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This post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs.Available data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1-3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age ( 65 versus ≥ 65 years). Logistic regression models evaluated risk factors for influenza AEs in the RA Overall tofacitinib cohort.In randomized cohorts, combined influenza AE IRs were generally similar across tofacitinib, adalimumab, methotrexate, and placebo groups, across indications. Among Overall tofacitinib cohorts, combined influenza AE IRs with tofacitinib 5/10 mg BID, respectively, were higher in the UC (3.66/5.09) versus RA (2.38/2.19) and PsA (1.74/1.29) cohorts. IRs were generally similar across tofacitinib dose and age groups. Most influenza AEs were nonserious and did not require changes to tofacitinib treatment. Significant risk factors for influenza AEs in patients with RA were geographic region, baseline oral corticosteroid and methotrexate use, and tofacitinib dose.In the RA, UC, and PsA clinical programs, combined influenza AE IRs were highest in UC, while in each indication they were generally similar across tofacitinib, placebo, and comparator groups. Influenza AEs were predominantly nonserious and not associated with changes to tofacitinib treatment.NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Paralytic shellfish poisoning is caused by saxitoxin and its analogues. The paralytic shellfish toxins (PSTs) are produced by marine dinoflagellates and can be accumulated in filter feeding shellfish, such as mussel, clam, oyster and ark shell. The worldwide regulatory limits for PSTs in shellfish are set at 80 μg STX eq./100 g meat and this is widely accepted as providing adequate public health protection. In this study, we have determined five individual PSTs (STX, GTX1, GTX2, GTX3 and GTX4) in shellfish using LC-MS/MS and assessed the human acute and chronic exposures to PSTs through shellfish consumption. Food consumption data was obtained from the Korea National Health and Nutrition Examination Survey ( KNHANES 2010–2015 ). The acute exposure using a large portion size of 88 g/day (95th percentile for consumers only) with maximum toxin level of 198.7 μg/kg was 0.30 μg/kg bw. Even though we estimated the acute exposure with a conservative manner, it was below the ARfDs (0.5 or 0.7 μg STX eq./kg bw) proposed by the international organizations, representing 43–60% of the ARfDs. The chronic exposures using mean consumption data for whole population with mean concentration of PSTs were ranged from 0.002 to 0.026 μg STX eq./kg bw/day. For consumers only, the chronic exposures were in the range of 0.012–0.128 μg STX eq./kg bw/day.

The present study was carried out to survey the levels of plutonium isotopes (238,239,240Pu) and strontium (90Sr) in domestic seafood in Korea. In current, regulatory authorities have analyzed radionuclides, such as 134Cs, 137Cs and 131I, in domestic and imported food. However, people are concerned about contamination of other radionuclides, such as plutonium and strontium, in food. Furthermore, people who live in Korea have much concern about safety of seafood. Accordingly, in this study, we have investigated the activity concentrations of plutonium and strontium in seafood. For the analysis of plutonium isotopes and strontium, a rapid and reliable method developed from previous study was used. Applicability of the test method was verified by examining recovery, minimum detectable activity (MDA), analytical time, etc. Total 40 seafood samples were analyzed in 2014-2015. As a result, plutonium isotopes (238,239,240Pu) and strontium (90Sr) were not detected or below detection limits in seafood. The detection limits of plutonium isotopes and strontium-90 were 0.01 and 1 Bq/kg, respectively.

An analytical method using liquid chromatography-tandem mass spectrometry has been developed for the determination of 5 paralytic shellfish poisoning (PSP) toxins (saxitoxin, gonyautoxin1-4) in shellfish and tunicate. The tested parameters included extraction solvent, clean-up method, mobile phase and mass spectrometric detection parameters including multiple reaction monitoring (MRM) conditions. The PSP toxins were extracted with 0.1 N hydrochloric acid and cleaned up using C18 SPE cartridges. Chromatographic separation of the 5 PSP toxins was carried out on a TSK-gel Amide-80 column with gradient elution. The developed method was validated according to the requirements of SANCO 12571/2013. The average recoveries of the PSP toxins ranged from 82.7% to 110.7%, the intra-day precisions were in the range of 0.3–10.9%, the inter-day precisions were in the range of 0.8–10.0% and the limits of quantification (LOQs) were in the range of 25–100 μg/kg, depending on the analytes and matrices. The validated method was successfully applied for the determination of 5 PSP toxins in real shellfish and tunicate samples, including mussel, oyster, ark shell, sea squirt and styela clava.

