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Chikungunya is an emerging arthropod-borne disease that has spread from tropical endemic areas to more temperate climates of the USA and Europe. However, no specific treatment or preventive measure is yet available. We aimed to investigate the immunogenicity and safety of a live recombinant measles-virus-based chikungunya vaccine. We did a randomised, double-blind, placebo-controlled, active-comparator, phase 1, dose-escalation study at one centre in Vienna, Austria. Healthy men and women aged 18–45 years with no comorbidities were randomly assigned, by computer-generated block randomisation (block size of 14), to receive either one of three escalating doses of the measles-virus-based candidate vaccine (low dose [1·5 × 104 median tissue culture infection doses (TCID50) per 0·05 mL], medium dose [7·5 × 104 TCID50 per 0·25 mL], or high dose [3·0 × 105 TCID50 per 1·0 mL]), or the active comparator—Priorix. Participants were additionally block-randomised to receive a booster injection on either day 28 or day 90 after the first vaccination. Participants and study investigators were masked to group allocation. The primary endpoint was the presence of neutralising anti-chikungunya antibodies on day 28, as assessed by 50% plaque reduction neutralisation test. Analysis was by intention to treat and per protocol. This trial is registered with EudraCT, number 2013-001084-23. Between Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) of the measles-virus-based candidate vaccine, or Priorix (n=6), of whom 36 participants (86%; n=9, n=12, n=10, n=5, respectively) were included in the per-protocol population. The candidate vaccine raised neutralising antibodies in all dose cohorts after one immunisation, with seroconversion rates of 44% (n=4) in the low-dose group, 92% (n=11) in the medium-dose group, and 90% (n=10) in the high-dose group. The immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded. The live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of anti-vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings. Themis Bioscience GmBH.

•A robust purification process for larger viruses such the Paramyxoviridae family, like measles.•The order of process steps influences measles virus purity and titer.•Process consists of restricted access chromatography and ultrafiltration.•Process is suited for operation in a functional closed system under aseptic conditions.•Scaleability to pilot scale level is proven. Purification of very large and complex, enveloped viruses, such as measles virus is very challenging, it must be performed in a closed system because the final product cannot be sterile filtered and often loss of virus titer and poor product purity has been observed. We developed a purification process where the clarified and endonuclease treated culture supernatant is loaded on a restricted access chromatography medium where small impurities are bound and the virus is collected in the flow-through, which is then concentrated, and buffer exchanged by ultra/diafiltration. Up to 98.5% of host cell proteins could be captured by direct loading of clarified and endonuclease treated cell culture supernatant. Reproducible process performance and scalability of the chromatography step were demonstrated from small to pilot scale, including loading volumes from 50 mL up to 9 L. A 10-fold virus concentration was achieved by the ultrafiltration using a 100 kDa flat-sheet membrane. The order of individual process steps had a large impact on the virus infectivity and total process yields. The developed process maintained virus infectivity and is twice as fast as the traditional process train, where concentration is performed before loading on the chromatography column. Capturing impurities by the restricted access medium makes it a platform purification process with a high flexibility, which can be easily and quickly adapted to other vectors based on the measles virus vector platform.

Lassa fever is a substantial health burden in west Africa. We evaluated the safety, tolerability, and immunogenicity of a recombinant, live-attenuated, measles-vectored Lassa fever vaccine candidate (MV-LASV). This first-in-human phase 1 trial—consisting of an open-label dose-escalation stage and an observer-blinded, randomised, placebo-controlled treatment stage—was conducted at a single site at the University of Antwerp, Antwerp, Belgium, and involved healthy adults aged 18–55 years. Participants in the dose-escalation stage were sequentially assigned to a low-dose group (two intramuscular doses of MV-LASV at 2 × 104 times the median tissue culture infectious dose) or a high-dose group (two doses at 1 × 105 times the median tissue culture infectious dose). Participants in the double-blinded treatment stage were randomly assigned in a 2:2:1 ratio to receive low dose, high dose, or placebo. The primary endpoint was the rate of solicited and unsolicited adverse events up to study day 56 and was assessed in all participants who received at least one dose of investigational product. The trial is registered with ClinicalTrials.gov, NCT04055454, and the European Union Drug Regulating Authorities Clinical Trials Database, 2018-003647-40, and is complete. Between Sept 26, 2019, and Jan 20, 2020, 60 participants were enrolled and assigned to receive placebo (n=12) or MV-LASV (n=48). All 60 participants received at least one study treatment. Most adverse events occurred during the treatment phase, and frequencies of total solicited or unsolicited adverse events were similar between treatment groups, with 96% of participants in the low-dose group, 100% of those in the high-dose group, and 92% of those in the placebo group having any solicited adverse event (p=0·6751) and 76% of those in the low-dose group, 70% of those in the high-dose group, and 100% of those in the placebo group having any unsolicited adverse event (p=0·1047). The only significant difference related to local solicited adverse events, with higher frequencies observed in groups receiving MV-LASV (24 [96%] of 25 participants in the low-dose group; all 23 [100%] participants in the high-dose group) than in the placebo group (6 [50%] of 12 participants; p=0·0001, Fisher-Freeman-Halton test). Adverse events were mostly of mild or moderate severity, and no serious adverse events were observed. MV-LASV also induced substantial concentrations of LASV-specific IgG (geometric mean titre 62·9 EU/ml in the low-dose group and 145·9 EU/ml in the high-dose group on day 42). MV-LASV showed an acceptable safety and tolerability profile, and immunogenicity seemed to be unaffected by pre-existing immunity against the vector. MV-LASV is therefore a promising candidate for further development. Coalition for Epidemic Preparedness Innovations.

BackgroundLassa fever is a substantial health burden in west Africa. We evaluated the safety, tolerability, and immunogenicity of a recombinant, live-attenuated, measles-vectored Lassa fever vaccine candidate (MV-LASV).MethodsThis first-in-human phase 1 trial—consisting of an open-label dose-escalation stage and an observer-blinded, randomised, placebo-controlled treatment stage—was conducted at a single site at the University of Antwerp, Antwerp, Belgium, and involved healthy adults aged 18–55 years. Participants in the dose-escalation stage were sequentially assigned to a low-dose group (two intramuscular doses of MV-LASV at 2 × 104 times the median tissue culture infectious dose) or a high-dose group (two doses at 1 × 105 times the median tissue culture infectious dose). Participants in the double-blinded treatment stage were randomly assigned in a 2:2:1 ratio to receive low dose, high dose, or placebo. The primary endpoint was the rate of solicited and unsolicited adverse events up to study day 56 and was assessed in all participants who received at least one dose of investigational product. The trial is registered with ClinicalTrials.gov, NCT04055454, and the European Union Drug Regulating Authorities Clinical Trials Database, 2018-003647-40, and is complete.FindingsBetween Sept 26, 2019, and Jan 20, 2020, 60 participants were enrolled and assigned to receive placebo (n=12) or MV-LASV (n=48). All 60 participants received at least one study treatment. Most adverse events occurred during the treatment phase, and frequencies of total solicited or unsolicited adverse events were similar between treatment groups, with 96% of participants in the low-dose group, 100% of those in the high-dose group, and 92% of those in the placebo group having any solicited adverse event (p=0·6751) and 76% of those in the low-dose group, 70% of those in the high-dose group, and 100% of those in the placebo group having any unsolicited adverse event (p=0·1047). The only significant difference related to local solicited adverse events, with higher frequencies observed in groups receiving MV-LASV (24 [96%] of 25 participants in the low-dose group; all 23 [100%] participants in the high-dose group) than in the placebo group (6 [50%] of 12 participants; p=0·0001, Fisher-Freeman-Halton test). Adverse events were mostly of mild or moderate severity, and no serious adverse events were observed. MV-LASV also induced substantial concentrations of LASV-specific IgG (geometric mean titre 62·9 EU/ml in the low-dose group and 145·9 EU/ml in the high-dose group on day 42).InterpretationMV-LASV showed an acceptable safety and tolerability profile, and immunogenicity seemed to be unaffected by pre-existing immunity against the vector. MV-LASV is therefore a promising candidate for further development.FundingCoalition for Epidemic Preparedness Innovations.

Atomic-scale investigations of metal oxide surfaces exposed to aqueous environments are vital to understand degradation phenomena (e.g. dissolution and corrosion) as well as the performance of these materials in applications. Here, we utilize a new experimental setup for the UHV-compatible dosing of liquids to explore the stability of the Fe3O4(001)-c(2x2) surface following exposure to liquid and ambient pressure water. X-ray photoelectron spectroscopy (XPS) and low energy electron diffraction (LEED) data show that extensive hydroxylation causes the surface to revert to a bulk-like (1x1) termination. However, scanning tunnelling microscopy (STM) images reveal a more complex situation, with the slow growth of an oxyhydroxide phase, which ultimately saturates at approximately 40% coverage. We conclude that the new material contains OH groups from dissociated water coordinated to Fe cations extracted from subsurface layers, and that the surface passivates once the surface oxygen lattice is saturated with H because no further dissociation can take place. The resemblance of the STM images to those acquired in previous electrochemical STM (EC-STM) studies lead us to believe a similar structure exists at the solid-electrolyte interface during immersion at pH 7.

The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We find that placebo vs. control treatments induce small, widespread reductions in pain-related activity, particularly in regions belonging to ventral attention (including mid-insula) and somatomotor networks (including posterior insula). Behavioral placebo analgesia correlates with reduced pain-related activity in these networks and the thalamus, habenula, mid-cingulate, and supplementary motor area. Placebo-associated activity increases occur mainly in frontoparietal regions, with high between-study heterogeneity. We conclude that placebo treatments affect pain-related activity in multiple brain areas, which may reflect changes in nociception and/or other affective and decision-making processes surrounding pain. Between-study heterogeneity suggests that placebo analgesia is a multi-faceted phenomenon involving multiple cerebral mechanisms that differ across studies. The neural mechanisms of placebo analgesia are not fully understood. Here the authors conducted a large scale meta-analysis of individual data from fMRI studies of pain and placebo conditions.

Restricted spinopelvic mobility received attention as a contributing factor for total hip arthroplasty (THA) instability. However, it is still unknown, how the spinopelvic function is influenced by age. In identifying the patients at highest risk for altered spinopelvic mechanics the study aimed to determine the association of age on the individual segments of the spinopelvic complex and global spinal sagittal alignment in patients undergoing THA. 197 patients were included in the prospective observational study conducting biplanar stereoradiography (EOS) in standing and sitting position pre-and postoperatively. Two independent investigators assessed C7-sagittal vertical axis (C7-SVA), cervical lordosis (CL), thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), sacral slope (SS), anterior plane pelvic tilt (APPT), and pelvic femoral angle (PFA). Key segments of the spinopelvic complex are defined as lumbar flexibility (∆ LL = LL standing  − LL sitting ), pelvic mobility (∆ SS = SS standing  − SS sitting ) and hip motion (∆ PFA = PFA standing  − PFA sitting ). Pelvic mobility was further defined based on ∆ SS = SS standing  − SS sitting as stiff (∆ SS < 10°), normal (∆ SS ≥ 10°–30°) and hypermobile (∆ SS > 30°). The patient collective was classified into three groups: (1) < 60 years (n = 56), (2) ≥ 60–79 years (n = 112) and (3) ≥ 80 years (n = 29). Lumbar flexibility (∆ LL) was decreased with increasing age between all groups (36.1° vs. 23.1° vs. 17.2°/p 1+2  < 0.000, p 2+3  = 0.020, p 1+3  < 0.000) postoperatively. Pelvic mobility (∆ SS) was decreased in the groups 2 and 3 compared to group 1 (21.0° and 17.9° vs. 27.8°/p 1+2  < 0.000, p 2+3  = 0.371, p 1+3  = 0.001). Pelvic retroversion in standing position (APPT) was higher in group 2 and 3 compared to group 1 (1.9° and − 0.5° vs 6.9°/p 1+2  < 0.000, p 2+3  = 0.330, p 1+3  < 0.000). Global sagittal spinal balance (C7-SVA) showed more imbalance in groups 2 and 3 compared to group 1 (60.4 mm and 71.2 mm vs. 34.5 mm/p 1+2  < 0.000, p 2+3  = 0.376, p 1+3  < 0.000) postoperatively. The preoperative proportion of patients with stiff pelvic mobility in group 1 was distinctly lower than in group 3 (23.2% vs. 35.7%) and declined in group 1 to 1.8% compared to 20.7% in group 3 after THA. Changes after THA were reported for groups 1 and 2 representing spinopelvic complex key parameter lumbar flexibility (∆ LL), pelvic mobility (∆ SS) and hip motion (∆ PFA), but not for group 3. This is the first study to present age-adjusted normative values for spinopelvic mobility. The subgroups with increased age were identified as risk cohort for altered spinopelvic mechanics and enhanced sagittal spinal imbalance and limited capacity for improvement of mobility after THA. This valuable information serves to focus in the preoperative screening on the THA candidates with the highest risk for abnormal spinopelvic function.

Background Total hip arthroplasty (THA) instability is influenced by acetabular component positioning, spinopelvic function and sagittal spinal alignment. Obesity is considered as a risk factor of THA instability, but the causal relationship remains unknown. This study aimed to investigate the influence of BMI on (1) spinopelvic function (lumbar flexibility, pelvic mobility and hip motion), (2) sagittal spinal alignment pre- and postoperatively and (3) acetabular cup position postoperatively in primary THA patients in a prospective setting. Methods One hundred ninety patients receiving primary total hip arthroplasty were enrolled in a prospective cohort study and retrospectively analysed. All patients received stereoradiography (EOS) in standing and relaxed sitting position pre-and postoperatively. C7-sagittal vertical axis (C7-SVA), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), anterior plane pelvic tilt (APPT), and pelvic femoral angle (PFA) were assessed. Key parameters of the spinopelvic function were defined as lumbar flexibility (∆ LL = LL standing  − LL sitting ), pelvic mobility (∆ PT = PT standing  − PT sitting ) and hip motion (∆ PFA = PFA standing  − PFA sitting ). Pelvic mobility was further defined based on ∆ PT as stiff, normal and hypermobile (∆ PT < 10°; 10°–30°; > 30°). The patients were stratified to BMI according to WHO definition: normal BMI ≥ 18.5–24.9 kg/m 2 (n = 68), overweight ≥ 25.0–29.9 kg/m 2 (n = 81) and obese ≥ 30–39.9 kg/m 2 (n = 41). Post-hoc analysis according to Hochberg's GT2 was applied to determine differences between BMI groups. Results Standing cup inclination was significant higher in the obese group compared to the normal BMI group (45.3° vs. 40.1°; p  = 0.015) whereas standing cup anteversion was significantly decreased (22.0° vs. 25.3°; p  = 0.011). There were no significant differences for spinopelvic function key parameter lumbar flexibility (∆ LL), pelvic mobility (∆ PT) and hip motion (∆ PFA) in relation to BMI stratified groups. The obese group demonstrated significant enhanced pelvic retroversion compared to the normal BMI group (APPT − 1.8° vs. 2.4°; p  = 0.028). The preoperative proportion of stiff pelvic mobility was decreased in the obese group (12.2%) compared to normal (25.0%) and overweight (27.2%) groups. Spinal sagittal alignment in C7-SVA and PI-LL mismatch demonstrated significantly greater imbalance in the obese group compared to the normal BMI group (68.6 mm vs. 42.6 mm, p  = 0.002 and 7.7° vs. 1.2°, p  = 0.032, respectively) The proportion of patients with imbalanced C7-SVA was higher in the obese (58.5%) than in the normal BMI group (44.1%). Conclusions The significantly increased spinal sagittal imbalance with altered pelvic mechanics is a potential cause for the reported increased risk of THA dislocations in obese patients. Consequently, the increased spinal sagittal imbalance in combination with normal pelvic mobility need to be taken into account when performing THA in obese patients.

Chronic inflammation is frequently observed on histological analysis of malignant and non-malignant prostate specimens. It is a suspected supporting factor for prostate diseases and their progression and a main cause of false positive PSA tests in cancer screening. We hypothesized that inflammation induces autoantibodies, which may be useful biomarkers. We aimed to identify and validate prostate inflammation associated serum autoantibodies in prostate cancer patients and evaluate the expression of corresponding autoantigens. Radical prostatectomy specimens of prostate cancer patients (N = 70) were classified into high and low inflammation groups according to the amount of tissue infiltrating lymphocytes. The corresponding pre-surgery blood serum samples were scrutinized for autoantibodies using a low-density protein array. Selected autoantigens were identified in prostate tissue and their expression pattern analyzed by immunohistochemistry and qPCR. The identified autoantibody profile was cross-checked in an independent sample set (N = 63) using the Luminex-bead protein array technology. Protein array screening identified 165 autoantibodies differentially abundant in the serum of high compared to low inflammation patients. The expression pattern of three corresponding antigens were established in benign and cancer tissue by immunohistochemistry and qPCR: SPAST (Spastin), STX18 (Syntaxin 18) and SPOP (speckle-type POZ protein). Of these, SPAST was significantly increased in prostate tissue with high inflammation. All three autoantigens were differentially expressed in primary and/or castration resistant prostate tumors when analyzed in an inflammation-independent tissue microarray. Cross-validation of the inflammation autoantibody profile on an independent sample set using a Luminex-bead protein array, retrieved 51 of the significantly discriminating autoantibodies. Three autoantibodies were significantly upregulated in both screens, MUT, RAB11B and CSRP2 (p>0.05), two, SPOP and ZNF671, close to statistical significance (p = 0.051 and 0.076). We provide evidence of an inflammation-specific autoantibody profile and confirm the expression of corresponding autoantigens in prostate tissue. This supports evaluation of autoantibodies as non-invasive markers for prostate inflammation.

Genetic variants including PNPLA3-rs738409 C>G, TM6SF2-rs58542926 C>T, MBOAT7-rs641738 C>T, and HSD17B13-rs72613567 T>TA have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)]) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the PNPLA3 minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, PNPLA3/TM6SF2/MBOAT7/HSD17B13 genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the PNPLA3 G-allele in the overall cohort. Finally, carriage of PNPLA3 G-allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in PNPLA3/TM6SF2/MBOAT7/HSD17B13 do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure.