Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study.

OBJECTIVE To identify the determinants of antibody responses to adjuvanted split influenza A (H1N1) vaccines in patients with inflammatory rheumatic diseases. METHODS One hundred seventy-three patients (82 with rheumatoid arthritis, 45 with spondylarthritis, and 46 with other inflammatory rheumatic diseases) and 138 control subjects were enrolled in this prospective single-center study. Controls received 1 dose of adjuvanted influenza A/09/H1N1 vaccine, and patients received 2 doses of the vaccine. Antibody responses were measured by hemagglutination inhibition assay before and 3-4 weeks after each dose. Geometric mean titers (GMTs) and rates of seroprotection (GMT≥40) were calculated. A comprehensive medical questionnaire was used to identify the determinants of vaccine responses and adverse events. RESULTS Baseline influenza A/09/H1N1 antibody levels were low in patients and controls (seroprotection rates 14.8% and 14.2%, respectively). A significant response to dose 1 was observed in both groups. However, the GMT and the seroprotection rate remained significantly lower in patients (GMT 146 versus 340, seroprotection rate 74.6% versus 87%; both P<0.001). The second dose markedly increased antibody titers in patients, with achievement of a similar GMT and seroprotection rate as elicited with a single dose in healthy controls. By multivariate regression analysis, increasing age, use of disease-modifying antirheumatic drugs (DMARDs) (except hydroxychloroquine and sulfasalazine), and recent (within 3 months) B cell depletion treatment were identified as the main determinants of vaccine responses; tumor necrosis factor α antagonist treatment was not identified as a major determinant. Immunization was well tolerated, without any adverse effect on disease activity. CONCLUSION DMARDs exert distinct influences on influenza vaccine responses in patients with inflammatory rheumatic diseases. Two doses of adjuvanted vaccine were necessary and sufficient to elicit responses in patients similar to those achieved with 1 dose in healthy controls.
Meta-analysis in clinical research

Meta-analysis is important in the evaluation of therapies for integrating the results of individual studies in order to advance or inform clinical research. In this special issue, different aspects of metaanalysis are reviewed using case studies to illustrate the methodologies being described. There can be issues when evaluating evidence when the events being observed are rare. Lane compares available methods for binary data considering different summary measures such as riskdifference, relative-risk and odds-ratio scale as well as fixed and random-effect methods in the assessment. The paper also highlights the benefit of how graphical approaches can add value. A case study is presented by Julious to highlight issues in evaluating evidence for safety and efficacy, which updates previous analyses with additionally reported trials. These data also consider the problem of the event of interest being rare. Graphical approaches are highlighted to investigate the assumptions in a meta-analysis. Often, however, a direct comparison of two therapies is not possible and indirect comparisons need to be made through a network meta-analysis. A sparsely connected network of 10 treatments for the treatment of diabetes is used by Senn et al. to make points about approaches to analysis. Graphical approaches, both of the network and of the results, are again described to summarise the data. Indirect comparisons are also used in the assessment, and design, of non-inferiority studies. In non-inferiority clinical trials, a test treatment is compared to an active-control rather than to placebo – when randomising to placebo is unethical or not feasible. A critical question is whether the test treatment would have been superior to placebo, had placebo been used in the non-inferiority trial. This question, as highlighted by Schmidli et al., can only be addressed indirectly, based on information from relevant historical trials with data on active-control and placebo. As highlighted multivariate meta-analysis is becoming increasingly popular. The advantages and limitations of multivariate meta-analysis have been discussed. The main limitation being computational complexity and hence, in a timely paper, Mavridis and Salanti review the statistical methods and the related software for multivariate meta-analysis. Pooling evidence from individual trials is important in the evaluation of research. For the individual trials adaptive designs have been recommended. However, there can be issues in pooling evidence when trials have stopped early. Bassler et al. review controversies associated with randomised controlled trials stopped early for apparent benefit and discussed how pooled effects from meta-analyses including trials stopped early could potentially overestimate an effect.
Implementation Aspects of Security and Privacy in Embedded Design (Beveiliging en privacy in ingebedde systemen: implementatieaspecten)