In order to detect damage in early stages and properly maintaining structures, the structural health monitoring technology is employed. In most cases, active-sensing SHM needs many piezoelectric (PZT) sensors and actuators. Thus, if there is a defect on PZT used for active-sensing SHM, the structural status could be misclassified. This study, for reliable SHM performance, investigated to detect defects of sensors by using the admittance-based sensor diagnostics. This study also introduced an algorithm that can diagnose sensor defects based only on data measured from the sensors in case that information about the changes in adhesive and environmental investigation, this study confirms that the proposed algorithm could be efficiently applied to real-world structures in which a significant temperature variation could take place.

Structural health monitoring (SHM) techniques based on the use of active-sensing piezoelectric (PZT) materials have received considerable attention. The validation of the PZT functionality during SHM operation is critical to successfully implementing a reliable SHM system. In this study, we investigated several parameters that affect the admittance-based sensor diagnostic process. We experimentally identified the temperature dependency of the active-sensor diagnostic process. We found that the admittance-based sensor diagnostic process can differentiate the adhesion conditions of bonding materials that are used to install a PZT on a structure, which is important when designing a sensor diagnostic process for an SHM system.

Number of responses received to the different sections of the survey. Q = question. AOM = acute otitis media. (PPTX 81 kb)

Background Acute otitis media (AOM) is the most common bacterial childhood infection. However, caregivers with children having mild episodes often do not seek healthcare services, which may lead to an under-appreciation of the disease experienced by the community. The objectives of this survey were to estimate the proportion of primary caregivers who went to a healthcare facility when they suspected that their child aged 6 to

Survey Questionnaire. Title of data: Additional file 1. Survey questionnaire. Description of data: List of questions and guidance used in the survey to assess demographic data, AOM symptoms, as well as potential healthcare-seeking behaviour and factors influencing this behaviour. (PDF 406 kb)

Various experimental studies have demonstrated that an impedance-based method is an effective means of structural damage detection. Using the self-sensing and active-sensing capabilities of piezoelectric materials, the electromechanical impedance response can be monitored to provide a qualitative indication of the overall health of a structure. In this article, two new signal processing tools for the impedance method are described in order to improve the damage detection capability and to reduce the amount of data to process for structural health assessment. The first approach is to instantaneously correlate the impedance data between different sensor sets, as opposed to be correlated to pre-stored baseline data. Another approach is to use the pre-defined parameter of impedance data to establish a generalized baseline for bolted joint monitoring. These approaches could reduce the number of data sets and could be efficiently used for low-power impedance devices. The proposed signal processing techniques are applied to several experimental structures, and the efficiency in damage detection is demonstrated.

PubMedID: 23731246 Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ?14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ?50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment. © 2013 John Wiley & Sons Ltd.

Platinum is a well known element which shows a significant electrocatalytic activity in many important applications. In glucose sensor, because of the poisoning effect of reaction intermediates and the low surface area, the electrocatalytic activity towards the glucose oxidation is low which cause the low sensitivity. So, we fabricate a nanoporous PtZn alloy electrode by deposition-dissolution method. It provides a high active surface and a large enzyme encapsulating space per unit area when it used for an enzymatic glucose sensor. Glucose oxidase was immobilized on the electrode surface by capping with PEDOT composite and PPDA. The composite and PPDA also can exclude the interference ion such as ascorbic acid and uric acid to improve the selectivity. The surface area was determined by cyclic voltametry method and the surface structure and the element were analyzed by Scanning Electron Microscope (SEM) and Energy Dispersive X-ray spectroscopy (EDX), respectively. The sensitivity is . It is a remarkable value with such simply prepared senor has high selectivity.

Whether pre-term birth culminates as a result of a de novo pathologic process or is more simply early activation of physiologic mechanisms is unknown. Exploration of the onset of labor in term women with classical risk factors for early delivery might provide insights into the mechanisms leading to pre-term birth. This study examines whether sociodemographic factors known to increase the risk of pre-term birth also affect the length of term gestations.From a large prospective cohort composed of women delivering from 1995-2000, a sample was selected of 441 women from Central North Carolina, US, who delivered singletons after 37 weeks gestation. An algorithm was designed to identify induced labors and gestational age was censored at the time of induction. Gestational age was assigned by sonography and menstrual dating. Data were analysed using the Cox proportional hazards model. The main outcome measure was time to spontaneous labor.Women with 12 years of education had longer periods of gestation than women with less than 12 years of education, HR = 0.57 [0.39, 0.84]. Shorter gestational periods were found for women with pre-term premature rupture of membranes (PPROM) in a previous pregnancy, HR = 3.70 [1.60, 8.52], even after adjusting for confounders. Smoking was not associated (p0.1) with the timing of labor at term.By studying the timing of spontaneous parturition at term we identified that there is little overlap in risk factors that affect timing of delivery between spontaneous term and pre-term births.

A sensor diagnostic and validation process that performs in-situ monitoring of the operational status of piezoelectric (PZT) active-sensors in structural health monitoring (SHM) applications is presented. The basis of this process is to track the changes in the capacitive value of piezoelectric materials, which shows up in measured admittance. Both degradation of the mechanical/electrical properties of a PZT transducer and the bonding defects between a PZT patch and a host structure could be identified by the proposed process. Due to the temperature dependent nature of piezoelectric materials, we investigated the effects of temperature on sensor diagnostic process. The effect of temperature found to be remarkable, modifying the measured capacitive values significantly. This results indicates that there is need for developing a rigorous signal processing technique to normalizing the temperature effects. It has been also found that, as the temperature changes, the sensor diagnostic process was influenced not only by a sensor and a structure, but by a bonding materials that was used for attaching a piezoelectric transducers to a structure, which would be an important characteristic when designing an SHM system. This paper summarizes considerations needed to develop such sensor diagnostic processes, experimental procedures and results, and additional issues that can be used as guidelines for future investigations.

BACKGROUND: Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. METHODS: We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period. RESULTS: Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P

