Reliability of a gymnastics vaulting feedback system

The current study assessed the intra- and inter-day reliability of a custom-built gymnastics vaulting feedback system. The system is a coach-friendly customized infra-red timing gate and contact timing mat system operated by the coach to augment the feedback provided to gymnasts on their vaulting performance during regular training practice. Thirteen Australian high performance gymnasts (eight males and five females) aged 11-23 years were assessed during two training sessions (Day 1 and Day 2) at their regular training centre. The approach velocity and board contact time measures were found to be reliable measures during vault training, with measures of pre-flight and table contact time less consistent. Future research should examine the validity of these measures as a tool for monitoring vault training.<br /

HOW SAFE ARE THE CODE OF POINTS LANDING TECHNICAL REQUIREMENTS IN ARTISTIC GYMNASTICS? PRELIMINARY RESULTS

To examine the effect of the code of points landing technical requirements in artistic gymnastics, eight female artistic gymnasts performed backward somersault dismounts off a 90 cm vaulting box. Three dimensional motion as well as upper back accelerations were measured for three landing techniques: current competition landing with feet together (FT); competition landing with a step back (SB); landing with feet shoulder width apart (FA). Group average impact forces were lowest for the FA technique; individual analyses showed SB or FA techniques were safer for 75% of gymnasts. Upper back accelerations indicating how well they could control the impact shock did not differ between the three landing techniques. The landing rule in gymnastics does have an effect on the initial and werall impact loads for backward somersault dismounts

Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models

PURPOSE ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. EXPERIMENTAL DESIGN We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). RESULTS Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSIONS In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells

Background: Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. Methods: Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. Results: Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRASQ61K mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. Conclusions: Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P &lt; 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P &lt; 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Reliability and variability of day-to-day vault training measures in artistic gymnastics

Inter-day training reliability and variability in artistic gymnastics vaulting was determined using a customised infra-red timing gate and contact mat timing system. Thirteen Australian high performance gymnasts (eight males and five females) aged 11-23 years were assessed during two consecutive days of normal training. Each gymnast completed a number of vault repetitions per daily session. Inter-day variability of vault run-up velocities (at -18 to -12 m, -12 to -6 m, -6 to -2 m, and -2 to 0 m from the nearest edge of the beat board), and board contact, pre-flight, and table contact times were determined using mixed modelling statistics to account for random (within-subject variability) and fixed effects (gender, number of subjects, number of trials). The difference in the mean (Mdiff) and Cohen\u27s effect sizes for reliability assessment and intra-class correlation coefficients, and the coefficient of variation percentage (CV%) were calculated for variability assessment. Approach velocity (-18 to -2 m, CV = 2.4-7.8%) and board contact time (CV = 3.5%) were less variable measures when accounting for day-to-day performance differences, than pre-flight time (CV = 17.7%) and table contact time (CV = 20.5%). While pre-flight and table contact times are relevant training measures, approach velocity and board contact time are more reliable when quantifying vaulting performance. <br /

Agreement between force and deceleration measures during backward somersault landings

This study examined the agreement between force platform and inertial measurement unit (IMU) measures of backward somersault landings. Seven female gymnasts performed three trials, taking off from a 90 cm vaulting box and using competition landing technique. Two force platforms (1000 Hz) covered with a 6.4 cm thick carpeted landing surface measured the ground reaction forces. One inertial measurement unit (500 Hz) fixed on the second thoracic vertebra measured peak resultant deceleration of the gymnast. Measurement agreement between vertical and resultant peak force measures, and resultant peak force and peak deceleration was assessed using mean differences, Pearson’s correlation, and Cohen’s effect size (ES) statistics. There was perfect measurement agreement between vertical and resultant peak forces (R = 1.0, p < 0.001; ES = 0.005), but only moderate measurement agreement between resultant peak force and peak resultant deceleration (Mean Difference = −2.16%, R = 0.4, p = ns; ES = 0.121). Backward somersault landings can be assessed using either uni-axial or tri-axial force platforms to measure ground impact load/force, as the landing movements are almost purely vertical. However, force measures are not the same as peak resultant decelerations from IMUs which give an indication of impact shock. Landing load/shock measures are potentially important for injury prevention

Development of X-ray micro-focus computed tomography to image and quantify biofilms in central venous catheter models in vitro

Bacterial infections of central venous catheters (CVCs) cause much morbidity and mortality, and are usually diagnosed by concordant culture of blood and catheter tip. However, studies suggest that culture often fails to detect biofilm bacteria. This study optimises X-ray micro computed tomography (X-ray µCT) for the quantification and determination of distribution and heterogeneity of biofilms in in vitro central venous catheter (CVC) model systems.Bacterial culture and scanning electron microscopy (SEM) were used to detect Staphylococcus epidermidis ATCC 35984 biofilms grown on catheters in vitro in both flow and static biofilm models. Alongside this, X-ray µCT techniques were developed in order to detect biofilms inside CVCs. Various contrast agent stains were evaluated using energy dispersive X-ray spectroscopy (EDS) to further optimise these methods. Catheter material and biofilm were segmented using a semi-automated MATLAB script and quantified using the Avizo Fire software package.X-ray µCT was capable of distinguishing between the degree of biofilm formation across different segments of a CVC flow model. EDS screening of single and dual compound contrast stains identified 10 nm gold and silver nitrate as the optimum contrast agent for X-ray µCT. This optimised method was then demonstrated to be capable of quantifying biofilms in an in vitro static biofilm formation model, with a strong correlation between biofilm detection via SEM and culture.X-ray µCT has good potential as a direct, non-invasive, non-destructive technology to image biofilms in CVCs, as well as other in vivo medical components in which biofilms accumulate in concealed areas