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•VSV-EBOV is the most advanced EBOV vaccine candidate in clinical development.•VSV-EBOV induces a shared signature of circulating miRNAs in vaccinees.•Early miRNA expression dynamics correlate with vaccine-induced immune responses.•Circulating miRNAs might serve as biomarkers for vaccine-induced immunogenicity.•The data provide novel insight into molecular mechanisms induced by VSV-EBOV. VSV-EBOV is a replication-competent Ebola virus (EBOV) vaccine, which was tested in clinical trials as response to the Ebola virus disease (EVD) outbreak 2013–2016. It is the most advanced EBOV candidate currently in the licensure process. The experimental vaccine was again administered as response to outbreaks in the Democratic Republic of Congo. However, underlying molecular mechanisms that convey protection remain incompletely understood. MicroRNAs (miRNAs) are known key regulators that influence gene expression on a post-transcriptional level. The miRNA-mediated control has emerged as a critical regulatory principle in the immune system, which strongly influences the balance of innate and adaptive immune responses by modulation of signaling pathways critical for differentiation of immune cells. We investigated expression levels of circulating miRNAs (c-miRNAs) in plasma from healthy vaccinees, as they may reflect cellular dynamics following VSV-EBOV immunization and additionally may serve as potential biomarkers for vaccine efficacy. As part of the WHO-led VEBCON consortium, we investigated safety and immunogenicity of VSV-EBOV in a phase I trial. A comprehensive analysis of expression levels on c-miRNAs from plasma samples following VSV-EBOV immunization (day 0, 1, 3 post vaccination) was conducted using RT-qPCR assays. Potential biological relevance was assessed using in silico analyses. Additionally, we correlated dynamics of miRNA expressions with our previously reported data on vaccine-induced antibody and cytokine responses and finally evaluated the prognostic power by generating ROC curves. We identified four promising miRNAs (hsa-miR-146a, hsa-miR-126, hsa-miR-199a, hsa-miR-484), showing a strong association with adaptive immune responses, exhibited favourable prognostic performance and are implicated in immunology-related functions. Our results provide evidence that miRNAs may serve as useful biomarkers for prediction of vaccine-induced immunogenicity. Furthermore, our unique data set provides insight into molecular mechanisms that underlie VSV-EBOV-mediated protective immune responses, which may help to decipher VSV-EBOV immune signature and accelerate strategic vaccine design or personalized approaches.

This paper describes the detailed analysis of a multi-stage canned motor pump by means of CFD (computational fluid dynamics) simulations to find the main losses and show optimization potential of the hydraulic parts. In a first step, the numerical model was successively generated including all details like impellers, guide vanes (GV), return vanes (RV), gaps and pressure relief holes as well as the hydraulically coupled rotor of the drive. Simulations were carried out with the commercial CFD package ANSYS CFX 17.1 in stationary and transient way where mainly structured grids were used with a final model of the existing pump consisting of more than 35 mio. nodes. The behavior of the components was analyzed in detail and additionally the CFD-simulations were validated with model tests. Based on the loss analysis, a 2-stage optimization procedure was performed by combining manual engineering with automated optimization to establish the desired objectives and validated with the full numerical model. The simulations predict a huge efficiency increase from part load up to the best efficiency point (BEP) with respect to all given limitations (identical head curve, suction behavior and dimensions) and were then validated on the test rig where they have proven their high accuracy and reliability.

In this set of four phase 1 studies, a recombinant vesicular stomatitis virus (rVSV)–based Ebola vaccine induced Ebola virus–specific immune responses and was associated with side effects that included fever and transient arthritis, rash, and VSV viremia. In August 2014, after the outbreak of Ebola virus disease was declared a public health emergency of international concern by the World Health Organization (WHO), the Canadian government donated 800 vials of the replication-competent recombinant vesicular stomatitis virus (rVSV)–vectored Zaire ebolavirus (rVSV-ZEBOV) candidate vaccine to the WHO. The VSV Ebola Consortium (VEBCON) was created under the auspices of the WHO to initiate phase 1 studies to facilitate rapid progression to phase 2 and 3 trials in affected countries. 1 Live replicating viral vaccines elicit humoral and cellular immune responses against viral pathogens. 2 , 3 A single injection of 10 million plaque-forming units . . .

