Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial

<div><p>Background</p><p>Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.</p><p>Methods</p><p>The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.</p><p>Results</p><p>Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.</p><p>Conclusions</p><p>The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01144637" target="_blank">NCT01144637</a></p></div

Critical heat flux around strongly-heated nanoparticles

We study heat transfer from a heated nanoparticle into surrounding fluid, using molecular dynamics simulations. We show that the fluid next to the nanoparticle can be heated well above its boiling point without a phase change. Under increasing nanoparticle temperature, the heat flux saturates which is in sharp contrast with the case of flat interfaces, where a critical heat flux is observed followed by development of a vapor layer and heat flux drop. These differences in heat transfer are explained by the curvature induced pressure close to the nanoparticle, which inhibits boiling. When the nanoparticle temperature is much larger than the critical fluid temperature, a very large temperature gradient develops resulting in close to ambient temperature just radius away from the particle surfac

RANCANG BANGUN ROBOT MOBIL DENGAN SISTEM NAVIGASI BERBASIS ODOMETRY MENGGUNAKAN ROTARY ENCODER

Dewasa ini penelitian mengenai dunia robotika berkembang begitu pesat. Temuan – temuan baru tersebut justru memaksa para peneliti untuk selalu mencari dan menemukan cara efektif agar robot yang dihasilkan lebih baik dari sebelumnya. Salah satunya berkaitan dengan proses pergerakan robot. Pada umumnya sistem navigasi robot memanfaatkan garis dan dinding yang tentunya membatasi pergerakan sebuah robot. Oleh karena itu metode odometry mulai dipakai untuk mengatasi keterbatasan tersebut. Pada prinsipnya metode odometry memperkirakan posisi relatif terhadap posisi awal dalam bernavigasi sehingga memungkinkan pergerakan sebuah robot lebih leluasa. Penelitian ini bertujuan untuk menerapkan suatu sistem navigasi robot yang baik dengan menggunakan metode odometry. Pembacaan jarak tersebut dilakukan oleh robot dengan menggunakan rotary encoder. Data yang diterima oleh sensor dalam rotary encoder akan diproses oleh mikrokontroler untuk mengatur pergerakan robot sesuai program yang telah ditanamkan. Hasil dari penelitian ini adalah posisi robot dengan koordinat akhir tidak selalu mengikuti koordinat akhir yang diberikan. Penyebabnya karena kurang tepatnya pemilihan konstanta pengubah sehingga berpengaruh pada tingkat kepresisian gerakan robot. Tetapi secara umum robot dapat bernavigasi odometry dengan cukup baik. Adapun faktor lain yang juga pengaruh terhadap hasil akhir pergerakan robot yakni adanya getaran pada robot serta permukaan lintasan. Keduanya sangat mempengaruhi pembacaan jumlah pulsa pada rotary encoder sehingga mempengaruhi juga hasil dari perhitungan odometry pada robot

Inpatient Antipsychotic Drug Use in 1998, 1993, and 1989

OBJECTIVE: Patterns of clinical use of antipsychotic agents have changed greatly in the past decade. The authors’ goal was to examine these patterns. METHOD: They evaluated medication use in all McLean Hospital inpatients treated with antipsychotic drugs during 3 months in 1998 (N=349) and compared the results with McLean Hospital inpatients treated with antipsychotics in 1993 (N=299) and Boston area inpatients in 1989 (N=50). RESULTS: The most commonly prescribed antipsychotics in 1998 were atypical agents; olanzapine was prescribed more often than risperidone or quetiapine, which were prescribed more often than other antipsychotics. Two or more antipsychotics were prescribed at some time during their hospitalization for 150 (43%) of the patients in 1998. The total discharge dose in chlorpromazine equivalents for the 349 patients for whom antipsychotics were prescribed at discharge was 371 mg/day, 29% higher than the total discharge dose for patients in 1993 and 46% greater than the dose in 1989. The dose of antipsychotics was greater for patients with psychotic illnesses than for those with affective illnesses. Higher doses were associated with greater clinical improvement, polypharmacotherapy, and younger patient age. CONCLUSIONS: Emerging trends toward higher total antipsychotic doses and polypharmacotherapy require critical assessments of cost-benefit relationships

