Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic profiling in primary care can enhance personalized drug therapy: reality or myth?

The right drug, for the right patient, at the right dose At the heart of every primary-care therapeutic decision is the above statement. To elaborate, the clinician aims to treat his or her patient with the most appropriate and effective therapy with the minimal side-effect profile. However, drugrelated adverse events are a reality in today’s healthcare system. The UK Department of Health estimated that one in every ten inpatients experiences some form of adverse event, costing the UK NHS over £2 billion in remedial care every year [1]. The nature of patient care in the NHS has changed over the past few decades. We have an increasingly aging population, with a growth in the number of patients with chronic long-term conditions, higher standards of treatment (through National Service Frameworks) and quicker availability of newer drugs through NICE technology appraisals and guidelines; and so it follows that the number of potential adverse drug events will also increase. Indeed, medical defense organizations report approximately 200 claims against British general practitioners (GPs) involving medicines each year, with this figure increasing annually [2]. If scientific literature is to be believed, we could potentially eradicate adverse events through personalized drug therapy. The completion of the Human Genome Project [3] heralded the advent of the genomic revolution, with a shift from the ‘one size fits all’ model to a more tailored, personalized approach for improved drug therapy for the patient. This, in turn, led to the birth of pharmacogenomics. Pharmacogenomics is the science of how an individual’s genetic inheritance affects their body’s response to drugs [101]. This aspect of pharmaceutical science has the potential to provide a shift in paradigm, where drugs are tailored according to the individual patient’s needs. Incorporation of pharmacogenomics into clinical practice has the potential to improve efficacy and reduce adverse effects for the patient. But is pharmacogenomics, the intersection of drugs and genetics, a reality or a myth for primary care?
Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems

Lipid-based drug delivery systems, or lipidic carriers, are being extensively employed to enhance the bioavailability of poorly-soluble drugs. They have the ability to incorporate both lipophilic and hydrophilic molecules and protecting them against degradation in vitro and in vivo. There is a number of physical attributes of lipid-based nanocarriers that determine their safety, stability, efficacy, as well as their in vitro and in vivo behaviour. These include average particle size/diameter and the polydispersity index (PDI), which is an indication of their quality with respect to the size distribution. The suitability of nanocarrier formulations for a particular route of drug administration depends on their average diameter, PDI and size stability, among other parameters. Controlling and validating these parameters are of key importance for the effective clinical applications of nanocarrier formulations. This review highlights the significance of size and PDI in the successful design, formulation and development of nanosystems for pharmaceutical, nutraceutical and other applications. Liposomes, nanoliposomes, vesicular phospholipid gels, solid lipid nanoparticles, transfersomes and tocosomes are presented as frequently-used lipidic drug carriers. The advantages and limitations of a range of available analytical techniques used to characterize lipidic nanocarrier formulations are also covered.
A regression-based system for accurate scalability prediction on large-scale machines

Scalability prediction is one of the key problems facing high performance computing today. Methods to predict scalability accurately are necessary in order to improve throughput and overall efficiency on large-scale machines. This dissertation presents our novel, regression-based system for accurately predicting the scalability of scientific applications on large-scale machines. Our regression-based system provides accurate runtime predictions on large processor counts for multiple scientific applications when run using strong scaling. Our system is also able to provide input parameters leading to accurate time-constrained scaling on larger processor counts. We also discuss the impact of noise on scalability prediction. This work takes large steps towards a general scalability prediction system that could be deployed on supercomputing systems in the near future. INDEX WORDS: Modeling, MPI, Prediction, Regression, Scalability, Noise, Theses (academic) A REGRESSION-BASED SYSTEM FOR ACCURATE SCALABILITY PREDICTION ON LARGE-SCALE MACHINES
Mugwort (Artemisia vulgaris, Artemisia douglasiana, Artemisia argyi) in the Treatment of Menopause, Premenstrual Syndrome, Dysmenorrhea and Attention Deficit Hyperactivity Disorder

Mugwort has many traditional uses around the world. The Chumash Indians of California use it to treat imbalances that women may suffer such as premenstrual syndrome, dysmenorrhea and menopausal symptoms. The plant contains a sesquiterpene that appears to work through a serotonergic mechanism and may be beneficial for women. Mugwort therapy is safer for menopausal women than hormone replacement therapy. Children affected by attention deficit hyperactivity disorder benefit from mugwort therapy. There is no doubt that mugwort therapy is safer for these children than methylphenidate or amphetamine.
Is it possible to assess free-living physical activity and energy expenditure in young people by self-report?

