Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial

Abstract Objective: Type 2 diabetes in the elderly is an important and insufficiently studied public health problem. This study evaluated sitagliptin monotherapy in patients with type 2 diabetes aged ≥65 years. Research design and methods: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted at 52 sites in the United States. Patients were treated with once-daily sitagliptin (100 or 50 mg, depending on renal function) or placebo for 24 weeks. Key endpoints included change from baseline in glycated hemoglobin (HbA1c), 2-hour post-meal glucose (2-h PMG) and fasting plasma glucose (FPG) at week 24, and average blood glucose on treatment days 3 and 7. Clinical trial registration: NCT00305604. Results: Among randomized patients (N = 206), mean age was 72 years and mean baseline HbA1c was 7.8%. At week 24, HbA1c decreased by 0.7%, 2-h PMG by 61 mg/dL, and FPG by 27 mg/dL in sitagliptin-treated patients compared with placebo (all p < 0.001). On day 3 of treatment, mean average blood glucose was decreased from baseline by 20.4 mg/dL in sitagliptin-treated patients compared with placebo (p < 0.001). In subgroups defined by baseline HbA1c <8.0% (n = 132), ≥8.0% to <9.0% (n = 42), and ≥9.0% (n = 18), the placebo-adjusted reductions in HbA1c with sitagliptin treatment were 0.5%, 0.9%, and 1.6%, respectively. Patients in the sitagliptin and placebo groups had similar rates of adverse events overall (46.1% and 52.9%, respectively); serious adverse events were reported in 6.9% and 13.5%, respectively. No adverse events of hypoglycemia were reported. Potential study limitations include a relatively small number of patients with more severe hyperglycemia (HbA1c ≥9.0%) and the exclusion of patients with severe renal insufficiency. Conclusion: In this study, sitagliptin treatment significantly and rapidly improved glycemic measures and was well tolerated in patients aged ≥65 years with type 2 diabetes.
HRM and Performance – The Role of Talent Management as a Transmission Mechanism in an Emerging Market Context

This paper examines the link between HRM practices, talent management and firm performance, and examines the role of HRM/business strategy alignment in an emerging market context. Through survey evidence gathered from 198 respondent firms, this study shows that talent management, when focused on a series of practices aimed at developing workforce networks and social capital, is a key transmission mechanism mediating the relationship between HRM and firm performance. HRM strategy and business strategy alignment increases these performance impacts but is not an essential component in the HRM-TM-performance link.
Impact of all oral anti-hepatitis C virus therapy: A meta-analysis.

AIM To investigate the efficacy, safety, and cost of treatment of direct acting antivirals (DAAs) with and without peg interferon alfa2a (P), and/or ribavirin (R) in treating hepatitis C virus (HCV) genotype 1 patients. METHODS MEDLINE was searched for randomized controlled trials (RCT) using DAAs for HCV treatment. Phase 1 trials and studies with investigational drugs on genotype 2 or 3, and on human immunodeficiency virus patients were excluded. Data were pooled for sustained virologic response (SVR), serious adverse effects, and drug discontinuation rate on various treatment arms in trials: P + R; 1(st) generation DAA (telaprevir or boceprevir) + P + R; 2(nd) generation DAA (sofosbuvir or simeprevir) + P + R; 2(nd) generation DAA + R; two 2(nd) generation DAA + R; and two 2(nd) gen DAA. Data were analyzed separately for each arm for treatment naive and non-responders (NR) to previous treatment. The cost of treatment with each regimen for achieving one SVR was also compared. RESULTS Twenty three RCTs (n = 9354, 62% male, 11% cirrhosis) were analyzed. All oral (P free) regimens with combination of 2 DAA achieved SVR above 95%. The cost of treatment to achieve an SVR with DAA based regimens was lower for NR compared to P+R regimen. However, the cost per SVR remained higher for treatment naive patients. CONCLUSION Second generation and emerging DAAs are promising agents in HCV treatment, with a very high level of safety and efficacy. An important drawback is their high cost. However, the present meta-analysis shows that the cost per SVR for non responders (but not for naive patients) was lower compared to P + R. This finding together with the superior safety profile and better compliance makes these drugs highly attractive. It is possible that further reduction in treatment duration may make them even more cost effective.
Role of Conserved Disulfide Bridges and Aromatic Residues in Extracellular Loop 2 of Chemokine Receptor CCR8 for Chemokine and Small Molecule Binding*