Embedded devices are nowadays largely represented across the compute continuum. From mobile phones to smart cards and RFID tags, digital devices are becoming increasingly ubiquitous, mobile and integrated with their environment. This gradual shift towards pervasive computing envisions many benefits in sectors as diverse as financial, entertainment, health care, information access, or automotive. Along with these possibilities however, there are also inherent risks to be addressed. It is in this context that this dissertation is situated. It provides contributions to the security of embedded devices and the privacy of the humans interacting with them. The first part of the thesis is devoted to physical security. Many existing and future applications have built-in security capabilities which rely on keeping cryptographic keys secret. Typical examples include payment tokens, digital identity documents, or access control cards. As these devices operate in hostile environments, they need protection against physical attacks. Among these, side channel attacks and fault attacks represent two of the major threats in the security of embedded devices. Our contributions in this area encompass three different but related aspects. First, we provide an in-depth analysis of vulnerabilities that lead to physical attacks. In particular, we characterize the effects of fault injections based on setup-time violations on a low-end microcontroller. Second, we show how physical attacks are still a prominent threat for secure devices by successfully attacking a widely used family of secure memories. And third, we devise and thoroughly evaluate a high-level mitigation against side channel attacks. More specifically, we employ the inner product construction to design a masking-based countermeasure implementable at any order. The second part of the thesis deals with privacy aspects. Systems such as location-based services, health-care monitoring, or smart homes rely on the collection and processing of fine-grained information about users. Hazards
Robustness against Consistency Models with Atomic Visibility

To achieve scalability, modern Internet services often rely on distributed databases with consistency models for transactions weaker than serializability. At present, application programmers often lack techniques to ensure that the weakness of these consistency models does not violate application correctness. We present criteria to check whether applications that rely on a database providing only weak consistency are robust, i.e., behave as if they used a database providing serializability. When this is the case, the application programmer can reap the scalability benefits of weak consistency while being able to easily check the desired correctness properties. Our results handle systematically and uniformly several recently proposed weak consistency models, as well as a mechanism for strengthening consistency in parts of an application.
Surface-structural analysis by use of spin-polarized low-energy electron diffraction: An investigation of the Cu(100) surface.

A detailed theoretical and experimental study of the Cu(100) surface using spin-polarized low-energy electron diffraction (SPLEED) is reported. An R-factor analysis of the present SPLEED data for the 10, 20, and 11-bar beams provides evidence of multilayer relaxation in Cu(100), and suggests that the first and second interlayer spacings deviate by -1.2% and +0.9%, respectively, from the bulk value. The present structural conclusions are in accord with those deduced in earlier LEED I-V studies, and suggest that combined measurements of spin-asymmetry and intensity profiles should provide an improved basis for structure determinations on surfaces of greater complexity.
DEPDC5 as a potential therapeutic target for epilepsy

ABSTRACT Introduction: Dishevelled, Egl-10 and Pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is a recently identified modulator of mechanistic target of rapamycin (mTOR) activity. mTOR is a key regulator of cell proliferation and metabolism; disruption of the mTOR pathway is implicated in focal epilepsy, both acquired and genetic. Tuberous sclerosis is the prototypic mTOR genetic syndrome with epilepsy, however GATOR1 gene mutations have recently been shown to cause lesional and non-lesional focal epilepsy. Areas covered: This review summarizes the mTOR pathway, including regulators and downstream effectors, emphasizing recent developments in the understanding of the complex role of the GATOR1 complex. We review the epilepsy types associated with mTOR overactivity, including tuberous sclerosis, polyhydramnios megalencephaly symptomatic epilepsy, cortical dysplasia, non-lesional focal epilepsy and post-traumatic epilepsy. Currently available mTOR inhibitors are discussed, primarily rapamycin analogs and ATP competitive mTOR inhibitors. Expert opinion: DEPDC5 is an attractive therapeutic target in focal epilepsy, as effects of DEPDC5 agonists would likely be anti-epileptogenic and more selective than currently available mTOR inhibitors. Therapeutic effects might be synergistic with certain existing dietary therapies, including the ketogenic diet.
Glycolytic Enzyme Binding during Entrance to Daily Torpor in Deer Mice (Peromyscus maniculatus)

