Multinational Trials - Recommendations on the Translations Required, Approaches to Using the Same Language in Different Countries, and the Approaches to Support Pooling the Data: The ISPOR Patient-Reported Outcomes Translation and Linguistic Validation Good Research Practices Task Force Report

Multinational Trials - Recommendations on the Translations Required, Approaches to Using the Same Language in Different Countries, and the Approaches to Support Pooling the Data: The ISPOR Patient-Reported Outcomes Translation and Linguistic Validation Good Research Practices Task Force Report Abstract. Objectives: With the internationalization of clinical trial programs, there is an increased need to translate and culturally adapt patient-reported outcome (PRO) measures. Although guidelines for good practices in translation and linguistic validation are available, the ISPOR Patient-Reported Outcomes Translation and Linguistic Validation Task Force identified a number of areas where they felt that further discussion around methods and best practices would be beneficial. The areas identified by the team were as follows: 1) the selection of the languages required for multinational trials; 2) the approaches suggested when the same language is required across two or more countries; and 3) the assessment of measurement equivalence to support the aggregation of data from different countries. Methods: The task force addressed these three areas, reviewed the available literature, and had multiple discussions to develop this report. Results: Decision aid tools have also been developed and presented for the selection of languages and the approaches suggested for the use of the same language in different countries. Conclusion: It is hoped that this report and the decision tools proposed will assist those involved with multinational trials to 1) decide on the translations required for each country; 2) choose the approach to use when the same language is spoken in more than one country; and 3) choose methods to gather evidence to support the pooling of data collected using different language versions of the same tool

Biocompatibility and Biodegradation Studies of Subconjunctival Implants in Rabbit Eyes

Sustained ocular drug delivery is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Biodegradable subconjunctival implants with controlled drug release may circumvent these two problems. In our study, two microfilms (poly [d,l-lactide-co-glycolide] PLGA and poly[d,l-lactide-co-caprolactone] PLC were developed and evaluated for their degradation behavior in vitro and in vivo. We also evaluated the biocompatibility of both microfilms. Eighteen eyes (9 rabbits) were surgically implanted with one type of microfilm in each eye. Serial anterior-segment optical coherence tomography (AS-OCT) scans together with serial slit-lamp microscopy allowed us to measure thickness and cross-sectional area of the microfilms. In vitro studies revealed bulk degradation kinetics for both microfilms, while in vivo studies demonstrated surface erosion kinetics. Serial slit-lamp microscopy revealed no significant inflammation or vascularization in both types of implants (mean increase in vascularity grade PLGA50/50 12±0.5% vs. PLC70/30 15±0.6%; P = 0.91) over a period of 6 months. Histology, immunohistochemistry and immuno-fluorescence also revealed no significant inflammatory reaction from either of the microfilms, which confirmed that both microfilms are biocompatible. The duration of the drug delivery can be tailored by selecting the materials, which have different degradation kinetics, to suit the desired clinical therapeutic application

Nanoparticle-based bioactive agent release systems for bone and cartilage tissue engineering

The inability to deliver bioactive agents locally in a transient but sustained manner is one of the challenges on the development of bio-functionalized scaffolds for tissue engineering (TE) and regenerative medicine. The mode of release is especially relevant when the bioactive agent is a growth factor (GF), because the dose and the spatiotemporal release of such agents at the site of injury are crucial to achieve a successful outcome. Strategies that combine scaffolds and drug delivery systems have the potential to provide more effective tissue regeneration relative to current therapies. Nanoparticles (NPs) can protect the bioactive agents, control its profile, decrease the occurrence and severity of side effects and deliver the bioactive agent to the target cells maximizing its effect. Scaffolds containing NPs loaded with bioactive agents can be used for their local delivery, enabling site-specific pharmacological effects such as the induction of cell proliferation and differentiation, and, consequently, neo-tissue formation. This review aims to describe the concept of combining NPs with scaffolds, and the current efforts aiming to develop highly multi-functional bioactive agent release systems, with the emphasis on their application in TE of connective tissues.POLARIS (REGPOT-CT2012-316331-POLARIS), RL3 – TECT – NORTE-01-0124-FEDER-000020, co-financed by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF), the OsteoGraphy (PTDC/EME-MFE/2008) and MaxBone (PTDC/SAU-ENB/115179/2009) project

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

An Investigation of Temporal and Spatial Variability of Egg Production in the Gulf of Mexico: A Study of Six Calanoid Copepods

A study was conducted in the Gulf of Mexico to investigate the spatial and temporal variability in secondary production of western Florida waters. The area of interest was divided into four regions representing shelf and oceanic environments of the northern and southern Gulf waters. Physical parameters measured at the same locations in each region were examined in the spring (March 1992) and fall (October 1992). Secondary production of copepods was estimated indirectly from preserved plankton samples. Six copepod species chosen for this study were: Centropages velifurcatus, Eucalanus monachus, Rhincalanus cornutus, Temora stylifera, Temora turbinata and Undinula vulgaris. Adult (C6) female copepods were stained with celestine blue to examine their gonads to determine their level of oocyte maturation. A potential egg production index (PEPI) was determined for each female using the number of mature eggs multiplied by the state of gonad maturity, as determined by Runge (1985). The average PEPI was calculated for each species in both spring and fall in each of the four shelf regions. Centropages velifurcatus, Temora stylifera, and Undinula vulgaris appeared to be in an advanced state of reproductive readiness at all locations at which they were sampled. The remaining three species, Eucalanus monachus, Rhincalanus cornutus, and Temora turbinata, were immature. A regression analysis of physical parameters showed a significant correlation (P\u3c0.05) with fluorescence as an indicator of potential food. The results of a MANOVA for season, species, and location against PEPI showed U. vulgaris as the most productive and R. cornutus as the least. Mean PEPI differed significantly between spring and fall for all species. Southern oceanic location C was the least productive of the four regions sampled (P\u3c0.05). The remaining three regions exhibited no significant differences in their average potential egg production indexes

A Filterable Lytic Agent Obtained from a Red Tide Bloom That Caused Lysis of \u3cem\u3eKarenia brevis (Gymnodinum breve)\u3c/em\u3e Cultures

A filterable lytic agent (FLA) was obtained from seawater in the southeastern Gulf of Mexico during a red tide bloom that caused lysis of Karenia brevis (formerly Gymnodinium breve) Piney Island. This agent was obtained from \u3c 0.2 μm filtrates that were concentrated by ultrafiltration using a 100 kDa filter. The FLA was propagated by passage on K. brevis cultures, and the filtered supernatants of such cultures resulted in K. brevis lysis when added to such cultures. The lytic activity was lost upon heating to 65°C or by 0.02 μm filtration. Epifluorescence and transmission electron microscopy (TEM) of supernatants of K. brevis cultures treated with the lytic agent indicated a high abundance of viral particles (4 x 109 to 7 x 109 virus-like particles [VLPs] ml-1) compared to control cultures (~107 ml-1). However, viral particles were seldom found in TEM photomicrograph thin sections of lysing K. brevis cells. Although a virus specific for K. brevis may have been the FLA, other explanations such as filterable bacteria or bacteriophages specific for bacteria associated with the K. brevis cultures cannot be discounted

The Organic diamond disk (ODD) versus brazed diamond disk (BDD) for chemical mechanical planarization

Diamond pad conditioners can determine the efficiency of CMP processes and the quality of polished wafers. Conventional pad conditioners are made with metal bonded diamond grits, such as brazed diamond disks (BDD). In this research, we evaluated pad conditioners manufactured with polymer bonded diamond grits known as organic diamond disk (ODD). The latter is not only metal free that avoids the possible contamination of the dissolved metal in slurry, but also its diamond tips are better leveled by a reverse casting technology that has never been adapted in making metallized diamond disks. ODD and BDD were fabricated in the form of dressing bars and used in the CMP for polishing tungsten slugs that bridged circuits at different levels of IC wafers. The results demonstrated that ODD dressed pads generated lower defect counts on IC wafers than BDD. Although the dressing rate of pads may be slower for ODD, the removal rate of wafers can be actually higher. Hence, by using ODD in mass production, not only the longevities of both disks and pads may be increased, but also the throughput of IC wafers produced during CMP. Finally, ODD is made metal free and there is nothing that is soluble in slurry, so in-situ CMP can be adapted to further boost of manufacturing throughput