Chemokine receptors play important roles in the immune system and are linked to several human diseases. The initial contact of chemokines with their receptors depends on highly specified extracellular receptor features. Here we investigate the importance of conserved extracellular disulfide bridges and aromatic residues in extracellular loop 2 (ECL-2) for ligand binding and activation in the chemokine receptor CCR8. We used inositol 1,4,5-trisphosphate accumulation and radioligand binding experiments to determine the impact of receptor mutagenesis on both chemokine and small molecule agonist and antagonist binding and action in CCR8. We find that the seven-transmembrane (TM) receptor conserved disulfide bridge (7TM bridge) linking transmembrane helix III (TMIII) and ECL-2 is crucial for chemokine and small molecule action, whereas the chemokine receptor conserved disulfide bridge between the N terminus and TMVII is needed only for chemokines. Furthermore, we find that two distinct aromatic residues in ECL-2, Tyr184 (Cys + 1) and Tyr187 (Cys + 4), are crucial for binding of the CC chemokines CCL1 (agonist) and MC148 (antagonist), respectively, but not for small molecule binding. Finally, using in silico modeling, we predict an aromatic cluster of interaction partners for Tyr187 in TMIV (Phe171) and TMV (Trp194). We show in vitro that these residues are crucial for the binding and action of MC148, thus supporting their participation in an aromatic cluster with Tyr187. This aromatic cluster appears to be present in a large number of CC chemokine receptors and thereby could play a more general role to be exploited in future drug development targeting these receptors.
Landing Posture Control for a Generalized Twin-Body System Using Methods of Input–Output Linearization and Computed Torque

This study aims to examine landing posture control for a generalized twin-body system using methods of input-output linearization and computed torque. The considered system mimics the mechanism of a certain popular cellular phone that is composed of two rigid links and an active joint that not only connects the two links but also offers torques about three orthogonal axes. A standard modeling procedure for robotic dynamics is employed to capture the twin-body dynamics in terms of 312 Euler angles on the basis of the Newton-Euler formulation. Herein, the posture components, i.e., the included angle, the tilt angle, and the first landing body, are employed to represent the landing posture that is particularly designed to prevent the fragile areas of the system from being damaged. Since the three posture components are nonlinear functions of state variables, the standard control strategy cannot be applied. In order to resolve this difficulty, the three posture components are transformed into three control outputs, which are linear functions of state variables. However, the system reveals a nonlinear control problem, and the method of input-output linearization is used to cancel the nonlinear terms. The computed torque method is then utilized to determine the input torques. Finally, the feasibility of the proposed landing posture control is confirmed via MATLAB simulations. This study successfully implemented a standard control strategy to realize landing posture control by establishing transformations from real landing posture components to simulated control outputs, and the controllable regions were defined completely.
Macrophage-derived cytokine and nuclear factor kappaB p65 expression in synovial membrane and skin of patients with psoriatic arthritis.