Associations of glycolytic enzymes with the subcellular particulate fraction of skeletal muscle and heart were examined during entrance to daily torpor in deer mice (Peromyscus maniculatus). In skeletal muscle a significant decrease in enzyme binding occurred during torpor entrance for phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase, with an additional significant decrease for phosphofructokinase and pyruvate kinase during the deepest state of torpor. Reductions in enzyme binding during torpor entrance also occurred in heart; significant changes were observed in hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase binding. Contrary to the finding of additional reductions in enzyme binding seen in skeletal muscle, significant increases in enzyme binding during the deepest torpor state were observed for hexokinase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, and lactate dehydrogenase in heart. These results suggest that a decrease in the binding of glycolytic enzymes to subcellular structures in skeletal muscle and heart may be at least partially responsible for initiating the reduction in metabolic rate during torpor entrance. This decreased binding may continue to mediate the metabolic reduction in skeletal muscle throughout torpor; heart, however, may require the use of different molecular mechanisms. The increased binding in heart during the deepest state of torpor may represent an anticipatory response in preparation for increased activity during arousal.
Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.

BACKGROUND Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32). CONCLUSIONS Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).
Learning Enabled Optimization: Towards a Fusion of Statistical Learning and Stochastic Optimization

Several emerging applications, such as “Analytics of Things” and “Integrative Analytics” call for a fusion of statistical learning (SL) and stochastic optimization (SO). The Learning Enabled Optimization paradigm fuses concepts from these disciplines in a manner which not only enriches both SL and SO, but also provides a framework which supports rapid model updates and optimization, together with a methodology for rapid model-validation, assessment, and selection. Moreover, in many big data/big decisions applications these steps are repetitive, and possible only through a continuous cycle involving data analysis, optimization, and validation. This paper sets forth the foundation for such a framework by introducing several novel concepts such as statistical optimality, hypothesis tests for model-fidelity, generalization error of stochastic optimization, and finally, a non-parametric methodology for model selection. These new concepts provide a formal framework for modeling, solving, validating, and reporting solutions for Learning Enabled Optimization (LEO). We illustrate the LEO framework by applying it to an inventory control model in which we use demand data available for ARIMA modeling in the statistical package “R”. In addition, we also study a production-marketing coordination model based on combining a pedagogical production planning model with an advertising data set intended for sales prediction. Because the approach requires the solution of several stochastic programming instances, some using continuous random variables, we leverage stochastic decomposition (SD) for the fusion of regression and stochastic linear programming. In this sense, the novelty of this paper is its framework, rather than a specific new algorithm. Finally, we present an architecture of a software framework to bring about the fusion we envision.
Diurnal Tracking of Blink and Relationship to Signs and Symptoms of Dry Eye

Purpose: To assess diurnal changes in the signs and symptoms of dry eyes and their relationship to diurnal interblink interval (IBI) in normal subjects and in subjects with dry eye. Methods: Blink data were collected from 9:00 AM to 8:00 PM during 2 days of normal activity using an electrocardiogram monitoring device. All subjects recorded ocular discomfort (0–5 scale) and primary activity hourly each day in a diary. Inferior and central fluorescein staining was graded by slit lamp (0–4) at the start and end of each day. Blink activity was detected using an algorithm based on recognition of the waveform corresponding to the kinematic properties of the blink signal. Results: Normal subjects (N = 12) reported negligible symptoms, and results did not show a diurnal change in group hourly IBI. Mean daily IBI for the group with dry eye (N = 15) (4.63 ± 1.63 s) was shorter than that for the normal group (5.28 ± 1.48 s) (P = 0.0483). Correlation of diurnal symptoms and mean hourly IBI was relatively weak (r = −0.248). A repeated-measures model found IBI to be significantly associated with the time of day (P = 0.0028). Inferior corneal staining showed a small but significant diurnal increase for both normal group and group with dry eyes. Conclusions: Diurnal blink tracking reveals significant trending with symptoms. Diurnal change in IBI may be an appropriate surrogate for symptoms in the study of dry eye.
Pleural tuberculosis: an update

Purpose of review Pleural tuberculosis accounts for fewer than 1% of all exudative effusions in western countries, occurring in only 3–5% of tuberculous patients. However, in developing countries like India, it is responsible for 30–80% of all pleural effusions encountered and may complicate tuberculosis in 31% of all cases. Thus, tuberculous pleuritis remains a major contributor to global morbidity and mortality. Tuberculous pleurisy presents a diagnostic and therapeutic problem due to the low sensitivity of the diagnostic tools. There have been many advances in the field that we have attempted to update. Recent findings Due to the limitations of conventional tests and the delay of several weeks for mycobacterial culture results, there has been a resurgence of interest in newer rapid tests and biomarkers. This review highlights the deficiencies of the traditional tests, while providing an overview of the newer tests. In addition, we provide an update on the changing epidemiology, clinical features and current treatment options. Summary Newer immunological tests and scoring systems will revolutionize the way tuberculous pleurisy is diagnosed in the years ahead. Future research needs include validating the available diagnostic tests in larger randomized studies, finding newer specific biomarkers that are simple, accurate and cost-effective for the developing world and determining treatment regimens specific for tuberculous pleurisy.
Anatomical studies of the circle of Willis in normal brain.

Introduction The present study was undertaken in order to determine the anatomical structures of the circle of Willis, 27 with the purpose of learning its normal configuration, the frequency of deficient or incomplete circles, and, if possible, how these findings can be correlated with the clinical problems of vascular disease, such as infarcts, aneurysms, and vascular anomalies. There are many problems in vascular disease of the brain which make desirable an intimate knowledge of variants in the anatomy of the circle of Willis. The state of the circle becomes important in determining the adequacy of the brain circulation in operations for cerebral aneurysm and in ligation of the carotid artery. The possibility of bypassing or shunting effects in occlusion of one of the cerebral vessels and the adequacy of recovery or lack of recovery after vascular occlusion might be explained in part by variations in the anatomy of the circle
A Simple Cost-sensitive Multiclass Classification Algorithm Using One-versus-one Comparisons

Many real-world applications require varying costs for different types of misclassification errors. Such a cost-sensitive classification setup can be very different from the regular classification one, especially in the multiclass case. Thus, traditional meta-algorithms for regular multiclass classification, such as the popular one-versus-one approach, may not always work well under the cost-sensitive classification setup. In this paper, we extend the one-versus-one approach to the field of cost-sensitive classification. The extension is derived using a rigorous mathematical tool called the cost-transformation technique, and takes the original one-versus-one as a special case. Experimental results demonstrate that the proposed approach can achieve better performance in many cost-sensitive classification scenarios when compared with the original one-versus-one as well as existing cost-sensitive classification algorithms.
Chemotherapy advances in small cell lung cancer.

Small cell lung cancer accounts for 13–15% of all lung cancer worldwide. There has been a decrease in the number of cases, with no clear explanation, except probably to changing in smoking habits in the last two decades. In the early 1980s, it became clear that SCLC was an extremely sensitive tumour to radiation as it was to chemotherapeutic agents. With cisplatinum etoposide combinations or cyclophosphamide, anthracycline and vincristine/etyoposide regimens responses were observed in 50–70%, with 20–30% complete remissions in extensive disease. For limited-stage patients chemotherapy associated with thoracic radiation was able to produce a cure rate of 10–20%. The addition of prophylactic brain irradiation to limited stage cases has reduced mortality by a factor of nearly 5%. But despite these early good results no breakthrough came later on, and in the last decade or so, we are still facing this plateau. New agents have recently been included in the therapeutic armamentarium, such as gemcitabine, irinotecan, paclitaxel and more recently pemetrexed. This fact has allowed many patients to receive a relatively active second line therapy, but the overall survival remains unchanged. Targeted therapies are undergoing some evaluations, but the data are too premature and, so far, quite discouraging. At the present time there is an urgent need to improve clinical research in this somehow forgotten disease.