Molecular Basis for Surface-Initiated Non-Thrombin-Generated Clot Formation Following Viral Infection.

In this paper, we propose a model that connects two standard inflammatory responses to viral infection, namely, elevation of fibrinogen and the lipid drop shower, to the initiation of non-thrombin-generated clot formation. In order to understand the molecular basis for the formation of non-thrombin-generated clots following viral infection, human epithelial and Madin-Darby Canine Kidney (MDCK, epithelial) cells were infected with H1N1, OC43, and adenovirus, and conditioned media was collected, which was later used to treat human umbilical vein endothelial cells and human lung microvascular endothelial cells. After direct infection or after exposure to conditioned media from infected cells, tissue surfaces of both epithelial and endothelial cells, exposed to 8 mg/mL fibrinogen, were observed to initiate fibrillogenesis in the absence of thrombin. No fibers were observed after direct viral exposure of the endothelium or when the epithelium cells were exposed to SARS-CoV-2 isolated spike proteins. Heating the conditioned media to 60 °C had no effect on fibrillogenesis, indicating that the effect was not enzymatic but rather associated with relatively thermally stable inflammatory factors released soon after viral infection. Spontaneous fibrillogenesis had previously been reported and interpreted as being due to the release of the alpha C domains due to strong interactions of the interior of the fibrinogen molecule in contact with hydrophobic material surfaces rather than cleavage of the fibrinopeptides. Contact angle goniometry and immunohistochemistry were used to demonstrate that the lipids produced within the epithelium and released in the conditioned media, probably after the death of infected epithelial cells, formed a hydrophobic residue responsible for fibrillogenesis. Hence, the standard inflammatory response constitutes the ideal conditions for surface-initiated clot formation.

Human parainfluenza virus 3 vaccine candidates attenuated by codon-pair deoptimization are immunogenic and protective in hamsters.

Human parainfluenza virus type 3 (HPIV3) is a major pediatric respiratory pathogen lacking available vaccines or antiviral drugs. We generated live-attenuated HPIV3 vaccine candidates by codon-pair deoptimization (CPD). HPIV3 open reading frames (ORFs) encoding the nucleoprotein (N), phosphoprotein (P), matrix (M), fusion (F), hemagglutinin-neuraminidase (HN), and polymerase (L) were modified singly or in combination to generate 12 viruses designated Min-N, Min-P, Min-M, Min-FHN, Min-L, Min-NP, Min-NPM, Min-NPL, Min-PM, Min-PFHN, Min-MFHN, and Min-PMFHN. CPD of N or L severely reduced growth in vitro and was not further evaluated. CPD of P or M was associated with increased and decreased interferon (IFN) response in vitro, respectively, but had little effect on virus replication. In Vero cells, CPD of F and HN delayed virus replication, but final titers were comparable to wild-type (wt) HPIV3. In human lung epithelial A549 cells, CPD F and HN induced a stronger IFN response, viral titers were reduced 100-fold, and the expression of F and HN proteins was significantly reduced without affecting N or P or the relative packaging of proteins into virions. Following intranasal infection in hamsters, replication in the nasal turbinates and lungs tended to be the most reduced for viruses bearing CPD F and HN, with maximum reductions of approximately 10-fold. Despite decreased in vivo replication (and lower expression of CPD F and HN in vitro), all viruses induced titers of serum HPIV3-neutralizing antibodies similar to wt and provided complete protection against HPIV3 challenge. In summary, CPD of HPIV3 yielded promising vaccine candidates suitable for further development.

Feasibility Study: Towards a Robot-Assisted Gait Training in Ophthalmological Rehabilitation.

The idea of using mobile assistance robots for gait training in rehabilitation has been increasingly explored in recent years due to the associated benefits. This paper describes how the previous results of research and praxis on gait training with a mobile assistance robot in orthopedic rehabilitation can be transferred to ophthalmic-related orientation and mobility training for blind and visually impaired people. To this end, the specific requirements for such orientation and mobility training are presented from a therapeutic perspective. Using sensory data, it is investigated how the analysis of training errors can be automated and transferred back to the training person. These pre-examinations are the prerequisite for any form of robot-assisted mobile gait training in ophthamological rehabilitation, which does not exist so far and which is expected to be of great benefit to these patients.

Resistance, Motor Control, and Mindfulness-Based Exercises Are Effective for Treating Chronic Nonspecific Neck Pain: A Systematic Review With Meta-Analysis and Dose-Response Meta-Regression.

OBJECTIVE: We aimed to analyze the effects and dose-response relationship of the most effective exercises for improving pain and disability in people with chronic nonspecific neck pain. DESIGN: Intervention systematic review with meta-analysis. LITERATURE SEARCH: We searched the PubMed, PEDro, and CENTRAL databases from their inception to September 30, 2022. STUDY SELECTION CRITERIA: We included randomized controlled trials that involved people with chronic neck pain adopting a longitudinal exercise intervention and assessed one pain and/or disability outcome. DATA SYNTHESIS: Restricted maximum-likelihood random-effects meta-analyses were modeled separately for resistance, mindfulness-based, and motor control exercises; standardized mean differences (Hedge's g, standardized mean difference [SMD]) were effect estimators. Meta-regressions (dependent variable: effect sizes of the interventions; independent variables: training dose and control group effects) were conducted to explore the dose-response relationship for therapy success of any exercise type. RESULTS: We included 68 trials. Compared to true control, effects on pain and disability were significantly larger for resistance exercise (pain: SMD, -1.27; 95% confidence interval [CI]: -2.26, -0.28; |2 = 96%; disability: SMD, -1.76; 95% CI: -3.16, -0.37; |2 = 98%), motor control exercise (pain: SMD, -2.29; 95% CI: -3.82, -0.75; |2 = 98%; disability: SMD, -2.42; 95% CI: -3.38, -1.47; |2 = 94%), and Yoga/Pilates/Tai Chi/Qui Gong exercise (pain: SMD, 1.91; 95% CI:-3.28, -0.55; |2 = 96%; disability: SMD, -0.62; 95% CI: -0.85, -0.38; |2 = 0%). Yoga/Pilates/Tai Chi/Qui Gong exercise was more effective than other exercises (SMD, -0.84; 95% CI: -1.553, -0.13; |2 = 86%) for reducing pain. For disability, motor control exercise was superior to other exercises (SMD, -0.70; 95% CI: -1.23, -0.17; |2 = 98%). There was no dose-response relationship for resistance exercise (R2 = 0.32). Higher frequencies (estimate = -0.10) and longer durations (estimate = -0.11) of motor control exercise had larger effects on pain (R2 = 0.72). Longer sessions (estimate = -0.13) of motor control exercise had larger effects on disability (R2 = 0.61). CONCLUSION: Resistance, mindfulness-based, and motor control exercises were effective for reducing neck pain (very low- to moderate-certainty evidence). Higher frequencies and longer duration of sessions had a significant effect on pain for motor control exercise. J Orthop Sports Phys Ther 2023;53(8):1-41. Epub: 20 June 2023. doi:10.2519/jospt.2023.11820.

Comparative Effectiveness of Upper Limb Exercise Interventions in Individuals With Stroke: A Network Meta-Analysis.

BACKGROUND: Although numerous effective exercise interventions can treat upper limb motor impairments after stroke, it remains unknown as to which are the most effective. The objective of the present study was to investigate the comparative effectiveness of various exercise interventions of the upper limb for individuals with an acute or subacute stroke. METHODS: For this systematic review with network meta-analysis, we searched PubMed/MEDLINE, Cochrane Library CENTRAL and Web of Science from database inception to September 2021 for randomized controlled trials examining individuals within 6 months of stroke onset, active upper limb exercise interventions, and any kind of control intervention. The primary outcome was upper limb motor function, secondary outcomes were activities of daily living and social participation, both assessed at post-intervention and follow-up. Nonspecific/multimodal active upper limb therapy was the standard comparator. Standardized mean differences, that is, Hedge's g, were the effect size estimators. We calculated Frequentist-based network meta-analysis for the comparative effectiveness calculations using the R package netmeta. Main analyses were network plotting to display the geometry of the network and P-scores to summarize the intervention hierarchy. Results were derived from direct within-study and indirect between-study evidence comparisons. The Cochrane risk-of-bias tool II assessed all risk of bias domains. RESULTS: This review involved 145 randomized controlled trial on 6432 participants and 45 different treatment categories. The network meta-analysis analyzed 119 randomized controlled trials on 5553 participants and 41 different treatment categories. Electrical stimulation combined with task-specific training (standardized mean difference, 1.03 [95% CI, 0.51-1.55]; P<0.0001, P-score=0.11), high-volume constraint-induced movement therapy (0.86 [0.4-1.32]; P=0.0003, P-score=0.18), and strength training (0.65 [0.17-1.13]; P=0.01, P-score=0.28) were the most effective interventions (each k=107). CONCLUSIONS: Electrical stimulation combined with task-specific training (low evidence), high-volume constraint-induced movement therapy (moderate evidence), and strength training (low evidence) were the most effective interventions in improving upper limb motor function in individuals with a stroke. As the results were sensitive against a high risk of bias, likewise, these interventions should receive more attention in research and practice. Due to the heterogeneous use, electrical stimulation in combination with task-specific training should be further investigated in well-designed studies alongside other successful interventions (eg, constraint-induced movement therapy). REGISTRATION: URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021284064.

How to measure children's feet: 3D foot scanning compared with established 2D manual or digital methods.

BACKGROUND: In infants and young children, a wide heterogeneity of foot shape is typical. Therefore, children, who are additionally influenced by rapid growth and maturation, are a very special cohort for foot measurements and the footwear industry. The importance of foot measurements for footwear fit, design, as well as clinical applications has been sufficiently described. New measurement techniques (3D foot scanning) allow the assessment of the individual foot shape. However, the validity in comparison to conventional methods remains unclear. Therefore, the purpose of this study was to compare 3D foot scanning with two established measurement methods (2D digital scanning/manual foot measurements). METHODS: Two hundred seventy seven children (125 m / 152 f; mean ± SD: 8.0 ± 1.5yrs; 130.2 ± 10.7cm; 28.0 ± 7.3kg) were included into the study. After collection of basic data (sex, age (yrs), body height (cm), body weight (kg)) geometry of the right foot was measured in static condition (stance) with three different measurement systems (fixed order): manual foot measurement, 2D foot scanning (2D desk scanner) and 3D foot scanning (hand-held 3D scanner). Main outcomes were foot length, foot width (projected; anatomical; instep), heel width and anatomical foot ball breadth. Analysis of variances for dependent samples was applied to test for differences between foot measurement methods (Post-hoc analysis: Tukey-Kramer-Test; α=0.05). RESULTS: Significant differences were found for all outcome measures comparing the three methods (p<0.0001). The span of foot length differences ranged from 3 to 6mm with 2D scans showing the smallest and 3D scans the largest deviations. Foot width measurements in comparison of 3D and 2D scans showed consistently higher values for 3D measurements with the differences ranging from 1mm to 3mm. CONCLUSIONS: The findings suggests that when comparing foot data, it is important to consider the differences caused by new measurement methods. Differences of about 0.6cm are relevant when measuring foot length, as this is the difference of a complete shoe size (Parisian point). Hence, correction factors may be required to compare the results of different measurements appropriately. The presented results may have relevance in the field of ergonomics (shoe industry) as well as clinical practice.

A Live Attenuated COVID-19 Candidate Vaccine for Children: Protection against SARS-CoV-2 Challenge in Hamsters.

Children are at risk of infection from severe acute respiratory syndrome coronavirus-2 virus (SARS-CoV-2) resulting in coronavirus disease (COVID-19) and its more severe forms. New-born infants are expected to receive short-term protection from passively transferred maternal antibodies from their mothers who are immunized with first-generation COVID-19 vaccines. Passively transferred antibodies are expected to wane within first 6 months of infant's life, leaving them vulnerable to COVID-19. Live attenuated vaccines, unlike inactivated or viral-protein-based vaccines, offer broader immune engagement. Given effectiveness of live attenuated vaccines in controlling infectious diseases such as mumps, measles and rubella, we undertook development of a live attenuated COVID-19 vaccine with an aim to vaccinate children beyond 6 months of age. An attenuated vaccine candidate (dCoV), engineered to express sub-optimal codons and deleted polybasic furin cleavage sites in the spike protein of the SARS-CoV-2 WA/1 strain, was developed and tested in hamsters. Hamsters immunized with dCoV via intranasal or intramuscular routes induced high levels of neutralizing antibodies and exhibited complete protection against the SARS-CoV-2 wild-type isolates, i.e., the Wuhan-like (USA-WA1/2020) and Delta variants (B.1.617.2) in a challenge study. In addition, the dCoV formulated with the marketed measles-rubella (MR) vaccine, designated as MR-dCoV, administered to hamsters via intramuscular route, also protected against both SARS-CoV-2 challenges, and dCoV did not interfere with the MR vaccine-mediated immune response. The safety and efficacy of the dCoV and the MR-dCoV against both variants of SARS-CoV-2 opens the possibility of early immunization in children without an additional injection.

Acute effects of game-based biofeedback training on trunk motion in chronic low back pain: a randomized cross-over pilot trial.

BACKGROUND: Improving movement control might be a promising treatment goal during chronic non-specific low back pain (CLBP) rehabilitation. The objective of the study is to evaluate the effect of a single bout of game-based real-time feedback intervention on trunk movement in patients with CLBP. METHODS: Thirteen CLBP patients (8female;41 ± 16 years;173 ± 10 cm;78 ± 22 kg) were included in this randomized cross-over pilot trial. During one laboratory session (2 h), participants performed three identical measurements on trunk movement all including: first, maximum angle of lateral flexion was assessed. Secondly, a target trunk lateral flexion (angle: 20°) was performed. Main outcome was maximum angle ([°]; MA). Secondary outcomes were deviation [°] from the target angle (angle reproduction; AR) and MA of the secondary movement planes (rotation; extension/flexion) during lateral flexion. The outcomes were assessed by an optical 3D-motion-capture-system (2-segment-trunk-model). The measurements were separated by 12-min of intervention and/or resting (randomly). The intervention involved a sensor-based trunk exergame (guiding an avatar through virtual worlds). After carryover effect-analysis, pre-to-post intervention data were pooled between the two sequences followed by analyses of variances (paired t-test). RESULTS: No significant change from pre to post intervention for MA or AR for any segment occurred for the main movement plane, lateral flexion (p > .05). The upper trunk segment showed a significant decrease of the MA for trunk extension/flexion from pre to post intervention ((4.4° ± 4.4° (95% CI 7.06-1.75)/3.5° ± 1.29° (95% CI 6.22-0.80); p = 0.02, d = 0.20). CONCLUSIONS: A single bout of game-based real-time feedback intervention lead to changes in the secondary movement planes indicating reduced evasive motion during trunk movement. TRIAL REGISTRATION NO: DRKS00029765 (date of registration 27.07.2022). Retrospectively registered in the German Clinical Trial Register.

A standardized marking procedure for ENT operations to prevent wrong-site surgery: development, establishment and subsequent evaluation among patients and medical personnel.

PURPOSE: Wrong-site surgeries are rare but potentially serious clinical errors. Marking the surgical site is crucial to preventing errors, but is hindered in the ENT field by the presence of many internal organs. In addition, there is no standardized marking procedure. METHODS: Here, an ENT surgical-marking procedure was developed and introduced at a clinic. The procedure was evaluated through anonymized questionnaires. This study was conducted over a 6-month period by interviewing patients and, at the beginning and end of this period, doctors and other surgical staff. RESULTS: The internal organ-marking problem was solved by applying a fixed abbreviation for each procedure onto the shoulder in addition to marking the skin surface as close to the organ as possible. The procedure was described as practicable by 100% of the interviewees; 75% of the ENT physicians and 96.3% of the other surgical staff considered the procedure highly important for preventing site confusion, and 75% of the physicians had a consequently greater feeling of safety. Of the 248 patients surveyed, 96.0% considered the marking procedure useful, and 75.8% had a consequently greater feeling of safety. For 52.0%, the marking reduced their fear of the operation. CONCLUSIONS: For the first time, a standardized procedure was developed to mark the site of ENT surgery directly, uniformly and safely on patients. The procedure was judged to be useful and practicable and was also deemed crucial for preventing site confusion. Patients felt safer and less fearful of the operation due to the marking.

Potentiometric Biosensors Based on Molecular-Imprinted Self-Assembled Monolayer Films for Rapid Detection of Influenza A Virus and SARS-CoV-2 Spike Protein.

Rapid, yet accurate and sensitive testing has been shown to be critical in the control of spreading pandemic diseases such as COVID-19. Current methods which are highly sensitive and can differentiate different strains are slow and cannot be conveniently applied at the point of care. Rapid tests, meanwhile, require a high titer and are not sufficiently sensitive to discriminate between strains. Here, we report a rapid and facile potentiometric detection method based on nanoscale, three-dimensional molecular imprints of analytes on a self-assembled monolayer (SAM), which can deliver analyte-specific detection of both whole virions and isolated proteins in microliter amounts of bodily fluids within minutes. The detection substrate with nanoscale inverse surface patterns of analytes formed by a SAM identifies a target analyte by recognizing its surface nano- and molecular structures, which can be monitored by temporal measurement of the change in substrate open-circuit potential. The sensor unambiguously detected and differentiated H1N1 and H3N2 influenza A virions as well as the spike proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle-East respiratory syndrome (MERS) coronavirus in human saliva with limits of detection reaching 200 PFU/mL and 100 pg/mL for the viral particles and spike proteins, respectively. The demonstrated speed and specificity of detection, combined with a low required sample volume, high sensitivity, ease of potentiometric measurement, and simple sample collection and preparation, suggest that the technique can be used as a highly effective point-of-care diagnostic platform for a fast, accurate, and specific detection of various viral pathogens and their variants.

Effect of Six-Week Resistance and Sensorimotor Training on Trunk Strength and Stability in Elite Adolescent Athletes: A Randomized Controlled Pilot Trial.

Intervention in the form of core-specific stability exercises is evident to improve trunk stability. The purpose was to assess the effect of an additional 6 weeks sensorimotor or resistance training on maximum isokinetic trunk strength and response to sudden dynamic trunk loading (STL) in highly trained adolescent athletes. The study was conducted as a single-blind, 3-armed randomized controlled trial. Twenty-four adolescent athletes (14f/10 m, 16 ± 1 yrs.;178 ± 10 cm; 67 ± 11 kg; training sessions/week 15 ± 5; training h/week 22 ± 8) were randomized into resistance training (RT; n = 7), sensorimotor training (SMT; n = 10), and control group (CG; n = 7). Athletes were instructed to perform standardized, center-based training for 6 weeks, two times per week, with a duration of 1 h each session. SMT consisted of four different core-specific sensorimotor exercises using instable surfaces. RT consisted of four trunk strength exercises using strength training machines, as well as an isokinetic dynamometer. All participants in the CG received an unspecific heart frequency controlled, ergometer-based endurance training (50 min at max. heart frequency of 130HF). For each athlete, each training session was documented in an individual training diary (e.g., level of SMT exercise; 1RM for strength exercise, pain). At baseline (M1) and after 6 weeks of intervention (M2), participants' maximum strength in trunk rotation (ROM:63°) and flexion/extension (ROM:55°) was tested on an isokinetic dynamometer (concentric/eccentric 30°/s). STL was assessed in eccentric (30°/s) mode with additional dynamometer-induced perturbation as a marker of core stability. Peak torque [Nm] was calculated as the main outcome. The primary outcome measurements (trunk rotation/extension peak torque: con, ecc, STL) were statistically analyzed by means of the two-factor repeated measures analysis of variance (α = 0.05). Out of 12 possible sessions, athletes participated between 8 and 9 sessions (SMT: 9 ± 3; RT: 8 ± 3; CG: 8 ± 4). Regarding main outcomes of trunk performance, experimental groups showed no significant pre-post difference for maximum trunk strength testing as well as for perturbation compensation (p > 0.05). It is concluded, that future interventions should exceed 6 weeks duration with at least 2 sessions per week to induce enhanced trunk strength or compensatory response to sudden, high-intensity trunk loading in already highly trained adolescent athletes, regardless of training regime.

Tobacco use in patients with ENT tumours: Deficits in the provision of education and smoking cessation support.

PURPOSE: Smoking is not only one of the main risk factors for the development of most malignant and numerous benign ENT tumours but also has an important influence on therapy and prognosis. Even quitting smoking at the time of diagnosis significantly reduces mortality. Patients have a particularly strong desire to stop smoking when they are diagnosed. The present study investigated to what extent patients were aware of the relationships between smoking and the development and prognosis of tumours and how much information and smoking cessation support they were offered by physicians. METHODS: A total of 194 patients (74.7% male, 62.0 ±10.6 a) with malignant primary ENT tumours, pre-cancerous tumours, Reinke's oedema and salivary gland tumours were interviewed. RESULTS: 22.7% were nonsmokers, 49.5% were cigarette smokers and 27.8% were ex-smokers. A total of 57.0% of the smokers said they would have quit before the onset of the disease if they had known about the association. Forty-one percent did not receive information about the association between smoking and the development of their disease, while 45.5% did not receive information about the relationship with their prognosis. The provision of information lasted less than 5 min for 40.4% of the patients and more than 10 min for only 13.5%. In total, 50.7% of the patients were directly requested not to smoke. A total of 7.7% received offers of smoking cessation support from otolaryngologists and 18.2% received such offers from family physicians. CONCLUSIONS: There is a pronounced need for improvements in the provision of medical information about the health risks associated with smoking and offers to support patient efforts to stop smoking. In particular, the appointment during which the diagnosis is communicated to the patient should be considered a 'teachable moment' that can lead to smoking cessation.

Socioeconomic influence on treatment and outcome of patients with oral cancer in Germany.

PURPOSE: To illustrate the influence of different socioeconomic factors on the treatment and outcome of patients in Germany with oral cancer. METHODS: In this retrospective single-center study, 400 patients of our department of oral and maxillofacial surgery with primary cases of oral cancer were included. Preoperative diagnostics, occupational groups, and marital and health insurance status were evaluated. Overall and disease-specific survival were analyzed. Occupations were distinguished in 5 groups (unemployed, physically light workers, physically hard worker, university graduate, and freelancer). Data were adjusted to covariables like tumor size, positive lymph nodes, age, alcohol, or tobacco abuse. RESULTS: There was no differences between private and statutory insured patients concerning overall (p = 0.858) or disease-specific survival (p = 0.431). Private insured patients received more preoperative PET-CT (p = 0.046) and had a better dental status (p = 0.006). The occupational groups showed also no differences in survival (p = 0.963). The hospitalization of freelancers was in average 2 days shorter. Physically hard workers were diagnosed with bigger tumors (p = 0.018) and consumed more tobacco and alcohol. The 5-year survival rate of married patients was approximately 20% points better than not married patients, without showing a significant difference over the entire observation time (p = 0.084). CONCLUSION: In our cohort, socioeconomic factors have just a limited influence on the survival or treatment of patients with oral cancer. A sufficient statutory health insurance system is a reasonable explanation for this.

An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality.

Although cancer is traditionally considered a genetic disease, the epigenetic abnormalities, including DNA hypermethylation, histone deacetylation, and/or microRNA dysregulation, have been demonstrated as a hallmark of cancer. Compared with gene mutations, aberrant epigenetic changes occur more frequently, and cellular epigenome is more susceptible to change by environmental factors. Excess cancer risks are positively associated with exposure to occupational and environmental chemical carcinogens, including those from gasoline combustion exhausted in vehicles. Of note, previous studies proposed particulate matter index (PMI) as a measure for gasoline sooting tendency, and showed that, compared with the other molecules in gasoline, 1,2,4-Trimethylbenzene, 2-methylnaphthalene and toluene significantly contribute to PMI of the gasoline blends. Mechanistically, both epigenome and genome are important in carcinogenicity, and the genotoxicity of chemical agents has been thoroughly studied. However, less effort has been put into studying the epigenotoxicity. Moreover, as the blending of ethanol into gasoline substitutes for carcinogens, like benzene, toluene, xylene, butadiene, and polycyclic aromatic hydrocarbons, etc., a reduction of secondary aromatics has been achieved in the atmosphere. This may lead to diminished cancer initiation and progression through altered cellular epigenetic landscape. The present review summarizes the most important findings in the literature on the association between exposures to carcinogens from gasoline combustion, cancer epigenetics and the potential epigenetic impacts of biofuels.

Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy.

Successfully combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. Here, we describe COVI-VAC, the only live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine currently in clinical development. COVI-VAC was developed by recoding a segment of the viral spike protein with synonymous suboptimal codon pairs (codon-pair deoptimization), thereby introducing 283 silent (point) mutations. In addition, the furin cleavage site within the spike protein was deleted from the viral genome for added safety of the vaccine strain. Except for the furin cleavage site deletion, the COVI-VAC and parental SARS-CoV-2 amino acid sequences are identical, ensuring that all viral proteins can engage with the host immune system of vaccine recipients. COVI-VAC was temperature sensitive in vitro yet grew robustly (>107 plaque forming units/mL) at the permissive temperature. Tissue viral loads were consistently lower, lung pathology milder, and weight loss reduced in Syrian golden hamsters (Mesocricetus auratus) vaccinated intranasally with COVI-VAC compared to those inoculated with wild-type (WT) virus. COVI-VAC inoculation generated spike IgG antibody levels and plaque reduction neutralization titers similar to those in hamsters inoculated with WT virus. Upon challenge with WT virus, COVI-VAC vaccination reduced lung challenge viral titers, resulted in undetectable virus in the brain, and protected hamsters from almost all SARS-CoV-2-associated weight loss. Highly attenuated COVI-VAC is protective at a single intranasal dose in a relevant in vivo model. This, coupled with its large-scale manufacturing potential, supports its potential use in mass vaccination programs.

Scapular kinematics during unloaded and maximal loaded isokinetic concentric and eccentric shoulder flexion and extension movements.

Characterization of scapular kinematics under demanding load conditions might aid to distinguish between physiological and clinically relevant alterations. Previous investigations focused only on submaximal external load situations. How scapular movement changes with maximal load remains unclear. Therefore, the present study aimed to evaluate 3D scapular kinematics during unloaded and maximal loaded shoulder flexion and extension. Twelve asymptomatic individuals performed shoulder flexion and extension movements under unloaded and maximal concentric and eccentric loaded isokinetic conditions. 3D scapular kinematics assessed with a motion capture system was analyzed for 20° intervals of humeral positions from 20° to 120° flexion. Repeated measures ANOVAs were used to evaluate kinematic differences between load conditions for scapular position angles, scapulohumeral rhythm and scapular motion extent. Increased scapular upward rotation was seen during shoulder flexion and extension as well as decreased posterior tilt and external rotation during eccentric and concentric arm descents of maximal loaded compared to unloaded conditions. Load effects were further seen for the scapulohumeral rhythm with greater scapular involvement at lower humeral positions and increased scapular motion extent under maximal loaded shoulder movements. With maximal load applied to the arm physiological scapular movement pattern are induced that may imply both impingement sparing and causing mechanisms.

Patients' quality of life improves after surgical intervention of stage III medication-related osteonecrosis of the jaw.

PURPOSE: The treatment of advanced stages of medication-related osteonecrosis of the jaw (MRONJ) remains challenging. In order to improve decision making concerning the therapy, we examined the change of patients' quality of life (QoL) after surgical treatment of MRONJ stage III. METHOD: The primary outcome variable was patients' QoL. It was preoperative (T0), 6 weeks postoperative (T1) and 6 months postoperative (T2) assessed by the European Organisation for Research and Treatment of Cancer QoL-H&N35 (EORTC QoL-H&N35) and the Oral Health Impact Factor-G14 (OHIP-G14) questionnaire in a prospective cohort study. Other variables included location, age, sex, risk factors, and recurrence. Descriptive statistics and general multivariate regression models were calculated. RESULTS: Forty-three patients with stage III MRONJ underwent surgery. OHIP-G14 scores decreased (improvement) statistically significant (p = .001) by 52.02% (T0-T1) and 56.45% (T1-T2). EORTC QoL-H&N35 showed statistical improvement for "swallowing" (p = .007), "opening mouth" (p = .045), "painkiller" (.005), "weight loss" (.004), "pain" (p = .001), "trouble with social eating" (p = .001), "trouble with social contact" (p = .001), and "teeth" (p = .001). Patients who developed a recurrence did not show any significant higher (worse) scores in OHIP G14 or EORTC QoL-H&N35 scores compared with patients without recurrence. Twenty-nine out of 36 patients showed full mucosal healing (T2). For patients with no full mucosal healing, a downgrade to stage I was achieved. CONCLUSION: In terms of QoL patients with stage III MRONJ do benefit from surgical treatment. The incident of a recurrence seems to have no significant impact on patients QoL.

Neuromuscular shoulder activity during exercises with different combinations of stable and unstable weight mass.

BACKGROUND: Recent shoulder injury prevention programs have utilized resistance exercises combined with different forms of instability, with the goal of eliciting functional adaptations and thereby reducing the risk of injury. However, it is still unknown how an unstable weight mass (UWM) affects the muscular activity of the shoulder stabilizers. Aim of the study was to assess neuromuscular activity of dynamic shoulder stabilizers under four conditions of stable and UWM during three shoulder exercises. It was hypothesized that a combined condition of weight with UWM would elicit greater activation due to the increased stabilization demand. METHODS: Sixteen participants (7 m/9 f) were included in this cross-sectional study and prepared with an EMG-setup for the: Mm. upper/lower trapezius (U.TA/L.TA), lateral deltoid (DE), latissimus dorsi (LD), serratus anterior (SA) and pectoralis major (PE). A maximal voluntary isometric contraction test (MVIC; 5 s.) was performed on an isokinetic dynamometer. Next, internal/external rotation (In/Ex), abduction/adduction (Ab/Ad) and diagonal flexion/extension (F/E) exercises (5 reps.) were performed with four custom-made-pipes representing different exercise conditions. First, the empty-pipe (P; 0.5 kg) and then, randomly ordered, water-filled-pipe (PW; 1 kg), weight-pipe (PG; 4.5 kg) and weight + water-filled-pipe (PWG; 4.5 kg), while EMG was recorded. Raw root-mean-square values (RMS) were normalized to MVIC (%MVIC). Differences between conditions for RMS%MVIC, scapular stabilizer (SR: U.TA/L.TA; U.TA/SA) and contraction (CR: concentric/eccentric) ratios were analyzed (paired t-test; p ≤ 0.05; Bonferroni adjusted α = 0.008). RESULTS: PWG showed significantly greater muscle activity for all exercises and all muscles except for PE compared to P and PW. Condition PG elicited muscular activity comparable to PWG (p > 0.008) with significantly lower activation of L.TA and SA in the In/Ex rotation. The SR ratio was significantly higher in PWG compared to P and PW. No significant differences were found for the CR ratio in all exercises and for all muscles. CONCLUSION: Higher weight generated greater muscle activation whereas an UWM raised the neuromuscular activity, increasing the stabilization demands. Especially in the In/Ex rotation, an UWM increased the RMS%MVIC and SR ratio. This might improve training effects in shoulder prevention and rehabilitation programs.

A codon-pair deoptimized live-attenuated vaccine against respiratory syncytial virus is immunogenic and efficacious in non-human primates.

Despite a critical need for a respiratory syncytial virus (RSV) vaccine and decades of development efforts, a vaccine to protect infants, elderly, and other at-risk populations from RSV infection remains elusive. We have previously generated a new, live-attenuated vaccine candidate against RSV using rational, computer-aided gene design and chemical synthesis through a process termed viral gene "deoptimization." In this study, we assessed the attenuation, immunogenicity, and efficacy of this synthetic, live-attenuated RSV vaccine candidate, RSV-MinL4.0, in African Green Monkeys. RSV-MinL4.0 was produced under good-manufacturing-practice (GMP) in Vero cells. Vaccination with RSV-MinL4.0 resulted in minimal virus shedding after vaccination, generation of robust humoral and cellular immune responses (despite the presence of baseline RSV neutralizing antibodies in one animal) that were comparable to a wildtype infection, and protection from virus shedding post-challenge with wildtype RSV. These findings demonstrate the promise of RSV-MinL4.0 as a live-attenuated vaccine which will undergo clinical trials to test its ability to safely and effectively protect pediatric and elderly populations from infection with RSV.