moderated by perceived control over risk for further venous thrombotic embolism. Health anxiety was associated with continuing symptoms and a negative emotional response to the venous thrombotic embolism. There is a need to intervene to reduce both short- and long-term distress in this population, ideally using a stepped-care model.
A topological interpretation of three Leibnizian principles within the functional extensions

Three philosophical principles are often quoted in connection with Leibniz: objects sharing the same properties are the same object (Identity of indiscernibles), everything can possibly exist, unless it yields contradiction (Possibility as consistency), and the ideal elements correctly determine the real things (Transfer). Here we give a precise logico-mathematical formulation of these principles within the framework of the Functional Extensions, mathematical structures that generalize at once compactifications, completions, and elementary extensions of models. In this context, the above Leibnizian principles appear as topological or algebraic properties, namely: a property of separation, a property of compactness, and a property of directeness, respectively. Abiding by this interpretation, we obtain the somehow surprising conclusion that these Leibnizian principles may be fulfilled in pairs, but not all three together.
Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Polygenic risk scores have shown great promise in predicting complex disease risk, and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves LD-pruning markers and applying a P-value threshold to association statistics, but this discards information and may reduce predictive accuracy. We introduce a new method, LDpred, which infers the posterior mean causal effect size of each marker using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the pruning/thresholding approach, particularly at large sample sizes. Accordingly, prediction R2 increased from 20.1% to 25.3% in a large schizophrenia data set and from 9.8% to 12.0% in a large multiple sclerosis data set. A similar relative improvement in accuracy was observed for three additional large disease data sets and when predicting in non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.
5′-Long Terminal Repeat-Selective CpG Methylation of Latent Human T-Cell Leukemia Virus Type 1 Provirus In Vitro and In Vivo

ABSTRACT CpG methylation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat (LTR) has been implicated in proviral latency, but there is presently little information available regarding the pattern of LTR methylation and its effect on viral gene expression. To gain insight into the mechanisms of HTLV-1 latency, we have studied methylation of individual CpG sites in the U3-R region of the integrated proviral LTR by using bisulfite genomic sequencing methods. Surprisingly, our results reveal selective hypermethylation of the 5′ LTR and accompanying hypomethylation of the 3′ LTR in both latently infected cell lines and adult T-cell leukemia (ATL) cells having a complete provirus. Moreover, we observed a lack of CpG methylation in the LTRs of 5′-defective proviruses recovered from ATL samples, which is consistent with the selective hypomethylation of the 3′ LTR. Thus, the integrated HTLV-1 provirus in these carriers appears to be hypermethylated in the 5′ LTR and hypomethylated in the 3′ LTR. These results, together with the observation that proviral gene expression is reactivated by 5-azacytidine in latently infected cell lines, indicate that selective hypermethylation of the HTLV-1 5′ LTR is common both in vivo and in vitro. Thus, hypermethylation of the 5′ LTR appears to be an important mechanism by which HTLV-1 gene expression is repressed during viral latency.
Thymus development and infant and child mortality in rural Bangladesh

Background Data from West Africa indicate that a small thymus at birth and at 6 months of age is a strong and independent risk factor for infection-related mortality up to 24 and 36 months of age, respectively. We investigated the association between thymus size (thymic index, TI) in infancy and subsequent infant and child survival in a contemporary South Asian population. Methods The study focused on the follow-up of a randomized trial of prenatal nutritional interventions in rural Bangladesh (ISRCTN16581394), with TI measured longitudinally in infancy (at birth and weeks 8, 24 and 52 of age) and accurate recording of mortality up to 5 years of age. Results A total of 3267 infants were born into the Maternal and Infant Nutrition Interventions, Matlab study; data on TI were available for 1168 infants at birth, increasing to 2094 infants by 52 weeks of age. TI in relation to body size was largest at birth, decreasing through infancy. For infants with at least one measure of TI available, there were a total of 99 deaths up to the age of 5 years. No association was observed between TI and subsequent mortality when TI was measured at birth. However, an association with mortality was observed with TI at 8 weeks of age [odds ratio (OR) for change in mortality risk associated with 1 standard deviation change in TI: all deaths: OR = 0.64, 95% confidence interval (CI) 0.41, 0.98; P = 0.038; and infection-related deaths only: OR = 0.32, 95% CI 0.14, 0.74; P = 0.008]. For TI when measured at 24 and 52 weeks of age, the numbers of infection-related deaths were too few (3 and 1, respectively) for any meaningful association to be observed. Conclusion These results confirm that thymus size in early infancy predicts subsequent survival in a lower mortality setting than West Africa. The absence of an effect at birth and its appearance at 8 weeks of age suggests early postnatal influences such as breast milk trophic factors.
Afferent Connectivity of the Zebrafish Habenulae