OBJECTIVE Monocyte-derived cytokines are important mediators in synovitis and represent novel therapeutic targets. This study was undertaken to analyze their expression in synovial membrane (SM) of patients with psoriatic arthritis (PsA) compared with that in skin of patients with PsA and SM of patients with rheumatoid arthritis (RA). METHODS Multiple synovial biopsy samples (24 from patients with PsA, 20 from patients with RA, 5 from patients with osteoarthritis [OA]) and skin biopsy samples (lesional and perilesional skin from 25 PsA patients) were obtained. Standard leukocyte antigens, cytokines (tumor necrosis factor alpha [TNFalpha], interleukin-1apha [IL-1alpha], IL-1beta, IL-15, and IL-10) and the transcription factor nuclear factor KB (NF-kappaB; active p65 subunit) were localized and quantified immunohistochemically by light microscopy and digital image analysis. RESULTS Sublining cellular infiltration, lymphoid aggregation, and vascularity were similar in PsA and RA SM. Lining layer thickness was greater in RA SM, associated with more CD68+ macrophages. In PsA SM, TNFalpha, IL-1alpha, IL-1beta, IL-15, and IL-10 were primarily localized to lining layer and perivascular macrophages, as were cells expressing the active subunit of NF-kappaB (p65). TNFalpha, IL-1p, and IL-15 expression in PsA lining layer was less than that in RA lining layer, likely reflecting lower macrophage numbers. In sublining areas, levels of TNFalpha and IL-15 were lower in PsA patients than in RA patients, whereas IL-lalpha and IL-1beta expression was equivalent. IL-10 was identified at similar levels in RA and PsA SM lining layer and sublining. Expression of NF-kappaB (p65) was equal in lining layer from both patient groups, but lower in PsA than RA sublining. Histologic findings did not correlate with clinical parameters of disease. Cytokine expression in skin did not correlate directly with that in SM. Cytokine expression was greater in PsA and RA SM than in OA SM. CONCLUSION This study shows, for the first time, that monocyte-derived cytokines are found in PsA SM and demonstrates the relative paucity of the antiinflammatory cytokine IL-10 in PsA skin and SM. Significant divergence from RA SM expression was observed, despite similar clinical and demographic features in the 2 patient groups.
Permethrin-impregnated curtains and bed-nets prevent malaria in western Kenya.

The effectiveness of permethrin-impregnated (0.5 g/m2) bed-nets and curtains as malaria control measures was evaluated in Uriri, Kenya in 1988. One hundred five families were randomly assigned to 1 of 3 study groups (control, bed-net, or curtain). All participants were cured of parasitemia with pyrimethamine/sulfadoxine. Selective epidemiologic and entomologic parameters were measured weekly, while knowledge, attitude, and practices surveys were conducted at the beginning and end of the 15 week study. Plasmodium falciparum infections per person week at risk were significantly higher in the control group than in either the curtain group (5.42 vs. 2.35 cases/100 person weeks risk) or the bed-net group (5.42 vs. 3.77 cases/100 person weeks risk). The curtain group had fewer infections per person week at risk than the bed-net group (2.35 vs. 3.77 cases/100 person weeks risk). A difference was found in clinical malaria among the groups: 45% of persons in the bed-net and curtain groups vs. 30% of those in the control group reported no episodes of fever and chills (chi 2, P less than 0.05). Indoor resting Anopheles gambiae or An. funestus were found on 94 occasions in the control houses, but only twice in the treated houses during weekly visits to each house over the study period (chi 2 P less than 0.001). The pyrethrum knockdown method produced similar results with a total of 195, 23, and 3 An. gambiae and An. funestus collected in the control, bed-net, and curtain houses during the same period, respectively. (ABSTRACT TRUNCATED AT 250 WORDS)
Cytosolic Phospholipase A2 (cPLA2) Regulation of Human Monocyte NADPH Oxidase Activity