Abstract 4187 Introduction: Prophylaxis with anti-inhibitor complex concentrate (AICC; FEIBA NF, Baxter Healthcare Corporation, Westlake Village, CA) has been shown to safely and significantly decrease the frequency of joint and other bleeding events in patients with severe hemophilia A and inhibitors. Nonetheless, AICC prophylaxis is an expensive therapeutic intervention, and evidence of its cost-effectiveness is needed to guide healthcare decision-making in this era of global economic downturn. Methods: Hemophilia A patients >2 years of age with inhibitors and using bypassing therapy to treat bleeding were enrolled in a prospective, randomized, crossover study comparing 6 months of AICC infused prophylactically at a dose of 85U/kg ± 15% on 3 nonconsecutive days per week with 6 months of AICC used on-demand for bleeding episodes at a dose of 85 U/kg ± 15%. The 2 treatment periods were separated by a 3-month washout during which patients used on-demand therapy for bleeding. Clotting factor costs were quantitated in 2011 US dollars using the US price for US patients ($1.56 per unit) and the average price in Europe for European patients ($1.13 per unit). Results: Twenty-six subjects (median age 28.7 years; range, 2.8–62.8) completed both treatment periods and were evaluable per protocol for the cost-effectiveness analysis. The per-patient cost of 6 months of AICC prophylaxis was $493,633 compared with $205,549 for on-demand therapy. These totals were calculated by adding the per-patient cost of all clotting factors used during the prophylaxis period (AICC – $489,473 and recombinant activated factor VII [rFVIIa] – $4,160) and the on-demand period (AICC – $198,862473, rFVIIa – $6,272, and FVIII – $415). The incremental cost of AICC per bleed avoided during the prophylaxis period was $35,565, or $585/kg body weight for our somewhat older study population (mean body weight 60.8 kg). Sixteen of 26 subjects (62%) experienced a ≥50% reduction in bleeding events (“good responders”). For these subjects, the per-patient cost of 6 months of AICC prophylaxis was $499,453 as compared with $202,757 for on-demand therapy. The incremental cost-effectiveness ratio for the prophylaxis versus the on-demand period was $27,282 per bleeding event avoided ($449/kg body weight). In subjects with a Discussion: The magnitude of the difference in factor costs during the prophylaxis and on-demand treatment periods was proportional to the corresponding difference in bleeding rate. During the on-demand period, factor cost was reduced by 58% compared with the prophylaxis period, whereas during the prophylaxis period, bleeding events were reduced by 62% compared with the on-demand period. The incremental cost effectiveness ratio was more favorable in good responders and is attributable to the marked difference in prophylactic efficacy. These costs do not reflect the potential benefits of prophylaxis, including fewer hospitalizations and days lost from work or school and prevention of long term complications, such as worsening joint disease and disability. After taking into consideration the bleeding rate, the cost of on-demand therapy is consistent with those previously reported in hemophilia A patients without inhibitors. The incremental cost of AICC per bleed avoided during the prophylaxis period suggests that prophylaxis may will be most cost-effective in those who experience a good response in bleed reduction and in children, who may also derive additional benefit through the prevention of joint disease and long-term disability. Disclosures: Gringeri: Baxter: Speakers Bureau. Leissinger:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients >2 years with a history of high-titer inhibitors who were using bypassing therapy for the treatment of bleeding episodes. Subjects on or planning immune tolerance therapy were excluded as were patients with thrombocytopenia or other bleeding disorders. This randomized, crossover study compared 6 months of AICC prophylactically dosed at 85 U/kg ± 15% on 3 nonconsecutive days per week (Prophy period) to 6 months of on-demand therapy (OD period) (target dose for the treatment of bleeds: 85 U/kg ± 15%). The 2 study periods were separated by a 3-month washout, during which time patients used on-demand therapy for bleeding. Patients were randomized to initially enter either the 6-month Prophy period or the 6-month OD period. Each patient then crossed-over to the alternate study period after a 3-month wash-out. Results: Thirty-four subjects were randomized; 26 subjects completed both study periods and were deemed evaluable per protocol (PP) for efficacy analysis of the primary outcome to compare bleeds in each 6-month treatment period. Eight subjects did not complete the study (1 patient in the Prophy treatment arm and 1 patient in the post-prophylaxis washout period died of complications associated with underlying illness and bleeding, 1 patient experienced an allergic reaction to study drug, 1 patient was lost to follow-up, and 4 patients withdrew from study). All randomized subjects were evaluated for safety. In the PP group, mean patient age was 26.9 years (median: 24.7; range: 2.8–67.9). In the total randomized group, mean patient age was 27.1 years (median: 28.7; range: 2.8–67.9). Of the 26 subjects who completed the study PP, 14 were randomized to enter the Prophy period first and then crossed-over to the OD period, while 12 subjects were initially randomized to enter the OD period and then crossed-over to the Prophy period. For the PP analysis, total bleeds and joint bleeds requiring treatment during the 2 study periods were compared (p-value is for the Wilcoxon signed-rank test of difference between OD and Prophy periods). In addition, bleeds for the 6-month period prior to enrollment were recorded retrospectively on study entry. Efficacy: Both total bleeds and joint bleeds were significantly reduced during the Prophy period as compared with the OD period (p < .0001) Table 1. There was no difference in bleed event rates based on randomization sequence (ie, no carry-over effect was detected when the Prophy period preceded the OD period). Safety: A total of 38 serious adverse events (SAEs) occurred, none of which was thrombotic in nature. One SAE was deemed by the study safety monitor to be related to the study drug (an allergic reaction). Otherwise, treatment was safe and well tolerated. Conclusion: These results in patients with hemophilia A and inhibitors show that AICC, dosed at 85 IU/kg +/− 15% given on 3 non-consecutive days each week was associated with a 62% reduction in all bleeds and a 61% reduction in joint bleeds as compared with on-demand therapy. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: This is a report of a clinical trial using the Anti-Inhibitor Coagulant Complex, FEIBA, as prophylactic therapy to prevent bleeding in hemophilia patients with inhibitors. FEIBA is not currently licensed for use in prophylaxis in the US. Berntorp:Baxter: Consultancy, Honoraria, Research Funding. Negrier:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rocino:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Windyga:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gringeri:Baxter: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria.

Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. The FGF signal pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, among which the RAS/MAP kinase pathway is known to be predominant. Several studies have recently implicated the in vitro biological functions of FGFs for tissue regeneration. However, to obtain optimal outcomes in vivo, it is important to enhance the half-life of FGFs and their biological stability. Future applications of FGFs are expected when the biological functions of FGFs are potentiated through the appropriate use of delivery systems and scaffolds. This review will introduce the biology and cellular functions of FGFs and deal with the biomaterials based delivery systems and their current applications for the regeneration of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve tissues.