The habenulae are bilateral nuclei located in the dorsal diencephalon that are conserved across vertebrates. Here we describe the main afferents to the habenulae in larval and adult zebrafish. We observe afferents from the subpallium, nucleus rostrolateralis, posterior tuberculum, posterior hypothalamic lobe, median raphe; we also see asymmetric afferents from olfactory bulb to the right habenula, and from the parapineal to the left habenula. In addition, we find afferents from a ventrolateral telencephalic nucleus that neurochemical and hodological data identify as the ventral entopeduncular nucleus (vENT), confirming and extending observations of Amo et al. (2014). Fate map and marker studies suggest that vENT originates from the diencephalic prethalamic eminence and extends into the lateral telencephalon from 48 to 120 hour post-fertilization (hpf). No afferents to the habenula were observed from the dorsal entopeduncular nucleus (dENT). Consequently, we confirm that the vENT (and not the dENT) should be considered as the entopeduncular nucleus “proper” in zebrafish. Furthermore, comparison with data in other vertebrates suggests that the vENT is a conserved basal ganglia nucleus, being homologous to the entopeduncular nucleus of mammals (internal segment of the globus pallidus of primates) by both embryonic origin and projections, as previously suggested by Amo et al. (2014).
Do “Brain-Training” Programs Work?

In 2014, two groups of scientists published open letters on the efficacy of brain-training interventions, or “brain games,” for improving cognition. The first letter, a consensus statement from an international group of more than 70 scientists, claimed that brain games do not provide a scientifically grounded way to improve cognitive functioning or to stave off cognitive decline. Several months later, an international group of 133 scientists and practitioners countered that the literature is replete with demonstrations of the benefits of brain training for a wide variety of cognitive and everyday activities. How could two teams of scientists examine the same literature and come to conflicting “consensus” views about the effectiveness of brain training? In part, the disagreement might result from different standards used when evaluating the evidence. To date, the field has lacked a comprehensive review of the brain-training literature, one that examines both the quantity and the quality of the evidence according to a well-defined set of best practices. This article provides such a review, focusing exclusively on the use of cognitive tasks or games as a means to enhance performance on other tasks. We specify and justify a set of best practices for such brain-training interventions and then use those standards to evaluate all of the published peer-reviewed intervention studies cited on the websites of leading brain-training companies listed on Cognitive Training Data (www.cognitivetrainingdata.org), the site hosting the open letter from brain-training proponents. These citations presumably represent the evidence that best supports the claims of effectiveness. Based on this examination, we find extensive evidence that brain-training interventions improve performance on the trained tasks, less evidence that such interventions improve performance on closely related tasks, and little evidence that training enhances performance on distantly related tasks or that training improves everyday cognitive performance. We also find that many of the published intervention studies had major shortcomings in design or analysis that preclude definitive conclusions about the efficacy of training, and that none of the cited studies conformed to all of the best practices we identify as essential to drawing clear conclusions about the benefits of brain training for everyday activities. We conclude with detailed recommendations for scientists, funding agencies, and policymakers that, if adopted, would lead to better evidence regarding the efficacy of brain-training interventions.
Detecting differential copy number variation between groups of samples

We present a method to detect copy number variants (CNVs) that are differentially present between two groups of sequenced samples. We use a finite-state transducer where the emitted read depth is conditioned on the mappability and GC-content of all reads that occur at a given base position. In this model, the read depth within a region is a mixture of binomials, which in simulations matches the read depth more closely than the often-used negative binomial distribution. The method analyzes all samples simultaneously, preserving uncertainty as to the breakpoints and magnitude of CNVs present in an individual when it identifies CNVs differentially present between the two groups. We apply this method to identify CNVs that are recurrently associated with postglacial adaptation of marine threespine stickleback (Gasterosteus aculeatus) to freshwater. We identify 6664 regions of the stickleback genome, totaling 1.7 Mbp, which show consistent copy number differences between marine and freshwater populations. These deletions and duplications affect both protein-coding genes and cis-regulatory elements, including a noncoding intronic telencephalon enhancer of DCHS1. The functions of the genes near or included within the 6664 CNVs are enriched for immunity and muscle development, as well as head and limb morphology. Although freshwater stickleback have repeatedly evolved from marine populations, we show that freshwater stickleback also act as reservoirs for ancient ancestral sequences that are highly conserved among distantly related teleosts, but largely missing from marine stickleback due to recent selective sweeps in marine populations.
THE EFFECTS OF IMPLICIT INSTRUCTION ON IMPLICIT AND EXPLICIT KNOWLEDGE DEVELOPMENT

This study extends the evidence for implicit second language (L2) learning, which comes largely from (semi-)artificial language research, to German. Upper-intermediate L2 German learners were flooded with spoken exemplars of a difficult morphological structure, namely strong, vowel-changing verbs. Toward the end of exposure, the mandatory vowel change was omitted, yielding ungrammatical verb forms (compare Leung & Williams, 2012). Two pre- and posttests—word monitoring and controlled oral production—gauged the development of learners’ implicit and explicit knowledge, respectively. Interviews revealed 33 out of 38 L2 learners remained unaware of the ungrammatical verbs in the input flood; however, they showed significant sensitivity during listening as evidenced by a reaction time slowdown on ungrammatical trials. The unaware learners also improved significantly from pretest to posttest on the word-monitoring task, but not the oral production measure, unless the verbs’ salience in the input flood had resonated with them. Thus, implicit instruction affected implicit knowledge primarily, although prior knowledge and memory could potentially account for interactions between implicit processing, implicit knowledge, and explicit knowledge.
Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct

Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective: We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design: We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n–3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7–like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.