The NADPH oxidase of human monocytes is activated upon exposure to opsonized zymosan and a variety of other stimuli to catalyze the formation of superoxide anion. Assembly of the NADPH oxidase complex is believed to be a highly regulated process, and molecular mechanisms responsible for this regulation have yet to be fully elucidated. We have previously reported that cytosolic phospholipase A2 (cPLA2) expression and activity are essential for superoxide anion production in activated human monocytes. In this study, we investigated the mechanisms involved in cPLA2 regulation of NADPH oxidase activation by evaluating the effects of cPLA2 on translocation and phosphorylation of p67 phox and p47 phox . We report that translocation and phosphorylation of p67 phox , as well as p47 phox , occur upon activation of human monocytes and that decreased cPLA2 protein expression, mediated by antisense oligodeoxyribonucleotides (AS-ODN) specific for cPLA2mRNA, blocked the stimulation-induced translocation of p47 phox and p67 phox from the cytosol to the membrane fraction. Inhibition of translocation of both p47 phox and p67 phox by cPLA2 AS-ODN was above 85%. Arachidonic acid (AA), a product of cPLA2 enzymatic activity, completely restored translocation of both of these oxidase components in the AS-ODN-treated, cPLA2-deficient human monocytes. These results represent the first report that cPLA2activity or AA is required for p67 phox and p47 phox translocation in human monocytes. Although cPLA2 was required for translocation of p47 phox and p67 phox , it did not influence phosphorylation of these components. These results suggest that one mechanism of cPLA2 regulation of NADPH oxidase activity is to control the arachidonate-sensitive assembly of the complete oxidase complex through modulating the translocation of both p47 phox and p67 phox . These studies provide insight into the mechanisms by which activation signals are transduced to allow the induction of superoxide anion production in human monocytes.
Clinical treatment regimens for chronic heart failure: a review

Chronic heart failure (CHF) is increasing in prevalence worldwide, particularly in the elderly. Accordingly, this epidemic is likely to translate into a major increase in healthcare costs. Systolic heart failure is the most common cause of CHF presentations. Although the causes vary, the most common single aetiological factor is ischaemic heart disease, which accounts for ∼ 50% of heart failure presentations. Research into CHF pharmacotherapy has been copious, with the focus principally centred on systolic heart failure. The evidence base for pharmacotherapy in CHF is amongst the largest currently in clinical medicine. There have been multiple trials establishing the mortality and morbidity benefits of pharmacotherapy. Amongst these, large scale trials of angiotensin-converting enzyme inhibitors, β-blockers and spironolactone have provided a sound basis for evidence-based treatment approaches to the CHF patient. Recently research interest has increased in biomedical engineering with studies being performed in biventricular pacing and mechanical hearts. Early data with biventricular pacing or cardiac resynchronisation therapy is encouraging. Diastolic heart failure alone accounts for at least 20 – 40% of CHF presentations and whilst it may occur in isolation, is most commonly seen in association with systolic heart failure. In this study, we present a broad overview of the current therapeutic modalities for the management of CHF, with particular emphasis on pharmacotherapy.
Sport policy analysis revisited: the sport policy process as an interlinked chain of legitimating acts

ABSTRACT By providing an analytical framework that draws on a conceptualisation of legitimacy in organisation studies, this paper demonstrates that the sport policy process can be understood as an interlinked chain of legitimating acts. Based on recent suggestions in organisation theory literature on how to approach legitimacy and legitimation, we applied the framework on a small sample of published sport policy studies to demonstrate its utility. By applying the framework, six interweaved and interweaving elements of the legitimating act within sport policy processes were identified: legitimacy-seeking organisation, subject, source(s), strategy, bases and scenario. The analysis shows that each of the six elements works by intersecting within each phase of the policy process. The main conclusion is that consequences – often unintended – resulting from legitimating acts in one phase have legitimacy-related implications for the other phases of the policy process. As pressing as pinpointing the use of all elements of the framework is, it is equally important to distinguish each of the elements in order to fulfil the analytical potential of the proposed framework. Since sport policy processes in practice rely primarily on organisations and organisational action, future sport policy research would benefit from this type of framework connecting organisations and organising to policy processes.
The Generation Gap in Direct Democracy

We provide the first systematic documentation and analysis of a generation gap in direct democracy outcomes across a wide range of topics using postelection survey data covering more than 300 Swiss referenda and four decades. We find that older voters are more likely to resist reform projects, particularly those that are associated with the political left. We separate age and cohort effects without imposing functional form constraints using a panel rank regression approach. The aging effect on political orientation is robust for controlling for arbitrary cohort effects and appears to be driven by expected utility maximization and not by habituation-induced status-quo bias. Our results suggest that population aging raises the hurdle for investment-like reform projects with positive net present values, long-run benefits and short-run costs in direct polls.
Investigation of bioinspired gecko fibers to improve adhesion of HeartLander surgical robot

HeartLander is a medical robot proposed for minimally invasive epicardial intervention on the beating heart. To date, all prototypes have used suction to gain traction on the epicardium. Gecko-foot-inspired micro-fibers have been proposed for repeatable adhesion to surfaces. In this paper, a method for improving the traction of HeartLander on biological tissue is presented. The method involves integration of gecko-inspired fibrillar adhesives on the inner surfaces of the suction chambers of HeartLander. Experiments have been carried out on muscle tissue ex vivo assessing the traction performance of the modified HeartLander with bio-inspired adhesive. The adhesive fibers are found to improve traction on muscle tissue by 57.3%.
Host specificity and incidence of Trypanosoma in some African rainforest birds: a molecular approach

Studies of host–parasite interactions in birds have contributed greatly to our understanding of the evolution and ecology of disease. Here we employ molecular techniques to determine the incidence and study the host‐specificity of parasitic trypanosomes in the African avifauna. We developed a polymerase chain reaction (PCR)‐based diagnostic test that amplified the small subunit ribosomal RNA gene (SSU rRNA) of Trypanosoma from avian blood samples. This nested PCR assay complements and corroborates information obtained by the traditional method of blood smear analysis. The test was used to describe the incidence of trypanosomes in 479 host individuals representing 71 rainforest bird species from Cameroon, the Ivory Coast and Equatorial Guinea. Forty‐two (59%) of these potential host species harboured trypanosomes and 189 individuals (35%) were infected. To examine host and geographical specificity, we examined the morphology and sequenced a portion of the SSU rRNA gene from representative trypanosomes drawn from different hosts and collecting locations. In traditional blood smear analyses we identified two trypanosome morphospecies, T. avium and T. everetti. Our molecular and morphological results were congruent in that these two morphospecies had highly divergent SSU rRNA sequences, but the molecular assay also identified cryptic variation in T. avium, in which we found seven closely allied haplotypes. The pattern of sequence diversity within T. avium provides evidence for widespread trypanosome mixing across avian host taxa and across geographical locations. For example, T. avium lineages with identical haplotypes infected birds from different families, whereas single host species were infected by T. avium lineages with different haplotypes. Furthermore, some conspecific hosts from geographically distant sampling locations were infected with the same trypanosome lineage, but other individuals from those locations harboured different trypanosome lineages. This apparent lack of host or geographical specificity may have important consequences for the evolutionary and ecological interactions between parasitic trypanosomes and their avian hosts.
Upregulation of Fas and downregulation of CD94/NKG2A inhibitory receptors on circulating natural killer cells in patients with new‐onset psoriasis

Background Psoriasis has been considered as a T‐helper 1 cell‐mediated autoimmune disease driven by collaboration with multiple components of innate and acquired immune cells. Natural killer (NK) cells have been shown to bridge innate and acquired immunity, and thus could potentially contribute to the pathophysiology of psoriasis.
Therapeutic approaches in Parkinson's disease and related disorders

The lack of effective therapies for neurodegenerative disorders is one of the most relevant challenges of this century, considering that, as the global population ages, the incidence of these type of diseases is quickly on the rise. Among these disorders, synucleinopathies, which are characterized by the abnormal accumulation and spreading of the synaptic protein alpha‐synuclein in the brain, already constitute the second leading cause of parkinsonism and dementia in the elderly population. Disorders with alpha‐synuclein accumulation include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Numerous therapeutic alternatives for synucleinopathies are being tested in pre‐clinical models and in the clinic; however, only palliative treatments addressing the dopaminergic deficits are approved to date, and no disease‐modifying options are available yet. In this article, we provide a brief overview of therapeutic approaches currently being explored for synucleinopathies, and suggest possible explanations to the clinical trials outcomes. Finally, we propose that a deeper understanding of the pathophysiology of synucleinopathies, together with a combination of therapies tailored to each disease stage, may lead to better therapeutic outcomes in synucleinopathy patients.