Polymeric Nanoparticles Enable mRNA Transfection and Its Translation in Intervertebral Disc and Human Joint Cells, Except for M1 Macrophages.

Chronic lower back pain caused by intervertebral disc degeneration and osteoarthritis (OA) are highly prevalent chronic diseases. Although pain management and surgery can alleviate symptoms, no disease-modifying treatments are available. mRNA delivery could halt inflammation and degeneration and induce regeneration by overexpressing anti-inflammatory cytokines or growth factors involved in cartilage regeneration. Here, we investigated poly(amidoamine)-based polymeric nanoparticles to deliver mRNA to human joint and intervertebral disc cells. Human OA chondrocytes, human nucleus pulposus (NP) cells, human annulus fibrosus (AF) cells, fibroblast-like synoviocytes (FLS) and M1-like macrophages were cultured and transfected with uncoated or PGA-PEG-coated nanoparticles loaded with EGFP-encoding mRNA. Cell viability and transfection efficiency were analyzed for all cell types. Nanoparticle internalization was investigated in FLS and M1-like macrophages. No significant decrease in cell viability was observed in most conditions. Only macrophages showed a dose-dependent reduction of viability. Transfection with either nanoparticle version resulted in EGFP expression in NP cells, AF cells, OA chondrocytes and FLS. Macrophages showed internalization of nanoparticles by particle-cell co-localization, but no detectable expression of EGFP. Taken together, our data show that poly (amidoamine)-based nanoparticles can be used for mRNA delivery into cells of the human joint and intervertebral disc, indicating its potential future use as an mRNA delivery system in OA and IVDD, except for macrophages.

Alterations in stride-to-stride fluctuations in patients with chronic obstructive pulmonary disease during a self-paced treadmill 6-minute walk test.

Evaluating variability and stability using measures for nonlinear dynamics may provide additional insight into the structure of the locomotor system, reflecting the neuromuscular system's organization of gait. This is in particular of interest when this system is affected by a respiratory disease and it's extrapulmonary manifestations. This study assessed stride-to-stride fluctuations and gait stability in patients with chronic obstructive pulmonary disease (COPD) during a self-paced, treadmill 6-minute walk test (6MWT) and its association with clinical outcomes. In this cross-sectional study, eighty patients with COPD (age 62±7y; forced expiratory volume in first second 56±19%predicted) and 39 healthy older adults (62±7y) were analyzed. Gait parameters including stride-to-stride fluctuations (coefficient of variation (CoV), predictability (sample entropy) and stability (Local Divergence Exponent (LDE)) were calculated over spatiotemporal parameters and center of mass velocity. Independent t-test, Mann-Whitney U test and ANCOVA analyses were conducted. Correlations were calculated between gait parameters, functional mobility using Timed Up and Go Test, and quadriceps muscle strength using dynamometry. Patients walked slower than healthy older adults. After correction for Speed, patients demonstrated increased CoV in stride length (F(1,116) = 5.658, p = 0.019), and increased stride length predictability (F(1,116) = 3.959, p = 0.049). Moderate correlations were found between mediolateral center of mass velocity LDE and normalized maximum peak torque (ρ = -0.549). This study showed that patients with COPD demonstrate alterations in stride length fluctuations even when adjusted for walking speed, highlighting the potential of nonlinear measures to detect alterations in gait function in patients with COPD. Association with clinical outcomes were moderate to weak, indicating that these clinical test are less discriminative for gait alterations.

Normative 3D gait data of healthy adults walking at three different speeds on an instrumented treadmill in virtual reality.

A normative gait dataset of 246 healthy adults (122 men / 124 women, range in age 18-91 years, body weight 46.80-116.10 kg, height 1.53-1.97 m and BMI 18.25-35.63 kg/m2) is presented and publicly shared for three walking speed conditions. Raw and processed data are presented for each subject separately and for each walking speed, including data of every single step of both legs. The subject demographics and results from the physical examination are also presented which allows researchers and clinicians to create a self-selected reference group based on specific demographics. Besides the data per individual, data are also presented in age and gender groups. This provides a quick overview of healthy gait parameters which is relevant for use in clinical practice. Three dimensional gait analysis was performed at the Computer Assisted Rehabilitation Environment (CAREN) at the Maastricht University Medical Centre (MUMC+). Subjects walked on the instrumented treadmill surrounded with twelve 3D cameras, three 2D cameras and a virtual industrial environment projected on a 180° screen using the Human Body Lower Limb Model with trunk markers (HBM-II) as biomechanical model [1], [2]. Subjects walked at comfortable walking speed, 30% slower and 30% faster. These walking speed conditions were applied in a random sequence. Comfortable walking speed was determined using a RAMP protocol: subjects started to walk at 0.5m/s and every second the speed was increased with 0.01 m/s until the preferred speed was reached. The average of three repetitions was considered the comfortable speed. For each walking speed condition, 250 steps were recorded. The 3D gait data was collected using the D-flow CAREN software. For each subject, raw data of each walking speed condition is provided in .mox files, including the output from the model such as subject data (e.g. gender, body mass, knee and ankle width), center of mass (CoM), marker and force data, kinematic data (joint angles) and kinetic data (joint moments, ground reaction forces (GRFs) and joint powers) for each single step of both legs. Unfiltered and filtered data are included. C3D files with raw marker and GRF data were recorded in Nexus (Vicon software, version 2.8.1) and are available upon request. Raw data were processed in Matlab (Mathworks 2016), including quality check, step determination and the exportation of data to .xls files. For each adult and for each walking speed, an .xls file was created, containing spatiotemporal parameters, medio-lateral (ML) and back-forward (BF) margins of stability (MoS), 3D joint angles, anterior-posterior (AP) and vertical GRFs, 3D joint moments and 3D joint power of each step of both legs. Overview files per walking speed condition are created in .xls, presenting the averaged gait parameters (calculated as average over all valid steps) of every subject. The processed data is also presented and visualized per gender for different age groups (18-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, ≥70 years). This can serve as normative data for treadmill based 3D gait analyses in adults, applicable for clinical and research purposes. Data is available at OSF.io (https://osf.io/t72cw/).

How a broken vertebra can lead to a fatal hemorrhage: a case report.

BACKGROUND: Unintentional falls are common among the elderly and given the expected increase of the aging population, these falls contribute to a high number of admissions to the emergency department. Relatively low-energy trauma mechanisms can lead to serious injuries in the elderly, with contributing factors being comorbidities, medication use and degenerative abnormalities. CASE PRESENTATION: A 94-year-old female suffered an unintentional fall at home. Upon arrival of the ambulance at her house she was hemodynamically stable and mobilized to the gurney with assistance. During primary survey at the emergency department, her blood pressure and oxygen saturation decreased, she was not able to move her legs anymore and lost consciousness. A full-body CTA was performed, which showed a fracture through the vertebral body of L2 with significant dislocation and a large active bleeding of the corpus, extending to the retroperitoneum and the epidural space. Despite resuscitation, her vital signs deteriorated and given the severe abnormalities on CTA, it was decided to discontinue further treatment, after which she deceased. The performed CTA and an x-ray from 2016 suggested diffuse idiopathic skeletal hyperostosis, which might have contributed to the severity and instability of the vertebral fracture. Mobilization after the fall might have increased the dislocation of the fracture. The use of oral anticoagulants worsened the subsequent bleeding and the extension to the epidural space caused the paralysis of the legs. CONCLUSIONS: It is important to be aware of the possible serious consequences of unintentional falls in the elderly population and to provide strict immobilization of the spinal column until proper imaging.

The Evidence for the Use of Osteobiologics in Hybrid Constructs (Anterior Cervical Discectomy and Fusion and Total Disc Replacement) in Multilevel Cervical Degenerative Disc Disease: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVE: Examine the clinical evidence for the use of osteobiologics in hybrid surgery (combined anterior cervical discectomy and fusion (ACDF) and total disc replacement (TDR)) in patients with multilevel cervical degenerative disc disease (DDD). METHODS: PubMed and Embase were searched between January 2000 and August 2020. Clinical studies investigating 18-80 year old patients with multilevel cervical DDD who underwent hybrid surgery with or without the use of osteobiologics were considered eligible. Two reviewers independently screened and assessed the identified articles. The methodological index for non-randomized studies (MINORS) tool and the risk of bias (RoB 2.0) assessment tool were used to assess risk of bias. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to evaluate quality of evidence across studies per outcome. RESULTS: Eleven studies were included. A decrease in cervical range of motion was observed in most studies for both the hybrid surgery and the control groups consisting of stand-alone ACDF or TDR. Fusion rates of 70-100% were reported in both the hybrid surgery and control groups consisting of stand-alone ACDF. The hybrid surgery group performed better or comparable to the control group in terms of adjacent segment degeneration. Studies reported an improvement in visual analogue scale for pain and neck disability index values after surgery compared to preoperative scores for both treatment groups. The included studies had moderate methodological quality. CONCLUSIONS: There is insufficient evidence for assessing the use of osteobiologics in multilevel hybrid surgery and additional high quality and controlled research is deemed essential.

