Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. INTRODUCTION This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. METHODS Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. RESULTS For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). CONCLUSIONS Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Local Heat Application for the Treatment of Buruli Ulcer: Results of a Phase II Open Label Single Center Non Comparative Clinical Trial.

BACKGROUND Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37°C. We investigated the safety and efficacy of a local heat application device based on phase change material. METHODS In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints 'absence of clinical BU specific features' or 'wound closure' within 6 months ("primary cure"), and 'absence of clinical recurrence within 24 month' ("definite cure"). RESULTS Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm(2). Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. CONCLUSIONS Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. CLINICAL TRIALS REGISTRATION ISRCT 72102977.

Open-label study of faldaprevir plus peginterferon and ribavirin in hepatitis C virus genotype 1-infected patients who failed placebo plus peginterferon and ribavirin.

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥800 000 IU/mL (80% vs 58%) and a non-CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir.

A 2-year multicentre, open-label, randomized, controlled study of growth hormone (Genotropin(®) ) treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN) Study

OBJECTIVE In Europe, growth hormone (GH) treatment for children born small for gestational age (SGA) can only be initiated after 4 years of age. However, younger age at treatment initiation is a predictor of favourable response. To assess the effect of GH treatment on early growth and cognitive functioning in very young (<30 months), short-stature children born SGA. DESIGN A 2-year, randomized controlled, multicentre study (NCT00627523; EGN study), in which patients received either GH treatment or no treatment for 24 months. PATIENTS Children aged 19-29 months diagnosed as SGA at birth, and for whom sufficient early growth data were available, were eligible. Patients were randomized (1:1) to GH treatment (Genotropin(®) , Pfizer Inc.) at a dose of 0·035 mg/kg/day by subcutaneous injection, or no treatment. MEASUREMENTS The primary objective was to assess the change from baseline in height standard deviation score (SDS) after 24 months of GH treatment. RESULTS Change from baseline in height SDS was significantly greater in the GH treatment vs control group at both month 12 (1·03 vs 0·14) and month 24 (1·63 vs 0·43; both P < 0·001). Growth velocity SDS was significantly higher in the GH treatment vs control group at 12 months (P < 0·001), but not at 24 months. There was no significant difference in mental or psychomotor development indices between the two groups. CONCLUSIONS GH treatment for 24 months in very young short-stature children born SGA resulted in a significant increase in height SDS compared with no treatment.

Optimization of a label-free biosensor vertically characterized based on a periodic lattice of high aspect ratio SU-8 nano-pillars with a simplified 2D theoretical model

We have recently demonstrated a biosensor based on a lattice of SU8 pillars on a 1 μm SiO2/Si wafer by measuring vertically reflectivity as a function of wavelength. The biodetection has been proven with the combination of Bovine Serum Albumin (BSA) protein and its antibody (antiBSA). A BSA layer is attached to the pillars; the biorecognition of antiBSA involves a shift in the reflectivity curve, related with the concentration of antiBSA. A detection limit in the order of 2 ng/ml is achieved for a rhombic lattice of pillars with a lattice parameter (a) of 800 nm, a height (h) of 420 nm and a diameter(d) of 200 nm. These results correlate with calculations using 3D-finite difference time domain method. A 2D simplified model is proposed, consisting of a multilayer model where the pillars are turned into a 420 nm layer with an effective refractive index obtained by using Beam Propagation Method (BPM) algorithm. Results provided by this model are in good correlation with experimental data, reaching a reduction in time from one day to 15 minutes, giving a fast but accurate tool to optimize the design and maximizing sensitivity, and allows analyzing the influence of different variables (diameter, height and lattice parameter). Sensitivity is obtained for a variety of configurations, reaching a limit of detection under 1 ng/ml. Optimum design is not only chosen because of its sensitivity but also its feasibility, both from fabrication (limited by aspect ratio and proximity of the pillars) and fluidic point of view. (© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Relación óptima de metionina+cistina/lisina digestibles en gallinas isa Brown de 34 a 42 semanas de edad.

Los trabajos previos en los que se han estudiado las recomendaciones de metionina+cistina para gallinas ponedoras son muy numerosos, pero los resultados obtenidos presentan una gran variabilidad y, en algunos casos, son contradictorios. Esta variabilidad se explica por las condiciones en las que se ha realizado el estudio, la edad de las gallinas, la genética y el parámetro a optimizar. En este sentido, Novak et al. (2004) observaron que las necesidades totales de metionina+cistina eran mayores para maximizar el peso del huevo que para optimizar la producción de huevos o la eficacia alimenticia. Estas diferencias fueron menos importantes entre las 20 y 43 semanas (8%), que de las 44 a las 63 semanas de edad (16%). Además, las recomendaciones para optimizar la producción y el peso del huevo fueron un 17% y 11% mayores, respectivamente, en el primer periodo con respecto al segundo. Por el contrario, Waldroup y Hellwig (1995) encontraron que las necesidades totales de metionina+cistina para optimizar la producción y masa de huevo fueron más elevadas (12 y 10%, respectivamente) de 51 a 71 semanas de edad que de 25 a 45. Cuando las recomendaciones se expresan en unidades digestibles, el rango de necesidades de metionina+cistina digestibles con respecto a lisina digestible varía desde un 81 a un 107% (81%: Coon and Zhang, 1999; 90%: FEDNA, 2008; 91%: Rostagno et al., 2005; 93%: CVB, 1996; 94%: Bregendahl et al., 2008; 99%: Brumano et al., 2010a; 100%: Cupertino et al., 2009; Brumano et al., 2010a; 101%: Brumano et al., 2010b; 107%: Schmidt et al., 2009). Como consecuencia de esta alta variabilidad, es necesario seguir investigando sobre cuál sería el ratio óptimo metionina+cistina/lisina digestible para optimizar los rendimientos de gallinas ponedoras. Por tanto, el objetivo de este trabajo es determinar las necesidades óptimas de metionina+cistina digestibles con respecto a lisina digestible de gallinas Isa Brown desde las 34 a las 42 semanas de edad

Efficient design and optimization of bio-photonic sensing cells (BICELLs) for label free biosensing

In previous works we demonstrated the benefits of using micro–nano patterning materials to be used as bio-photonic sensing cells (BICELLs), referred as micro–nano photonic structures having immobilized bioreceptors on its surface with the capability of recognizing the molecular binding by optical transduction. Gestrinone/anti-gestrinone and BSA/anti-BSA pairs were proven under different optical configurations to experimentally validate the biosensing capability of these bio-sensitive photonic architectures. Moreover, Three-Dimensional Finite Difference Time Domain (FDTD) models were employed for simulating the optical response of these structures. For this article, we have developed an effective analytical simulation methodology capable of simulating complex biophotonic sensing architectures. This simulation method has been tested and compared with previous experimental results and FDTD models. Moreover, this effective simulation methodology can be used for efficiently design and optimize any structure as BICELL. In particular for this article, six different BICELL's types have been optimized. To carry out this optimization we have considered three figures of merit: optical sensitivity, Q-factor and signal amplitude. The final objective of this paper is not only validating a suitable and efficient optical simulation methodology but also demonstrating the capability of this method for analyzing the performance of a given number of BICELLs for label-free biosensing.

Biophotonic Sensing Cells (BICELLs) for label-free biosensing

Label free immunoassay sector is a ferment of activity, experiencing rapid growth as new technologies come forward and achieve acceptance. The landscape is changing in a “bottom up” approach, as individual companies promote individual technologies and find a market for them. Therefore, each of the companies operating in the label-free immunoassay sector offers a technology that is in some way unique and proprietary. However, no many technologies based on Label-free technology are currently in the market for PoC and High Throughput Screening (HTS), where mature labeled technologies have taken the market.

Characterization of the Performance of Optical Label-Free Biosensors

The field of optical label free biosensors has become a topic of interest during past years, with devices based on the detection of angular or wavelength shift of optical modes [1]. Common parameters to characterize their performance are the Limit of Detection (LOD, defined as the minimum change of refractive index upon the sensing surface that the device is able to detect, and also BioLOD, which represents the minimum amount of target analyte accurately resolved by the system; with units of concentration (common un its are p pm, ng/ml, or nM). LOD gives a first value to compare different biosensors, and is obtained both theoretically (using photonic calculation tools), and experimentally,covering the sensing area with fluids of different refractive indexes.