Characterization of heterogeneity and spatial distribution of phases in complex solid dispersions by thermal analysis by structural characterization and X-ray micro computed tomography

Purpose: This study investigated the effect of drug-excipient miscibility on the heterogeneity and spatial distribution of phase separation in pharmaceutical solid dispersions at a micron-scale using two novel and complementary characterization techniques, thermal analysis by structural characterization (TASC) and X-ray micro-computed tomography (XCT) in conjunction with conventional characterization methods. Method: Complex dispersions containing felodipine, TPGS, PEG and PEO were prepared using hot melt extrusion-injection moulding. The phase separation behavior of the samples was characterized using TASC and XCT in conjunction with conventional thermal, microscopic and spectroscopic techniques. The in vitro drug release study was performed to demonstrate the impact of phase separation on dissolution of the dispersions. Results: The conventional characterization results indicated the phase separating nature of the carrier materials in the patches and the presence of crystalline drug in the patches with the highest drug loading (30% w/w). TASC and XCT where used to provide insight into the spatial configuration of the separate phases. TASC enabled assessment of the increased heterogeneity of the dispersions with increasing the drug loading. XCT allowed the visualization of the accumulation of phase separated (crystalline) drug clusters at the interface of air pockets in the patches with highest drug loading which led to poor dissolution performance. Semi-quantitative assessment of the phase separated drug clusters in the patches were attempted using XCT. Conclusion: TASC and XμCT can provide unique information regarding the phase separation behavior of solid dispersions which can be closely associated with important product quality indicators such as heterogeneity and microstructure

Fast and efficient microfluidic cell filter for isolation of circulating tumor cells from unprocessed whole blood of colorectal cancer patients

Liquid biopsy offers unique opportunities for low invasive diagnosis, real-time patient monitoring and treatment selection. The phenotypic and molecular profile of circulating tumor cells (CTCs) can provide key information about the biology of tumor cells, contributing to personalized therapy. CTC isolation is still challenging, mainly due to their heterogeneity and rarity. To overcome this limitation, a microfluidic chip for label-free isolation of CTCs from peripheral blood was developed. This device, the CROSS chip, captures CTCs based on their size and deformability with an efficiency of 70%. Using 2 chips, 7.5 ml of whole blood are processed in 47 minutes with high purity, as compared to similar technologies and assessed by in situ immunofluorescence. The CROSS chip performance was compared to the CellSearch system in a set of metastatic colorectal cancer patients, resulting in higher capture of DAPI+/CK+/CD45- CTCs in all individuals tested. Importantly, CTC enumeration by CROSS chip enabled stratification of patients with different prognosis. Lastly, cells isolated in the CROSS chip were lysed and further subjected to molecular characterization by droplet digital PCR, which revealed a mutation in the APC gene for most patient samples analyzed, confirming their colorectal origin and the versatility of the technology for downstream applications

High Prevalence of the Amphibian Chytrid Fungus (\u3cem\u3eBatrachochytrium dendrobatidis\u3c/em\u3e) across Multiple Taxa and Localities in the Highlands of Ethiopia

Surveys of the potentially lethal amphibian chytrid fungus (Batrachochytrium dendrobatidis - Bd) in Africa are patchy, especially in some regions of high species endemicity. We present results of the first Bd surveys of wild amphibians in Ethiopia, for two upland regions on either side of the Rift Valley: the Bale Mountains and the Kaffa region. Surveys were opportunistic so that robust interpretation of the data is limited. Utilizing diagnostic qPCR assays, 51 out of 120 frogs (14 species in 10 genera) tested positive for Bd at altitudes of 1,620–3,225 m, across all genera and species, and all but two localities. Prevalence was not significantly different between the two regions or two years (2008, 2009) sampled. Prevalence and parasite load was higher in species with aquatic tadpoles than those with terrestrial early life-history stages, but these differences were not significant. Impacts of Bd infection were not investigated, but no dead or dying frogs were found. This is the first report of Bd in Ethiopia, a country in which approximately 40% of its more than 60 species are endemic. Declines have occurred in some frog species in some localities in Ethiopia, and although habitat degradation is a likely cause in at least some places, further studies of Bd in Ethiopia are required to understand if it is a threat

Evolutionary Relationships of the Critically Endangered Frog \u3cem\u3eEricabatrachus baleensis\u3c/em\u3e Largen, 1991 with Notes on Incorporating Previously Unsampled Taxa into Large-scale Phylogenetic Analyses

Background: The phylogenetic relationships of many taxa remain poorly known because of a lack of appropriate data and/or analyses. Despite substantial recent advances, amphibian phylogeny remains poorly resolved in many instances. The phylogenetic relationships of the Ethiopian endemic monotypic genus Ericabatrachus has been addressed thus far only with phenotypic data and remains contentious. Results: We obtained fresh samples of the now rare and Critically Endangered Ericabatrachus baleensis and generated DNA sequences for two mitochondrial and four nuclear genes. Analyses of these new data using de novo and constrained-tree phylogenetic reconstructions strongly support a close relationship between Ericabatrachus and Petropedetes, and allow us to reject previously proposed alternative hypotheses of a close relationship with cacosternines or Phrynobatrachus. Conclusions: We discuss the implications of our results for the taxonomy, biogeography and conservation of E. baleensis, and suggest a two-tiered approach to the inclusion and analyses of new data in order to assess the phylogenetic relationships of previously unsampled taxa. Such approaches will be important in the future given the increasing availability of relevant mega-alignments and potential framework phylogenies

Long-term data for endemic frog genera reveal potential conservation crisis in the Bale Mountains, Ethiopia

Populations of many frogs have declined alarmingly in recent years, placing nearly one third of the >6,000 species under threat of extinction. Declines have been attributed largely to habitat loss, environmental degradation and/or infectious diseases such as chytridiomycosis. Many frogs undergo dramatic natural population fluctuations such that long-term data are required to determine population trends without undue influence of stochastic factors. We present long-term quantitative data (individuals encountered per person hour of searching) for four monotypic frog genera endemic to an Afromontane region of exceptional importance but growing conservation concern: one endemic to the Ethiopian highlands (Spinophrynoides osgoodi) and three endemic to the Bale Mountains (Altiphrynoides malcolmi, Balebreviceps hillmani, Ericabatrachus baleensis), collected during 15 field trips to the Bale Mountains between 1971 and 2009. Only a single confirmed sighting of S. osgoodi has been made since 1995. The other three species have also declined, at least locally. E. baleensis appears to have been extirpated at its type locality and at the same site B. hillmani has declined. These declines are in association with substantial habitat degradation caused by a growing human population. Chytrid fungus has been found on several frog species in Bale, although no dead or moribund frogs have been encountered. These results expose an urgent need for more amphibian surveys in the Bale Mountains. Additionally, we argue that detrimental human exploitation must be halted immediately in at least some parts of the Harenna Forest if a conservation crisis is to be averte

A Mycobacterium avium subsp. paratuberculosis relA deletion mutant and a 35 kDa major membrane protein elicit development of cytotoxic T lymphocytes with ability to kill intracellular bacteria

Efforts to develop live attenuated vaccines against Mycobacterium avium subspecies paratuberculosis (Map), using indirect methods to screen Map deletion mutants for potential efficacy, have not been successful. A reduction in the capacity to survive in macrophages has not predicted the ability of mutants to survive in vivo. Previous studies for screening of three deletion mutants in cattle and goats revealed one mutant, with a deletion in relA (ΔMap/relA), could not establish a persistent infection. Further studies, using antigen presenting cells (APC), blood dendritic cells and monocyte derived DC, pulsed with ΔMap/relA or a 35 kDa Map membrane protein (MMP) revealed a component of the response to ΔMap/relA was directed towards MMP. As reported herein, we developed a bacterium viability assay and cell culture assays for analysis and evaluation of cytotoxic T cells generated against ΔMap/relA or MMP. Analysis of the effector activity of responding cells revealed the reason ΔMap/relA could not establish a persistent infection was that vaccination elicited development of cytotoxic CD8 T cells (CTL) with the capacity to kill intracellular bacteria. We demonstrated the same CTL response could be elicited with two rounds of antigenic stimulation of APC pulsed with ΔMap/relA or MMP ex vivo. Cytotoxicity was mediated through the perforin granzyme B pathway. Finally, cognate recognition of peptides presented in context of MHC I and II molecules to CD4 and CD8 T cells is required for development of CTL