Changes in running economy and running technique following 6 months of running with and without wearable-based real-time feedback.

BACKGROUND: An increasing number of commercially available wearables provide real-time feedback on running biomechanics with the aim to reduce injury risk or improve performance. OBJECTIVE: Investigate whether real-time feedback by wearable insoles (ARION) alters running biomechanics and improves running economy more as compared to unsupervised running training. We also explored the correlation between changes in running biomechanics and running economy. METHODS: Forty recreational runners were randomized to an intervention and control group and performed ~6 months of in-field training with or without wearable-based real-time feedback on running technique and speed. Running economy and running biomechanics were measured in lab conditions without feedback pre and post intervention at four speeds. RESULTS: Twenty-two individuals (13 control, 9 intervention) completed both tests. Both groups significantly reduced their energetic cost by an average of -6.1% and -7.7% for the control and intervention groups, respectively. The reduction in energy cost did not significantly differ between groups overall (-0.07 ± 0.14 J∙kg∙m-1 , -1.5%, p = 0.63). There were significant changes in spatiotemporal metrics, but their magnitude was minor and did not differ between the groups. There were no significant changes in running kinematics within or between groups. However, alterations in running biomechanics beyond typical session-to-session variation were observed during some in-field sessions for individuals that received real-time feedback. CONCLUSION: Alterations in running biomechanics as observed during some in-field sessions for individuals receiving wearable-based real-time feedback did not result in significant differences in running economy or running biomechanics when measured in controlled lab conditions without feedback.

Gait alterations in patients with adult spinal deformity.

Background: Adult spinal deformity patients (ASD) experience altered spinal alignment affecting spatiotemporal parameters and joint kinematics. Differences in spinal deformity between patients with symptomatic idiopathic scoliosis (ID-ASD) and patients with "de novo" scoliosis (DN-ASD) may affect gait characteristics differently. This study aims to compare gait characteristics between ID-ASD, DN-ASD, and asymptomatic healthy matched controls. Methods: In this observational case-control study, ID-ASD (n = 24) and DN-ASD (n = 26) patients visiting the out-patient spine clinic and scheduled for long-segment spinal fusion were included. Patients were matched, based on age, gender, leg length and BMI, with asymptomatic healthy controls. Gait was measured at comfortable walking speed on an instrumented treadmill with 3D motion capture system. Trunk, pelvic and lower extremities range of motion (ROM) and spatiotemporal parameters (SPT) are presented as median (first and thirds quartile). Independent t-test or Mann-Whitney U test was used to compare ID-ASD, DN-ASD and controls. Statistical Parametric Mapping (independent t-test) was used to compare 3D joint kinematics. Results: DN-ASD patients walk with increased anterior trunk tilt during the whole gait cycle compared with ID-ASD patients and controls. ID-ASD walk with decreased trunk lateroflexion compared with DN-ASD and controls. DN-ASD showed decreased pelvic obliquity and -rotation, increased knee flexion, and decreased ankle plantar flexion. ID-ASD and DN-ASD displayed decreased trunk, pelvic and lower extremity ROM compared with controls, but increased pelvic tilt ROM. ID-ASD patients walked with comparable SPT to controls, whereas DN-ASD patients walked significantly slower with corresponding changes in SPT and wider steps. Conclusions: DN-ASD patients exhibit distinct alterations in SPT and kinematic gait characteristics compared with ID-ASD and controls. These alterations seem to be predominantly influenced by sagittal spinal malalignment and kinematic findings in ASD patients should not be generalized as such, but always be interpreted with consideration for the nature of the ASD.

Functional electrical stimulation during walking in children with unilateral spastic cerebral palsy: A randomized cross-over trial.

AIM: To study if functional electrical stimulation (FES) of the peroneal nerve, which activates dorsiflexion, can improve body functions, activities, and participation and could be an effective alternative treatment in individuals with unilateral spastic cerebral palsy (CP). METHOD: A randomized cross-over trial was performed in 25 children with unilateral spastic CP (classified in Gross Motor Function Classification System levels I and II) aged 4 to 18 years (median age at inclusion 9 years 8 months, interquartile range = 7 years-13 years 8 months), 15 patients were male. The study consisted of two 12-week blocks of treatment, that is, conventional treatment (ankle foot orthosis [AFO] or adapted shoes) and FES, separated by a 6-week washout period. Outcome measures included the Goal Attainment Scale (GAS), the Cerebral Palsy Quality of Life questionnaire, and a three-dimensional gait analysis. RESULTS: Eighteen patients completed the trial. The proportion of GAS goals achieved was not significantly higher in the FES versus the conventional treatment phase (goal 1 p = 0.065; goal 2 p = 1.00). When walking while stimulated with FES, ankle dorsiflexion during mid-swing decreased over time (p = 0.006, average decrease of 4.8° with FES), with a preserved increased ankle range of motion compared to conventional treatment (p < 0.001, mean range of motion with FES +10.1° compared to AFO). No changes were found in the standard physical examination or regarding satisfaction with orthoses and feelings about the ability to dress yourself. In four patients, FES therapy failed; in 12 patients FES therapy continued after the trial. INTERPRETATION: FES is not significantly worse than AFO; however, patient selection is critical, and a testing period and thorough follow-up are needed.

Methodology and application of three-dimensional technology for brace design and production for treatment in patients with adolescent idiopathic scoliosis: a scoping review protocol.

INTRODUCTION: Conservative treatment for adolescent idiopathic scoliosis (AIS) using bracing has proven to be effective at reducing curve progression. However, variation in brace design and lack of brace specificity hamper clinical treatment outcomes as well as the predictability and comparison hereof. To overcome this, recent technological developments aim to generate transparent and objective criteria for brace manufacturing by applying computer-aided design software and additive manufacturing to produce braces for scoliosis treatment. Yet, the extent of its applicability and clinical implementation are to be determined. This study will identify and map the available evidence for the methodology and application of three-dimensional technology for the design and production of clinical braces used for treatment in patients with AIS. METHODS AND ANALYSIS: This scoping review will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. This scoping review will consider studies on methodology of three-dimensional technological methodology and applications that have been or are currently being applied in brace treatment of AIS. The following databases will be searched: MEDLINE, Web of Science, Cochrane Database of Systematic Reviews and Embase (OVID). Search limits will be applied; for example, only articles written in the English language published after 2000 will be included. The retrieved articles will be screened independently by two researchers. A third researcher will be consulted in case of disagreement. Data from relevant articles will be independently extracted by two researchers and presented in a tabular manner accompanied by a descriptive narration. ETHICS AND DISSEMINATION: Considering the nature of the study, no ethical approval needed to be requested. The study result will be submitted to a peer-reviewed journal.

Biomechanical evaluation of different semi-rigid junctional fixation techniques using finite element analysis.

BACKGROUND: Proximal junctional failure is a common complication attributed to the rigidity of long pedicle screw fixation constructs used for surgical correction of adult spinal deformity. Semi-rigid junctional fixation achieves a gradual transition in range of motion at the ends of spinal instrumentation, which could lead to reduced junctional stresses, and ultimately reduce the incidence of proximal junctional failure. This study investigates the biomechanical effect of different semi-rigid junctional fixation techniques in a T8-L3 finite element spine segment model. METHODS: First, degeneration of the intervertebral disc was successfully implemented by altering the height. Second, transverse process hooks, one- and two-level clamped tapes, and one- and two-level knotted tapes instrumented proximally to three-level pedicle screw fixation were validated against ex vivo range of motion data of a previous study. Finally, the posterior ligament complex forces and nucleus pulposus stresses were quantified. FINDINGS: Simulated range of motions demonstrated the fidelity of the general model and modelling of semi-rigid junctional fixation techniques. All semi-rigid junctional fixation techniques reduced the posterior ligament complex forces at the junctional zone compared to pedicle screw fixation. Transverse process hooks and knotted tapes reduced nucleus pulposus stresses, whereas clamped tapes increased nucleus pulposus stresses at the junctional zone. INTERPRETATION: The relationship between the range of motion transition and the reductions in posterior ligament complex and nucleus pulposus stresses was complex and dependent on the fixation techniques. Clinical trials are required to compare the effectiveness of semi-rigid junctional fixation techniques in terms of reducing proximal junctional failure incidence rates.

Immunogenicity, safety, and preliminary efficacy evaluation of OVX836, a nucleoprotein-based universal influenza A vaccine candidate: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: OVX836, a recombinant vaccine containing the nucleoprotein of the influenza A virus A/WSN/1933 (H1N1) and the oligomerisation domain OVX313, has displayed a good safety profile and elicited dose-dependent humoral and cellular immune responses at 90 µg or 180 µg (intramuscularly) in previous clinical trials. The aim of this study was to explore higher doses, since no maximum tolerated dose had been reached. METHODS: In this phase 2a, randomised, double-blind, placebo-controlled study, we recruited 137 healthy adults aged 18-55 years in a single centre in Belgium. Participants were randomly assigned (interactive web response system; block size=4) using SAS (version 9.4) to receive one single intramuscular administration of OVX836 influenza vaccine at three doses (180 µg [n=33], 300 µg [n=35], and 480 µg [n=36]) or placebo (n=33). The two primary endpoints were the safety and the cell-mediated immune response to OVX836 at the three doses in terms of change of nucleoprotein-specific IFNγ spot forming cell (SFC) frequencies in the peripheral blood mononuclear cell (PBMC) population, measured by IFNγ ELISpot, at day 8 versus pre-injection baseline (day 1). The population used for the safety analysis is the modified intention-to-treat cohort. The population used for the immunogenicity analysis is the per-protocol cohort. This trial is registered with ClinicalTrials.gov, NCT05060887, and EudraCT, 2021-002535-39. FINDINGS: Participants were recruited between Nov 15, 2021, and Feb 1, 2022. OVX836 had a favourable safety profile up to 480 µg without reaching the maximum tolerated dose, and showed a good safety profile at all doses with mild local and systemic reactogenicity. 7 days after vaccination, although no significant differences were observed between the doses, OVX836 increased the frequency of nucleoprotein-specific IFNγ SFCs per million PBMCs from days 1 to 8 (primary endpoint): by 124 SFCs per 106 PMBCs (95% CI 67 to 180; p=0·002) at 180 µg; by 202 SFCs per 106 PMBCs (95% CI 138 to 267; p<0·0001) at 300 µg; by 223 SFCs per 106 PMBCs (95% CI 147 to 299; p<0·0001) at 480 µg; and decreased by 1 SFCs per 106 PMBCs (95% CI -24 to 22] in the placebo group (Kruskal-Wallis test p<0·0001 followed by Mann-Whitney's tests; per-protocol cohort). Dose-dependent and polyfunctional nucleoprotein-specific CD4 T-cell responses were observed, and CD8 T-cell responses were elicited at 300 µg and 480 µg (secondary endpoints). INTERPRETATION: OVX836 appears to be a safe and well tolerated candidate vaccine that elicits humoral and cellular nucleoprotein-specific immune responses (including CD8 T cells at the highest dose levels) and showed a preliminary signal of protection against influenza. Therefore, OVX836 is a promising vaccine candidate for universal influenza A prevention, that warrants further trials. FUNDING: OSIVAX, Bpifrance, Wallonia Region, and the EUs Horizon 2020 Research and Innovation Program.

The economic and societal burden associated with adolescent idiopathic scoliosis: A burden-of-disease study protocol.

Background: Adolescent idiopathic scoliosis (AIS) has an estimated general population prevalence of 2% to 3%. The impact of adolescent idiopathic scoliosis (AIS) on the patients' experienced quality of life and psychological well-being and the resulting societal burden are increasingly recognized. However, there is limited knowledge on the economic burden of AIS. This cross-sectional, prevalence-based, bottom-up approach burden of disease study aims to determine the impact associated with adolescent idiopathic scoliosis in terms of the cost-of-illness and health-related quality of life from a societal perspective in the Netherlands. Methods: Persons diagnosed with AIS or parents of a child with AIS that are willing and able to answer the questionnaires will be eligible to participate. Patients will be included consecutively between June until January 2023. Costs and self-perceived health-related quality of life will be estimated using 3 steps: identification, measurement and valuation. To assess the costs associated with AIS the institute for Medical Technology Assessment - Medical Consumption Questionnaire and the institute for Medical Technology Assessment - Productivity Cost Questionnaire will be used. To assess the HRQoL of adult AIS patients the EuroQol 5-dimensions or EuroQol 5-dimensions Youth questionnaire for children under the age of 12 and the Scoliosis Research Society-22 revised questionnaire will be considered. Discussion: This is the first study in this field. It will help raise awareness for AIS and wider support for both the patient community and informal care takers among healthcare professionals and policymakers. Major strengths of this study will be the use of mostly validated, standardized questionnaires. Limitations include the cross-sectional and retrospective nature of the study design.

The accuracy of commercially available instrumented insoles (ARION) for measuring spatiotemporal running metrics.

Spatiotemporal metrics such as step frequency have been associated with running injuries in some studies. Wearables can measure these metrics and provide real-time feedback in-field, but are often not validated. This study assessed the validity of commercially available wireless instrumented insoles (ARION) for quantifying spatiotemporal metrics during level running at different speeds (2.78-5.0 m s-1 ,) and slopes (3° and 6° up/downhill) to an instrumented treadmill. Mean raw, percentage and absolute percentage error, and limits of agreement (LoA) were calculated. Agreement was statistically quantified using four thresholds: excellent, <5%; good, <10%; acceptable, <15%; and poor, >15% error. Excellent agreement (<5% error) was achieved for stride time across all conditions, and for step frequency across all but one condition with good agreement. Contact time and swing time generally showed at least good agreement. The mean difference across all conditions was -0.95% for contact time, 0.11% for stride time, 0.6% for swing time, -0.11% for step frequency, and -0.09% when averaged across all outcomes and conditions. The accuracy at an individual level was generally good to excellent, being <10% for all but two conditions, with these conditions being <15%. Additional experiments among four runners showed that step length could also be measured with an accuracy of 1.76% across different speeds with an updated version of the insoles. These findings suggests that the ARION wearable may not only be useful for large-scale in-field studies investigating group differences, but also to quantify spatiotemporal metrics with generally good to excellent accuracy for individual runners.

Predictors of poor outcome following lumbar spinal fusion surgery: a prospective observational study to derive two clinical prediction rules using British Spine Registry data.

PURPOSE: Lumbar spinal fusion surgery (LSFS) is common for lumbar degenerative disorders. The objective was to develop clinical prediction rules to identify which patients are likely to have a favourable outcome to inform decisions regarding surgery and rehabilitation. METHODS: A prospective observational study recruited 600 (derivation) and 600 (internal validation) consecutive adult patients undergoing LSFS for degenerative lumbar disorder through the British Spine Registry. Definition of good outcome (6 weeks, 12 months) was reduction in pain intensity (Numerical Rating Scale, 0-10) and disability (Oswestry Disability Index, ODI 0-50) > 1.7 and 14.3, respectively. Linear and logistic regression models were fitted and regression coefficients, Odds ratios and 95% CIs reported. RESULTS: Lower BMI, higher ODI and higher leg pain pre-operatively were predictive of good disability outcome, higher back pain was predictive of good back pain outcome, and no previous surgery and higher leg pain were predictive of good leg pain outcome; all at 6 weeks. Working and higher leg pain were predictive of good ODI and leg pain outcomes, higher back pain was predictive of good back pain outcome, and higher leg pain was predictive of good leg pain outcome at 12 months. Model performance demonstrated reasonable to good calibration and adequate/very good discrimination. CONCLUSIONS: BMI, ODI, leg and back pain and previous surgery are important considerations pre-operatively to inform decisions for surgery. Pre-operative leg and back pain and work status are important considerations to inform decisions for management following surgery. Findings may inform clinical decision making regarding LSFS and associated rehabilitation.

Dataset of 3D gait analysis in typically developing children walking at three different speeds on an instrumented treadmill in virtual reality.

In this article, gait data of typically developing (TD) children (24 boys/31 girls, mean (95% confidence interval) age 9.38 (8.51 - 10.25) years, body mass 35.67 (31.40 - 39.94) kg, leg length 0.73 (0.70 - 0.76) m, and height 1.41 (1.35 - 1.46) m) walking at different walking speeds is shared publicly. Raw and processed data is presented for each child separately and includes data of each single step of both legs. Beside, the subject demographics and the results from the physical examination are presented allowing to select TD children from the database to create a matched group, based on specific parameters (e.g. sex and body weight). For clinical application, gait data is also presented per age group, which provides quick insight into the normal gait pattern of TD children of varying age. Gait analysis was performed during treadmill walking in a virtual environment using the Computer Assisted Rehabilitation Environment (CAREN). The human body lower limb model with trunk markers (HBM2) was used as biomechanical model. Children walked at comfortable walking speed, 30% slower and 30% faster (random sequence) while wearing gymnastic shoes and a safety harness to prevent falling. For each speed condition, 250 steps were recorded. Data quality check, step detection and the calculation of gait parameters was done by custom made Matlab algorithms. Raw data files are provided per walking speed, for each child separately. The raw data is exported from the CAREN software (D-flow) and is provided in .mox and .txt files. It includes the output from the models such as subject data, marker and force data, kinematic data (joint angles), kinetic data (joint moments, GRFs, joint powers), as well as CoM data and EMG data (the last two are not described in this manuscript), for each speed condition and each child. Unfiltered and filtered data are included. C3D files with raw marker and GRF data were recorded in Nexus (Vicon software) and are available upon request. After analyzing the raw data into Matlab (R2016a, Mathworks) using custom made Matlab algorithms, processed data is obtained. The processed data is provided in .xls files and is also presented for each child separately. It contains spatiotemporal parameters, 3D joint angles, anterior-posterior and vertical ground reaction forces (GRF), 3D joint moments and sagittal joint power of each step of the left and right leg. In addition to each individual's data, overview files (.xls) are created per walking speed condition. These overviews present the averaged gait parameter (e.g. joint angle), calculated over all valid steps, of each child.

Predicting Survival in Patients Presenting With Spinal Epidural Metastases: The Limburg Spinal Metastasis Score.

BACKGROUND: Patients with spinal epidural metastases (SEM) often experience a reduction in ambulatory status and, thus, the quality of life. Predicting which patients will benefit from a surgical intervention remains a challenge. Life expectancy is an essential factor to be considered in surgical decision-making, although not the only one. Prediction models can add value in surgical decision-making. The goal of this study was to develop and internally validate a novel model (Limburg spinal metastases score [LSMS]) and compare the predictive value with 2 commonly used models: modified Bauer score and Oswestry Spinal Risk Index (OSRI). METHODS: We retrospectively analyzed 144 consecutive patients who underwent surgical decompression for SEM in our centers between November 2006 and December 2020. Clinical and surgical parameters were evaluated. The novel prediction model was based on multivariate analysis and was internally validated. External validation of the 2 most commonly used prediction models was performed. RESULTS: The median survival was 17 months, 55.7% of the immobile patients regained ambulation postoperatively. In 50 patients (34.7%), at least 1 complication occurred within 30 days after surgery. The LSMS consists of 4 parameters: primary tumor type, Karnofsky performance score, presence of visceral metastases, and presence of multiple spinal metastases. Bootstrap internal validation of the model developed on this cohort yielded an optimism-corrected c-statistic of 0.75 (95% CI: 0.71-0.80). The c-statistic of the OSRI score and the Bauer score was 0.69 (95% CI: 0.64-0.74) and 0.67 (95% CI: 0.62-0.72), respectively. CONCLUSION: The LSMS consists of 4 parameters to assist surgical decision-making for patients with SEM. The score is easy to use and appears more accurate in our population in comparison with previous existing models. CLINICAL RELEVANCE: A novel prediction model was developed to aid in surgical decision-making for patients with spinal epidural metastases.

Strengthening clinical development activities and preparedness for vaccine manufacturers from emerging countries: Results of a survey.

Vaccine development, in most cases, is a long, complex process, often lasting years and involving a combination of public and private stakeholders. Particularly, the vaccine clinical development process is highly regulated by several guidelines, regulatory pathways and science-based recommendations from experts. Designing and executing a successful clinical development plan for any candidate vaccine requires a solid scientific, medical, operational and regulatory knowledge and expertise, to comply with regulations and assure adequate benefit-risk balance for the product to be used in mass vaccination of healthy populations. The purpose of this study was to assess the approaches and practices related to Clinical Development functions, and related activities among vaccine manufacturers based in emerging countries, and to identify industry needs in terms of organizational development and training needs. A structured questionnaire designed specifically for assessing indicators of clinical activities, in the last five years, comprised of four sections aimed to collect information on (1) the organizational structure and the activities conducted by the clinical functions; (2) the clinical trial design ability and the management of clinical trial documents; (3) the clinical trial management and monitoring activities; (4) the quality aspects of clinical activities. The results suggest that the great majority of respondents is engaged in intense clinical development activities, as indicated by the high number of licensed vaccines available and supplied in the national markets or in foreign markets, including vaccines with WHO prequalification status. Areas to further strengthen the clinical activities and medical research preparedness were identified. Greater engagements of stakeholders' and investments will be required to expand the clinical basis in vaccine R&D, and to support achieving a high level of preparedness in emerging countries, for development of new vaccines against future regional epidemics and global pandemics.