In response to the Ebola virus (EBOV) crisis of 2013–2016, a recombinant vesicular stomatitis virus (VSV)–based EBOV vaccine was clinically tested (NCT02283099). A single-dose regimen of VSV-EBOV revealed a safe and immunogenic profile and demonstrated clinical efficacy. While EBOV-specific immune responses to this candidate vaccine have previously been investigated, limited human data on immunity to the VSV vector are available. Within the scope of a phase 1 study, we performed a comprehensive longitudinal analysis of adaptive immune responses to internal VSV proteins following VSV-EBOV immunization. While no preexisting immunity to the vector was observed, more than one-third of subjects developed VSV-specific cytotoxic T-lymphocyte responses and antibodies.

MERS-CoV is a respiratory pathogen with a case-fatality rate of 36%, and for which no vaccines are currently licensed. MVA-MERS-S is a candidate vaccine based on recombinant modified vaccinia virus Ankara (MVA). In this study, the safety, immunogenicity, and optimal dose schedule of MVA-MERS-S was assessed in individuals with previous exposure to SARS-CoV-2 infections and vaccines. We conducted a multicentre, double-blind, randomised controlled phase 1b clinical trial at two university medical centres in Germany and the Netherlands. Healthy volunteers aged 18–55 years were assigned by computer randomisation to receive three intramuscular injections of 107 or 108 plaque-forming units (PFU) of MVA-MERS-S, with two treatment groups each of either 28-day or 56-day intervals between the initial two doses, and one control arm that received only placebo, at a ratio of 2:2:2:2:1. The third dose was given after 224 days. The sponsor, clinical and laboratory staff, and participants were masked to both vaccine dose and dosing interval. The primary outcome was safety, assessed in the all participants who had received at least one injection; daily solicited vaccine reactions were recorded after each dose for 7 days, unsolicited adverse events for 28 days, and serious adverse events throughout the study. The secondary outcome was humoral immunogenicity, measured with vaccine-induced geometric mean antibody concentrations and seroconversion rates, analysed in all participants who received at least three allocated treatments. This study is registered at ClinicalTrials.gov (NCT04119440) and is completed. Between 26 July, 2021, and 3 March, 2022, 244 volunteers were screened, 177 of whom were eligible and 140 were randomly assigned either to the 28-day 107 PFU group (n=32), 56-day 107 PFU group (n=31), 28-day 108 PFU group (n=31), 56-day 108 PFU group (n=30), or placebo group (n=16). In total, 178 doses were administered of 107 PFU of MVA-MERS-S, 174 of 108 PFU, and 164 doses of placebo, and 139 participants received at least one injection. 73 (53%) were female and 66 (48%) were male. No serious vaccine-related adverse events occurred. Solicited local reactions were mild in 288 (93%, 95% CI 90–96) of 309 reports and consisted primarily of pain or tenderness. Pain or tenderness (of any severity) occurred after 69 (39%, 32–46) of 178 107 PFU injections, 138 (79%; 73–85) of 174 108 PFU injections, and 18 (11%; 7–11) of 164 placebo injections. Of 595 reported solicited systemic reactions, 479 (81%, 77–83) were graded as mild. Systemic reactions of any grade occurred after 77 (43%; 36–51) 107 PFU injections, 102 (59%; 51–66) 108 PFU injections, and 67 (41%; 34–49) of 164 placebo injections. At 28 days after the second dose, MERS-CoV neutralising antibodies were highest for participants assigned to 56-day 108 PFU, with geometric mean ratios of 7·2 (95% CI 3·9–13·3) for the 56-day 108 PFU group versus the 28-day 108 PFU group (p<0·0001), 3·9 (2·1–7·2) for the 56-day 108 PFU group versus the 56-day 107 PFU group (p=0·0031), and 5·4 (2·9–10·0) for the 56-day 108 PFU group versus the 28-day 107 PFU group (p=0·0003). MVA-MERS-S was safe and immunogenic in individuals with previous and concurrent SARS-CoV-2 exposure. The second vaccination with the 108 PFU dose of MVA-MERS-S elicited a stronger humoral immune response when administered 56 days after the first dose than a 28-day interval. Further studies are needed to verify these findings in groups at risk for MERS-CoV exposure, and at risk of severe disease, including older individuals and those with relevant comorbidities. Coalition for Epidemic Preparedness Innovations, the German Centre for Infection Research, and the German Research Foundation.

PurposeTo test if an encircling band improves outcomes in vitrectomy for pseudophakic retinal detachment (PRD) with inferior or with multiple (4 or more) breaks.MethodsSubgroup analysis of a prospective randomized controlled multicenter trial in patients with uncomplicated PRD assigned either to 20 G vitrectomy plus encircling band (group E1), or 20 G vitrectomy without any buckle (group C), or 23/25 G vitrectomy without any buckle (group E2). The primary endpoint was defined as no indication for any retina reattaching procedure during the review period of 6 months. One hundred out of 257 patients were identified with inferior breaks and 63 patients had 4 or more breaks.ResultsIn patients with retinal breaks between 5:00 and 7:00, treatment was successful in 77.4% (24/31, treatment arm E1) versus 57.1% (16/28, treatment arm C) (p = 0.301, odds ratio (OR) 1.83, 95% confidence interval (CI) 0.48 to 7.17). In patients with multiple breaks, success rates were 68.2% (15/22, E1) versus. 72.4% (21/29, C, p = 0.46, OR 0.52, CI 0.08–3.65).ConclusionCombining an encircling band with vitrectomy in patients with pseudophakic retinal detachment and inferior or multiple breaks does not significantly improve primary anatomical success in comparison to treatment with 20 G or 23/25 G vitrectomy alone.

Macular hole surgery including vitrectomy and peeling of epiretinal membranes and the internal limiting membrane (ILM) has become a standard procedure in retinal surgery. Poor visualization of the ILM is an obstacle for successful surgery. Recently, indocyanine green (ICG) has been reported to be a helpful intraocular substance in identifying these membranes. Eighteen eyes with macular holes stages 2-4 were included. Intraoperatively, the ILM was stained with three drops of 1:9-diluted ICG. After 1 min incubation, the vitreous cavity was rinsed with Ringer's lactate solution, and the ILM was peeled. Autologous thrombocytes were applied to the macular hole and the eye was endotamponaded with 20% SF-6 gas. Preoperatively, 6 weeks postoperatively, and in 3-month intervals thereafter, visual acuity, fundus photographs, scanning laser ophthalmoscope imaging, and Humphrey 24-2 static perimetry was performed. Intraoperatively, the ILM could be nicely visualized by ICG, which allowed easier and less traumatic peeling. At 6 weeks follow-up, visual acuity had improved in 14 of 18 patients, and the macular hole was closed 6 weeks after surgery. Scanning laser imaging revealed a strong signal. During prolonged follow-up, visual acuity declined due to cataract formation. ICG as an intraocular tool for staining of the ILM is helpful in macular hole surgery. We observed no negative effects on retinal function, but patients should be followed.

In this randomized trial comparing ACGME duty-hour policies with more flexible policies for surgical residents, the flexible policies resulted in noninferior patient outcomes and no significant difference in residents' satisfaction with overall well-being and education quality. In response to concerns about patient safety and resident well-being, the Accreditation Council for Graduate Medical Education (ACGME) introduced national regulations in 2003 that limited resident duty periods to 80 hours per week, capped overnight shift lengths, and mandated minimum time off between shifts. 1 , 2 Concerns persisted, 3 and in 2011, the ACGME implemented further restrictions to shorten maximum shift lengths for interns and increase time off after overnight on-call duty for residents. 1 , 4 , 5 Although most observers agree that some duty-hour regulation was necessary, critics cite a weak evidence base for the 2003 and 2011 reforms. 3 , 6 , 7 Several retrospective . . .