BACKGROUND It is unclear whether it is possible to accurately estimate physical activity energy expenditure (PAEE) by self-report in youth. OBJECTIVE We assessed the validity and reliability of 4 self-reports to assess PAEE and time spent at moderate and vigorous intensity physical activity (MVPA) over the previous week in British young people between 4 and 17 y of age. DESIGN PAEE and MVPA were derived from the Children's Physical Activity Questionnaire, Youth Physical Activity Questionnaire, and Swedish Adolescent Physical Activity Questionnaire; a lifestyle score indicative of habitual activity was derived from the Child Heart and Health Study in England Questionnaire. These data were compared with criterion methods, PAEE, and MVPA derived from simultaneous measurements by doubly labeled water and accelerometry in 3 age groups: 4-5 y (n = 27), 12-13 y (n = 25), and 16-17 y (n = 24). Validity was assessed by using Spearman correlations and the Bland-Altman method, and reliability was assessed by using intraclass correlation coefficients. RESULTS The strength of association between questionnaire and criterion methods varied (r = 0.09 to r = 0.46). Some questionnaires were able to accurately assess group-level PAEE and MVPA for some age groups, but the error was large for individual-level estimates throughout. Reliability of the Youth Physical Activity Questionnaire and Child Heart and Health Study in England Questionnaire was good (intraclass correlation coefficient: 0.64-0.92). CONCLUSIONS Absolute PAEE and MVPA estimated from these self-reports were not valid on an individual level in young people, although some questionnaires appeared to rank individuals accurately. Age (the outcome of interest) and whether individual or group-level estimates are necessary will influence the best choice of self-report method when assessing physical activity in youth.
TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy

Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca2+-dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5′-triphosphate (ATP), is also known as most potent Ca2+-mobilizing ligand that acts on purinergic receptors, ATP never induces cardiomyocyte hypertrophy. Here we show that ATP-induced production of nitric oxide (NO) negatively regulates hypertrophic signaling mediated by TRPC3/6 channels in NRCMs. Pharmacological inhibition of NO synthase (NOS) potentiated ATP-induced increases in NFAT activity, protein synthesis, and transcriptional activity of brain natriuretic peptide. ATP significantly increased NO production and protein kinase G (PKG) activity compared to angiotensin II and endothelin-1. We found that ATP-induced Ca2+ signaling requires inositol 1,4,5-trisphosphate (IP3) receptor activation. Interestingly, inhibition of TRPC5, but not TRPC6 attenuated ATP-induced activation of Ca2+/NFAT-dependent signaling. As inhibition of TRPC5 attenuates ATP-stimulated NOS activation, these results suggest that NO-cGMP-PKG axis activated by IP3-mediated TRPC5 channels underlies negative regulation of TRPC3/6-dependent hypertrophic signaling induced by ATP stimulation.
Identification of TOEFAZ1‐interacting proteins reveals key regulators of Trypanosoma brucei cytokinesis

The protist parasite Trypanosoma brucei is an obligate extracellular pathogen that retains its highly polarized morphology during cell division and has evolved a novel cytokinetic process independent of non‐muscle myosin II. The polo‐like kinase homolog TbPLK is essential for transmission of cell polarity during division and for cytokinesis. We previously identified a putative TbPLK substrate named Tip of the Extending FAZ 1 (TOEFAZ1) as an essential kinetoplastid‐specific component of the T. brucei cytokinetic machinery. We performed a proximity‐dependent biotinylation identification (BioID) screen using TOEFAZ1 as a means to identify additional proteins that are involved in cytokinesis. Using quantitative proteomic methods, we identified nearly 500 TOEFAZ1‐proximal proteins and characterized 59 in further detail. Among the candidates, we identified an essential putative phosphatase that regulates the expression level and localization of both TOEFAZ1 and TbPLK, a previously uncharacterized protein that is necessary for the assembly of a new cell posterior, and a microtubule plus‐end directed orphan kinesin that is required for completing cleavage furrow ingression. The identification of these proteins provides new insight into T. brucei cytokinesis and establishes TOEFAZ1 as a key component of this essential and uniquely configured process in kinetoplastids.
Knowledge Development Approaches and Breakthrough Innovations in Technology-Based New Firms

Compared to large established firms, technology-based new firms (TBNF) seem well placed to produce breakthrough innovations although questions remain as to their adeptness at subsequent exploitation. Building on the innovation and strategy literatures, the study identifies two different knowledge development approaches or modes (business models) in TBNFs – internal versus external - and examines their relation to breakthrough innovation and subsequent progression of the product to market. The internal mode assembles knowledge inside the firm to generate its innovations, whereas the external mode relies heavily on alliances to develop and assemble knowledge among firms embedded in a creative network. The study uses a unique panel dataset of 69 UK new biotechnology firms over an 11-year period to explore this issue empirically. The findings show that the external knowledge development mode is associated with more breakthrough innovations and a faster movement of innovations to market. The externally focused mode is not impeded by its relative lack of internal knowledge; it uses partners to access, assemble and develop a wide scope of knowledge in a flexible manner. In addition, partners provide deep domain expertise to undertake the requisite deep-dives. In contrast, the internal mode has the huge challenge of assembling knowledge resources internally and suffers from a quicker onset of path dependence that impedes the generation of breakthroughs. This study provides a choice of business models (internal or external) that is associated with different breakthrough and speed to market performance outcomes. Going forward, policy makers and managers seeking breakthrough innovations and speedy progression of the innovations to market should consider the potential resource efficiency of the external mode and the vital role played by collaborations – small firm versus large firm and private versus public entities.
UvA-DARE (Digital Academic Repository) Collaborative User Clustering for Short Text Streams

In this paper, we study the problem of user clustering in the context of their published short text streams. Clustering users by short text streams is more challenging than in the case of long documents associated with them as it is difﬁcult to track users’ dynamic interests in streaming sparse data. To obtain better user clustering performance, we propose a user collaborative interest tracking model (UCIT) that aims at tracking changes of each user’s dynamic topic distributions in collab-oration with their followees’, based both on the content of current short texts and the previously estimated distributions. We evaluate our proposed method via a benchmark dataset consisting of Twitter users and their tweets. Experimental results validate the effectiveness of our proposed UCIT model that integrates both users’ and their collaborative interests for user clustering by short text streams.
Fragility Fractures and Parkinsonism: Relationship of Fractures with Demography, Severity and Predictors of Adverse Outcomes

Background: The risk of falls is higher in patients with Parkinsonism (PwP) as compared to other older adults, leading to adverse outcomes including fragility fractures. Osteoporosis is under-recognised and the current prevalence of fragility fractures is not well-studied. The objectives of this study are to determine the prevalence of fragility fractures in PwP, to measure the relationship of fractures with demography, severity and to measure predictors of adverse outcomes in this population. Method/Description: This was a retrospective observational cohort study based on the analysis of existing data for all the patients attending Caerphilly Movement Disorder Clinic. Information on demographics, the severity of Parkinsonism and fragility fractures was extracted electronically from the clinical workstation, clinic letters and coding from January 2015 to October 2016. Results: 397 people (mean age = 77.1 ± 9.4, 46% females) were studied. Of these, 77% (306/397) had Parkinsonism and 80% (244/306) had idiopathic Parkinson’s disease (PD). The mean Hoehn & Yahr Score at the time assessment was 3.09 ± 1.16. Additionally, 23.5% (72/306) were deemed to have osteoporosis based on the radiological evidence of fragility fractures. The PwP who sustained fractures were comparatively older (80.4 ± 12.1) and 70% (50/72) were females. The most common site for fractures was vertebral (47.2%; 34/72). Also, 22.2% of the sample (16/72) had suffered a fragility fracture before the diagnosis of PD. However, a majority (77.8%; 56/72) had sustained a fracture during the course of PD with a mean lapse of 6 years (range = 0–13 years) from initial diagnosis. Only 40% (29/72) of patients were prescribed osteoporosis drugs as per guidelines. There is a significant correlation of advancing age, severity and duration of PD with fragility fractures. The single best predictor of mortality is severity of PD, followed by age and fractures. Conclusions: There is a high prevalence of fragility fractures in patients attending movement disorder clinics, although 60% do not receive evidence-based medical treatment for the underlying osteoporosis. The prevalence of fragility fractures is positively correlated with the duration and severity of PD. We acknowledge the relatively small sample size as the study’s limitation.
Comparison of GA & PSO in UPFC in A 39 Bus Network

In this Paper, the IEEE39 bus system is taken with problem parameters voltage stability, position of placing UPFC and the angle of series voltage injection. These parameters are determined with reference to IEEE39 bus values and power flow calculations are done in MATLAB. Genetic Algorithm (GA) and Particle Swarm Optimization (PSO) is done to find the best position maximum stability and series injection and the best optimization among the both is compared.
Diagnostic Accuracy of Bioelectrical Impedance Analysis Parameters for the Evaluation of Malnutrition in Patients Receiving Hemodialysis

BACKGROUND In the absence of a gold standard technique for assessing nutrition status in patients receiving hemodialysis (HD), we aimed to determine the diagnostic accuracy of single-frequency (50 kHz) bioelectrical impedance analysis parameters, resistance/height (R/H), reactance/height (Xc/H), and impedance/height (Z/H), and their cutoff points for malnutrition. METHODS The reference standards, Subjective Global Assessment (SGA), Malnutrition Inflammation Score, and Nutritional Risk Screening 2002, were performed at baseline and then once a year for 2 years. At least 2 assessments for each reference standard were performed during the monitoring period, and those patients who were assessed as malnourished on at least 2 consecutive occasions were classified as malnourished. RESULTS A total 101 patients receiving HD were evaluated. R/H and Z/H demonstrated low to moderate accuracy to diagnose malnutrition in men and low accuracy in women, whereas the accuracy of Xc/H was uncertain. The cutoff points of bioelectrical impedance vector analysis (BIVA) parameters, determined based on the SGA to maximize sensitivity and specificity simultaneously, were: R/H ≥330.05 and ≥420.92 ohms/m for men and women, respectively; Z/H ≥332.71 and ≥423.19 ohms/m for men and women, respectively. In men, sensitivity based on the cutoff points of R/H and Z/H together ranged from 73% to 89% and specificity ranged from 49% to 50%. In women, sensitivity ranged from 58% to 80% and specificity from 48% to 55%. CONCLUSION BIVA parameters demonstrated low to moderate accuracy in men and low accuracy in women for the diagnosis of malnutrition.
Efficacy and Safety of Dupilumab in Glucocorticoid‐Dependent Severe Asthma

BACKGROUND Dupilumab is a fully human anti–interleukin‐4 receptor α monoclonal antibody that blocks both interleukin‐4 and interleukin‐13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown. METHODS We randomly assigned 210 patients with oral glucocorticoid–treated asthma to receive add‐on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose‐adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed. RESULTS The percentage change in the glucocorticoid dose was ‐70.1% in the dupilumab group, as compared with ‐41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection‐site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%). CONCLUSIONS In patients with glucocorticoid‐dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab‐treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214.)
Continuum simulations of water flow in carbon nanotube membranes

We propose the use of the Navier–Stokes equations subject to partial-slip boundary conditions to simulate water flows in Carbon NanoTube (CNT) membranes. The finite volume discretizations of the Navier–Stokes equations are combined with slip lengths extracted from molecular dynamics (MD) simulations to predict the pressure losses at the CNT entrance as well as the enhancement of the flow rate in the CNT. The flow quantities calculated from the present hybrid approach are in excellent agreement with pure MD results while they are obtained at a fraction of the computational cost. The method enables simulations of system sizes and times well beyond the present capabilities of MD simulations. Our simulations provide an asymptotic flow rate enhancement and indicate that the pressure losses at the CNT ends can be reduced by reducing their curvature. More importantly, our results suggest that flows at nanoscale channels can be described by continuum solvers with proper boundary conditions that reflect the molecular interactions of the liquid with the walls of the nanochannel.
The protective effect of Montelukast against skeletal muscle ischemia reperfusion injury: An experimental rat model.

BACKGROUND Montelukast is a selective leukotriene D-4 receptor antagonist, which specifically and reversibly inhibits cysteinyl leukotriene-1 receptor. The aim of this study was to investigate the protective effect of Montelukast on skeletal muscle reperfusion injury created as acute ischemia-reperfusion (IR) injury in Wistar-albino rats. METHODS The study comprised 16 male Wistar-albino rats. The rats were randomly separated into two groups as control (IR) and treatment (IR+Montelukast). Ischemia was obtained using a femoral artery clamp. After reperfusion following a 2-hour ischemia, muscle samples were taken for biochemical and histopathological analyses. RESULTS Malondialdehyde levels were determined to be at statistically higher levels in the control compared with that in the Montelukast group (p=0.002, p<0.01). The superoxide dismutase levels were determined to be at statistically higher level in the Montelukast group compared with that in the control group (p=0.001, p<0.01). In the histopathological examination of the ischemic muscles, edema, polymorinfiltration and erythrocyte extravasation levels were found to be statistically significant higher in the control group than in the Montelukast group. Edema, polymorphonuclear infiltration, and erythrocyte extravasation levels were observed to be significantly reduced in the treatment group compared with that in the control. CONCLUSION In this model of skeletal muscle acute IR injury, the protective effect of Montelukast against skeletal muscle reperfusion injury was emphasized. We concluded that Montelukast could accelerate functional recovery in the extremity by limiting the local and systemic complications caused by reperfusion in cases such as extremity trauma with vascular injuries and extremity surgery with prolonged tourniquet application. However, further experimental and clinical studies are required to confirm this effect.