Miracle-dz/UniFAR-FTUs huggingface dataset:
Insulin Glargine : A Review in Type 1 and 2 Diabetes

Subcutaneous once-daily LY2963016 insulin glargine (LY insulin glargine) [Abasaglar (EU); Basaglar (USA)] has been approved in the EU as a biosimilar to reference insulin glargine (Lantus ), and in the USA as a follow-on biologic to reference insulin glargine, for use in patients with type 1 or 2 diabetes. Structural and functional characterization of LY insulin glargine in preclinical studies showed that it is similar to reference insulin glargine. In phase I euglycaemic clamp studies, LY insulin glargine demonstrated similar pharmacodynamic (including duration of action) and pharmacokinetic parameters to reference insulin glargine. In the phase III ELEMENT trials, LY insulin glargine and reference insulin glargine were noninferior to each other with respect to glycaemic control, indicating their equivalent efficacy, when administered with mealtime insulin in adults with type 1 diabetes or with oral antiglycaemic medications in adults with type 2 diabetes. LY insulin glargine was generally well tolerated, with a safety profile (including the risk of hypoglycaemia and immunogenicity) similar to that of reference insulin glargine and without any additional safety concerns identified. Basal insulin treatment status at baseline did not impact the relative efficacy, safety and immunogenicity of LY insulin glargine versus reference insulin glargine in the ELEMENT 1 and 2 trials. In conclusion, LY insulin glargine offers an additional basal insulin option for patients with type 1 or 2 diabetes, potentially at a lower cost. LY2963016 insulin glargine: clinical considerations in type 1 and 2 diabetes First biosimilar (EU) and follow-on biologic (US) to reference insulin glargine Similar pharmacodynamic and pharmacokinetic parameters to reference insulin glargine in healthy volunteers Similar duration of action to reference insulin glargine in patients with type 1 diabetes Provides effective glycaemic control equivalent to that of reference insulin glargine Generally well-tolerated, with a safety profile similar to that of reference insulin glargine
Use of &bgr;-Agonists in Inhalation Injury

Damage to the pulmonary parenchyma from smoke represents a second cause of inhalation injury. To date, the treatment of lung injury due to smoke has been largely supportive in nature. Patients are intubated, placed on mechanical ventilation, and maintained on support until pulmonary status improves, permanent airway access obtained, or the patient dies. Given that the insult associated with inhalation injury causes direct pulmonary damage and that the lungs have the ability of absorb drugs, the use of inhaled therapies for inhalation injury is appealing. The goal of this chapter is to describe the potential role of inhalation therapies in the treatment of smoke inhalation injury.
Bumetanide, an Inhibitor of Cation-chloride Cotransporter Isoform 1, Inhibits &ggr;-Aminobutyric Acidergic Excitatory Actions and Enhances Sedative Actions of Midazolam in Neonatal Rats

Background: It has been shown that &ggr;-aminobutyric acid exerts excitatory actions on the immature brain due to the increased expression of Na+–K+–2Cl− cotransporter isoform 1. The authors sought to clarify whether midazolam, a &ggr;-aminobutyric acid–mimetic hypnotic agent, causes neuronal excitation that can be blocked by bumetanide, a selective inhibitor of Na+–K+–2Cl− cotransporter isoform 1. Furthermore, the authors examined whether bumetanide potentiates the sedative effects of midazolam in neonatal rats. Methods: The authors measured the effects of midazolam with or without bumetanide on the cytosolic Ca2+ concentration ([Ca]2+i) in hippocampal slices (n = 3 in each condition) from rats at postnatal days 4, 7, and 28 (P4, P7, and P28) using fura-2 microfluorometry. Neuronal activity in the hippocampus and thalamus after intraperitoneal administration of midazolam with or without bumetanide was estimated by immunostaining of phosphorylated cyclic adenosine monophosphate–response element–binding protein (n = 12 in each condition). Furthermore, the authors assessed effects of bumetanide on the sedative effect of midazolam by measuring righting reflex latency (n = 6 in each condition). Results: Midazolam significantly increased [Ca]2+i in the CA3 area at P4 and P7 but not at P28. Bumetanide inhibited midazolam-induced increase in [Ca]2+i. Midazolam significantly up-regulated phosphorylated cyclic adenosine monophosphate–response element–binding protein expression in a bumetanide-sensitive manner in the hippocampus at P7 but not P28. Bumetanide enhanced the sedative effects of midazolam in P4 and P7 but not P28 rats. Conclusion: These results suggest that &ggr;-aminobutyric acid A receptor–mediated excitation plays an important role in attenuated sedative effects of midazolam in immature rats.
The safety profile of parecoxib for the treatment of postoperative pain: a pooled analysis of 28 randomized, double-blind, placebo-controlled clinical trials and a review of over 10 years of postauthorization data

Background Nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors are associated with safety issues including cardiovascular, renal, and gastrointestinal (GI) events. Objective To examine the safety of parecoxib, a COX-2 inhibitor, for the management of postoperative pain. Design Pooled analysis of 28 placebo-controlled trials of parecoxib and review of postauthorization safety data. Main outcome measures Prespecified safety events commonly associated with COX-2 inhibitors and/or NSAIDs. In the clinical trial analysis, the frequency of each event was compared between treatment groups using a chi-square test. In the postauthorization review, the number of confirmed cases, along with outcome, was presented for each event. Results In the clinical trial analysis, GI-related events occurred in ~0.2% of patients in the parecoxib and placebo groups. Renal failure and impairment was similar between parecoxib (1.0%) and placebo (0.9%). The occurrence of arterial (parecoxib=0.3%; placebo=0.2%) and venous (parecoxib=0.2%; placebo=0.1%) cardiovascular embolic and thrombotic events was similar between groups. Hypersensitivity reactions including anaphylactic reactions (parecoxib=8.7%; placebo=8.6%), hypotension (parecoxib=2.6%; placebo=2.1%), angioedema (parecoxib=2.5%; placebo=2.8%), and severe cutaneous adverse reactions (0% in both groups) were similar between groups. Incision site or other skin/tissue infections occurred in <0.1% of patients in both groups. The occurrence of these events (total reports/serious reports) in the postauthorization database, based on 69,567,300 units of parecoxib, was as follows: GI ulceration-related events (35/35), renal failure and impairment (77/68), cardiovascular embolic and thrombotic events (66/64), hypersensitivity reactions including hypotension-related events (32/25) and severe cutaneous adverse events (17/17), and masking signs of inflammation (18/18). A majority of reported outcomes were classified as recovered or recovering. Conclusions Potentially serious safety events occur infrequently with parecoxib, which high-lights its safety in patients with postoperative pain.
Association of the S267F Variant on NTCP Gene and Treatment Response to Pegylated Interferon in Patients with Chronic Hepatitis B: A Multicentre Study

Background Sodium taurocholate co-transporting polypeptide (NTCP) is a cell receptor for HBV. The S267F variant on the NTCP gene is inversely associated with the chronicity of HBV infection, progression to cirrhosis and hepatocellular carcinoma in East Asian populations. The aim of this study was to determine whether the S267F variant was associated with response to pegylated interferon (PEG-IFN) in patients with chronic HBV infection. Methods A total of 257 patients with chronic HBV, treated with PEG-IFN for 48 weeks, were identified from 13 tertiary hospitals included in the hepatitis B database of the Thai Association for the Study of the Liver (THASL). Results Of these, 202 patients were infected with HBV genotype C (84.9%); 146 patients were hepatitis B e antigen (HBeAg)-positive (56.8%). Genotypic frequencies of the S267F polymorphism were 85.2%, 14.8% and 0% for the GG, GA and AA genotypes, respectively. S267F GA was associated with sustained alanine aminotransferase (ALT) normalization (OR = 3.25, 95% CI 1.23, 8.61; P=0.02) in HBeAg-positive patients. Patients with S267F variant tended to have more virological response, sustained response with hepatitis B surface antigen (HBsAg) loss at 24 weeks following PEG-IFN treatment. There was no association between the S267F variant and improved patient outcomes in HBeAg-negative patients. Conclusions The S267F variant on the NTCP gene is independently associated with sustained normalization of ALT following treatment with PEG-IFN in patients with HBV infection who are HBeAg-positive. The findings of this study provide additional support for the clinical significance of the S267F variant of NTCP beyond HBV entry.
Protein Bread Fortification with Cumin and Caraway Seeds and By-Product Flour