Antibiotic release from PMMA spacers and PMMA beads measured with ELISA: Assessment of in vitro samples and drain fluid samples of patients.

For prosthetic joint infections, antibiotic loaded poly methyl methacrylate (PMMA) spacer or beads can be used to release high concentrations of antibiotics locally at the infection site, while minimizing systemic toxicity. The aim of this study is to determine in vitro and in vivo pharmacokinetic release profile of antibiotics from PMMA spacers and PMMA beads. For the in vitro experiment, the PMMA spacers or beads were submerged in phosphate-buffered saline and gentamicin concentrations were determined from collected specimen at several times points, measured with enzyme-linked immunosorbent assays (ELISA). To assess the in vivo antibiotic release profile of different spacers, wound drainage fluid samples were collected after implantation of a spacer over a period of maximum 14 days. After 48 h, the burst gentamicin concentration elution was 9862 ± 1782 ng/ml (mean ± SD) from spacers versus 38,394 ± 7071 ng/ml (mean ± SD) for beads. Over 35 days, spacers had eluted a cumulative mean concentration of 13,812 ± 3548 versus 55,048 ± 12,006 ng/ml for beads (p < 0.001). Clinical samples of patients with a Vancogenx® spacer showed higher gentamicin release than Refobacin™ spacers (p < 0.001). This is the first study that measured the release data of local antibiotics with ELISA. Compare to spacers, the exact release values of gentamicin from PMMA beads are more than 10 times higher and reached a maximum much later than spacers. This makes the use of PMMA beads more preferable to use for treatment of the infection itself.

'What you suggest is not what I expected': How pre-consultation expectations affect shared decision-making in patients with low back pain.

OBJECTIVE: Existing studies on shared decision-making (SDM) have hardly taken into consideration that patients could have independently developed expectations prior to their consultation with a healthcare provider, nor have studies explored how such expectations affect SDM. Therefore, we explore how pre-consultation expectations affect SDM in patients with low back pain. METHODS: We performed a qualitative study through telephone interviews with 10 patients and seven care professionals (physicians, nurse, physician assistants) and 63 in-person observations of patient-physician consultations in an outpatient clinic in the Netherlands. Transcripts were analyzed through an open coding process. RESULTS: A discrepancy existed between what patients expected and what care professionals could offer. Professionals perceived they had to undertake additional efforts to address patients' 'unrealistic' expectations while attempting SDM. Patients, in turn, were often dissatisfied with the outcomes of the SDM encounter, as they believed their own expectations were not reflected in the final decision. CONCLUSION: Unaddressed pre-consultation expectations form a barrier to constructive SDM encounters. PRACTICAL IMPLICATIONS: Patients' pre-consultation expectations need to be explored during the SDM encounter. To achieve decisions that are truly shared by care professionals and patients, patients' pre-consultation expectations should be better incorporated into SDM models and education.

Preoperative community based functional high intensity interval training (f-HIIT) with high-risk patients opting for lumbar spinal fusion: a pilot study.

PURPOSE: To determine the feasibility, safety and preliminary effectiveness of preoperative functional high-intensity interval training (f-HIIT) for high-risk patients undergoing LSF. MATERIALS AND METHODS: High-risk patients eligible for elective 1-3 level LSF were included. Feasibility and safety of the preoperative f-HIIT program was determined by measuring participation and attrition rates, training adherence, adverse events, reached training intensity and preoperative progression in physical fitness. Preliminary effect of the preoperative f-HIIT program was estimated on time to postoperative functional recovery and length of hospital stay (LoS) between high-risk patients who did and did not participate in the prehabilitation program. RESULTS: Eleven out of 23 high-risk patients opted to participate in the f-HIIT program, which was safe and feasible, as no adverse events occurred and only one out of 74 sessions was missed (1.4%). Trained high-risk patients improved their physical fitness with 21.2% on average and obtained faster time to functional recovery compared to matched untrained patients (median 4.5 vs 7.5 days; p = 0.013). No effect was seen on LoS (median 7 vs 8 days (p = 0.58)). CONCLUSIONS: The preoperative f-HIIT program is feasible, safe and shortened time to postoperative functional recovery in patients who underwent LSF.Implications for rehabilitationPreoperative high-intensity interval training is safe and feasible for high-risk patients opting for lumbar spinal fusion.In a relatively small sample the study shows preoperative high-intensity interval training could reduce time to functional recovery in high-risk patients opting for lumbar spinal fusion.