Malnutrition continues to be a key health problem in developing regions. The valorization of food waste appears as an ideal way to prevent malnutrition and improve people’s access to food. Cumin (Cuminum cyminum L.) and caraway (Carum carvi L.) oilseeds are commonly used for cuisine and medicinal purposes. However, remaining cakes after oil extraction are usually underutilized. In order to assess the usefulness of these by-products in food applications, this study investigated the effect of their addition to protein bread formulations. Different levels (2, 4 and 6%) of whole seeds and cakes flour were used in the study. Fortified protein bread samples were compared to control protein bread and evaluated for their sensory, color, moisture, hardness properties, nutritional values as well as their biological activity. Results indicated that bread fortification shows a significant effect on bread properties depending on fortification level. A higher acceptability was observed specially for bread fortified with by-products flour. Increased tendencies of color darkness, moisture content, bread hardness, nutritional values as well as total phenolic content and radical scavenging activity compared to control bread were observed as the percentage of fortification increased in both cases. The overall results showed that the addition of cumin and caraway seeds and by-product flour can improve the antioxidant potential and overall quality of protein bread.
Association Between Plasma Levels of Macrophage Inhibitory Cytokine-1 Before Diagnosis of Colorectal Cancer and Mortality.

BACKGROUND & AIMS Patients with colorectal cancer (CRC) have high circulating levels of macrophage inhibitory cytokine-1 (MIC1 or growth differentiation factor 15), a marker of inflammation that might be involved in carcinogenesis. We analyzed blood samples collected from individuals before they were diagnosed with CRC to determine whether levels of MIC1 were associated with mortality. METHODS We collected data on survival of 618 participants diagnosed with CRC who provided prediagnosis blood specimens in 1990 (Nurses' Health Study) and 1994 (Health Professionals' Follow-up Study) and were followed through 2010. Levels of MIC1 were measured by enzyme-linked immunosorbent assay and then were categorized into quartiles based on the known distribution of MIC1 levels among previously matched individuals without CRC (controls) within each cohort. We then examined the association of MIC1 levels with overall and CRC-specific mortality using Cox proportional hazards models, with adjustments for mortality-associated risk factors and other plasma markers of inflammation. We also assessed the relationship between levels of MIC1 and levels of prostaglandin-endoperoxide synthase 2 expression (PTGS2 or cyclooxygenase-2), measured in 245 tumor samples by immunohistochemistry. RESULTS Compared with participants in the lowest quartile for plasma level of MIC1, the multivariate hazard ratio for CRC-specific death for participants in the highest quartile of MIC1 level was 2.40 (95% confidence interval: 1.33-4.34; P for linear trend = .009). The association of MIC1 with survival varied with level of PTGS2 expression in tumor samples (Pinteraction = .04). For individuals with PTGS2-positive tumors, the hazard ratio for CRC-specific death among those with high levels of MIC1 (equal to or greater than the median) was 2.13 (95% confidence interval: 0.99-4.58) compared with participants with low levels of MIC1 (below the median). In individuals with PTGS2-negative CRC, a high level of MIC1 was not associated with an increased risk of CRC-specific death (multivariate hazard ratio = 0.61; 95% confidence interval: 0.13-2.93). CONCLUSIONS Based on an analysis of blood and colorectal tumor samples from 2 large studies, high plasma levels of MIC1 (growth differentiation factor 15) before diagnosis of CRC are associated with greater CRC-specific mortality, particularly in individuals with PTGS2-positive tumors.
Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency

Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection.
Strength development in fly ash and slag mixtures with lime

The main objective of this paper is to investigate the effect of the joint activation of fly ash, a by-product of thermal power plants, and ground granulated blast-furnace slag, a by-product of steel manufacture, on the unconfined compressive strength of mixtures of the two materials. Laboratory compaction and strength tests were carried out on ash–slag mixtures at different proportions. The strength was found to increase with slag content. However, the specimens consisting of 30 and 40% of slag and cured for 28 d showed higher strength than the individual materials. Additionally, the effect of different percentages of lime on the strength of the fly ash–slag mixtures was investigated. Tremendous increase in strength was observed with the addition of even 2% of lime. Scanning electron microscopy and X-ray diffraction studies showed the morphological and mineralogical changes that are associated with strength improvement. This study suggests that properly designed combinations of fly ash–slag–lime can be u.
Motor Learning in Stroke

Background and Objective: Stroke rehabilitation assumes motor learning contributes to motor recovery, yet motor learning in stroke has received little systematic investigation. Here we aimed to illustrate that despite matching levels of performance on a task, a trained patient should not be considered equal to an untrained patient with less impairment. Methods: We examined motor learning in healthy control participants and groups of stroke survivors with mild-to-moderate or moderate-to-severe motor impairment. Participants performed a series of isometric contractions of the elbow flexors to navigate an on-screen cursor to different targets, and trained to perform this task over a 4-day period. The speed-accuracy trade-off function (SAF) was assessed for each group, controlling for differences in self-selected movement speeds between individuals. Results: The initial SAF for each group was proportional to their impairment. All groups were able to improve their performance through skill acquisition. Interestingly, training led the moderate-to-severe group to match the untrained (baseline) performance of the mild-to-moderate group, while the trained mild-to-moderate group matched the untrained (baseline) performance of the controls. Critically, this did not make the two groups equivalent; they differed in their capacity to improve beyond this matched performance level. Specifically, the trained groups had reached a plateau, while the untrained groups had not. Conclusions: Despite matching levels of performance on a task, a trained patient is not equal to an untrained patient with less impairment. This has important implications for decisions both on the focus of rehabilitation efforts for chronic stroke, as well as for returning to work and other activities.
Estimation of Burn Depth at Burn Centers in the United States: A Survey

Accurate burn depth estimation remains one of the foundations of optimal burn care. The method by which burn depth is determined has traditionally been clinical examination alone. This continues to hold true in the United States, despite a plethora of literature supporting the use of more accurate modalities such as laser Doppler imaging (LDI). LDI has widespread use in burn centers in the United Kingdom and around the world. Thus, the reason for a lack of use in U.S. burn centers remains elusive. A survey of U.S. burn center directors was conducted to assess their current practices and attitudes with regard to burn depth estimation at U.S. burn centers in an effort to answer this question. Surveys were returned from 68 burn center directors (49% response rate). All respondents reported using clinical examination in their current practice for the daily evaluation of acute burns, with a biopsy being the next most commonly used modality. The most preferred modality was also clinical examination (60%), followed by LDI (6%) and biopsy (4%). The top three modalities ranked as “most promising” for daily use were clinical examination, LDI, and noncontact/high-frequency ultrasound. Directors identified the top three limitations to the use of new technology as cost (72%), availability (63%), and lack of support by evidence to date (35%). Future studies may need to focus on overcoming these perceived limitations before the widespread use of LDI or other new modalities will be realized at burn centers in the United States.
Scalable energy-efficient, low-latency implementations of trained spiking Deep Belief Networks on SpiNNaker

Deep neural networks have become the state-of-the-art approach for classification in machine learning, and Deep Belief Networks (DBNs) are one of its most successful representatives. DBNs consist of many neuron-like units, which are connected only to neurons in neighboring layers. Larger DBNs have been shown to perform better, but scaling-up poses problems for conventional CPUs, which calls for efficient implementations on parallel computing architectures, in particular reducing the communication overhead. In this context we introduce a realization of a spike-based variation of previously trained DBNs on the biologically-inspired parallel SpiNNaker platform. The DBN on SpiNNaker runs in real-time and achieves a classification performance of 95% on the MNIST handwritten digit dataset, which is only 0.06% less than that of a pure software implementation. Importantly, using a neurally-inspired architecture yields additional benefits: during network run-time on this task, the platform consumes only 0.3 W with classification latencies in the order of tens of milliseconds, making it suitable for implementing such networks on a mobile platform. The results in this paper also show how the power dissipation of the SpiNNaker platform and the classification latency of a network scales with the number of neurons and layers in the network and the overall spike activity rate.
Thermal fluctuations of grafted microtubules provide evidence of a length-dependent persistence length

Microtubules are hollow cylindrical structures that constitute one of the three major classes of cytoskeletal filaments. On the mesoscopic length scale of a cell, their material properties are characterized by a single stiffness parameter, the persistence length ℓp. Its value, in general, depends on the microscopic interactions between the constituent tubulin dimers and the architecture of the microtubule. Here, we use single-particle tracking methods combined with a fluctuation analysis to systematically study the dependence of ℓp on the total filament length L. Microtubules are grafted to a substrate with one end free to fluctuate in three dimensions. A fluorescent bead is attached proximally to the free tip and is used to record the thermal fluctuations of the microtubule's end. The position distribution functions obtained with this assay allow the precise measurement of ℓp for microtubules of different contour length L. Upon varying L between 2.6 and 47.5 μm, we find a systematic increase of ℓp from 110 to 5,035 μm. At the same time we verify that, for a given filament length, the persistence length is constant over the filament within the experimental accuracy. We interpret this length dependence as a consequence of a nonnegligible shear deflection determined by subnanometer relative displacement of adjacent protofilaments. Our results may shine new light on the function of microtubules as sophisticated nanometer-sized molecular machines and give a unified explanation of seemingly uncorrelated spreading of microtubules' stiffness previously reported in literature.
Timing of onset affects arthritis presentation pattern in antisyntethase syndrome.

OBJECTIVES To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility.