Introduction Changes in sensorimotor function and increased trunk muscle fatigability have been identified in patients with chronic low back pain (cLBP). This study assessed the control of trunk ...force production in conditions with and without local erector spinae muscle vibration and evaluated the influence of muscle fatigue on trunk sensorimotor control. Methods Twenty non-specific cLBP patients and 20 healthy participants were asked to perform submaximal isometric trunk extension torque with and without local vibration stimulation, before and after a trunk extensor muscle fatigue protocol. Constant error (CE), variable error (VE) as well as absolute error (AE) in peak torque were computed and compared across conditions. Trunk extensor muscle activation during isometric contractions and during the fatigue protocol was measured using surface electromyography (sEMG). Results Force reproduction accuracy of the trunk was significantly lower in the patient group (CE = 9.81 plus or minus 2.23 Nm; AE = 18.16 plus or minus 3.97 Nm) than in healthy participants (CE = 4.44 plus or minus 1.68 Nm; AE = 12.23 plus or minus 2.44 Nm). Local erector spinae vibration induced a significant reduction in CE (4.33 plus or minus 2.14 Nm) and AE (13.71 plus or minus 3.45 Nm) mean scores in the patient group. Healthy participants conversely showed a significant increase in CE (8.17 plus or minus 2.10 Nm) and AE (16.29 plus or minus 2.82 Nm) mean scores under vibration conditions. The fatigue protocol induced erector spinae muscle fatigue as illustrated by a significant decrease in sEMG median time-frequency slopes. Following the fatigue protocol, patients with cLBP showed significant decrease in sEMG root mean square activity at L4-5 level and responded in similar manner with and without vibration stimulation in regard to CE mean scores. Conclusions Patients with cLBP have a less accurate force reproduction sense than healthy participants. Local muscle vibration led to significant trunk neuromuscular control improvements in the cLBP patients before and after a muscle fatigue protocol. Muscle vibration stimulation during motor control exercises is likely to influence motor adaptation and could be considered in the treatment of cLBP. Further work is needed to clearly identify at what levels of the sensorimotor system these gains are achievable.
Objective: To investigate the reliability, concurrent validity, and error of a new video digitizing system for evaluating posture when applied to inanimate objects. Design: Delayed repeated measures ...of digital images of inanimate objects. Setting: University laboratory. Methods: Digital video images of inanimate objects (5 parallelograms) of different sizes and shapes were obtained with the BioTonix postural evaluation system. Three examiners digitized video images of inanimate objects twice; the second data collection was 1 week after the first set. The objects were digitized with both high- and low-resolution settings of the video screen. The Tonix's measurements were statistically compared with the actual object dimensions. Statistical evaluations of reliability and validity were conducted. Results: For distances, both intraclass and interclass correlation coefficients were very high, 0.99 for the estimate. The low- versus high-resolution settings were comparable for distances. For angles, on the low-resolution setting, both intraclass and interclass correlation coefficients were very high: 0.969 and 0.953. On the high-resolution setting, for angles, both intraclass and interclass coefficients were well above 0.99. The difference of the actual size and the means of the digitized measurements of the means were small: at most 1.5° for angles and 3.3 mm for distances. The standard deviations were small, and the confidence intervals were narrow. Conclusions: Our results demonstrate that the BioTonix's video system has high degrees of reliability and validity. Thus this system would seem suitable for clinical use in the analysis of posture. (J Manipulative Physiol Ther 2002;25:246-250)
Little information on quantitative sagittal plane postural alignment and evolution in children exists. The objectives of this study are to document the evolution of upright, static, sagittal posture ...in children and to identify possible critical phases of postural evolution (maturation).
A total of 1084 children (aged 4-12 years) received a sagittal postural evaluation with the Biotonix postural analysis system. Data were retrieved from the Biotonix internet database. Children were stratified and analyzed by years of age with n = 36 in the youngest age group (4 years) and n = 184 in the oldest age group (12 years). Children were analyzed in the neutral upright posture. Variables measured were sagittal translation distances in millimeters of: the knee relative to the tarsal joint, pelvis relative to the tarsal joint, shoulder relative to the tarsal joint, and head relative to the tarsal joint. A two-way factorial ANOVA was used to test for age and gender effects on posture, while polynomial trend analyses were used to test for increased postural displacements with years of age.
Two-way ANOVA yielded a significant main effect of age for all 4 sagittal postural variables and gender for all variables except head translation. No age x gender interaction was found. Polynomial trend analyses showed a significant linear association between child age and all four postural variables: anterior head translation (p < 0.001), anterior shoulder translation (p < 0.001), anterior pelvic translation (p < 0.001), anterior knee translation (p < 0.001). Between the ages of 11 and 12 years, for anterior knee translation, T-test post hoc analysis revealed only one significant rough break in the continuity of the age related trend.
A significant linear trend for increasing sagittal plane postural translations of the head, thorax, pelvis, and knee was found as children age from 4 years to 12 years. These postural translations provide preliminary normative data for the alignment of a child's sagittal plane posture.
Assessment of approved drugs and developmental drug candidates for rare cystic fibrosis (CF)-causing variants of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) requires abundant ...material from relevant models.
Isogenic cell lines harboring CFTR variants in the native genomic context were created through the development and utilization of a footprint-less, CRISPR/Cas9 gene editing pipeline in 16HBE14o- immortalized bronchial epithelial cells.
Isogenic, homozygous cell lines for three CFTR variants (F508del and the two most common CF-causing nonsense variants, G542X and W1282X) were established and characterized. The F508del model recapitulates the known molecular pathology and pharmacology. The two models of nonsense variants (G542X and W1282X) are sensitive to Nonsense Mediated mRNA Decay (NMD) and responsive to reference compounds that inhibit NMD and promote ribosomal readthrough.
We present a versatile, efficient gene editing pipeline that can be used to create CFTR variants in the native genomic context and the utilization of this pipeline to create homozygous cell models for the CF-causing variants F508del, G542X, and W1282X. The resulting cell lines provide a virtually unlimited source of material with specific pathogenic mutations that can be used in a variety of assays, including functional assays.
•A gene editing pipeline was developed to model CFTR variants in the genomic context.•The model of F508del/M470 responds to known pharmacological agents.•The G542X and W1282X models recapitulate non-sense mediated mRNA decay.•The G542X and W1282X models are sensitive to small molecule induced read-through.
Background: The reliability of a test depends on its standardization. Instrumental measurement of the reproducibility of the test is an effective way to evaluate the level of standardization ...obtained. Improved standardization is believed to yield greater reliability. Objective: The objectives of this study were to measure the technical ability of an examiner to reproduce the kinematics of motion palpation for cervical spine rotation and to evaluate the effect of standardization on the reliability of the test. Design: A study of reproducibility of the kinematics of the test for cervical spine rotation was conducted by means of a computerized system of analysis of movement. The reliability when reproducibility was achieved was compared with reliability when it failed. Results: The data collected enable us to establish a standardized protocol for the execution of the test. The standardized palpation is executed within 6° of inclination from the pure plane of rotation. The successful reproduction of the kinematics of the test raises its reliability to detect the presence of fixations (kappa raising from 0.337 and 0.352 to 0.682). Conclusions: A greater reliability, arising from a high level of reproducibility, enables us to document the advantages of the standardization of motion palpation in chiropractic. (J Manipulative Physiol Ther 2002;25:e7)
Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell ...lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs.
We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting.
Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 50%) or docetaxel (n=174 50%). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4–20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months 95% CI 4·3–7·8 vs 4·5 months 3·0–5·7; hazard ratio 0·66 0·51–0·86; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 33% vs n=61 40%) and serious treatment-related adverse events compared with docetaxel (n=18 11% vs n=34 23%). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 12%), alanine aminotransferase increase (n=13 8%), and aspartate aminotransferase increase (n=9 5%). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 9%), fatigue (n=9 6%), and febrile neutropenia (n=8 5%).
Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs.
Amgen.
PARP plays an important role in DNA repair. Veliparib, a PARP inhibitor, enhances the efficacy of platinum compounds and has been safely combined with carboplatin and paclitaxel. The primary endpoint ...of this phase II trial determined whether addition of veliparib to carboplatin and paclitaxel improved progression-free survival (PFS) in previously untreated patients with advanced/metastatic non-small cell lung cancer.
Patients were randomized 2:1 to carboplatin and paclitaxel with either veliparib or placebo. Veliparib (120 mg) or placebo was given on days 1 to 7 of each 3-week cycle, with carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m
) administered on day 3, for a maximum of 6 cycles.
Overall, 158 were included (median age, 63 years; male 68%, squamous histology 48%). Median PFS was 5.8 months in the veliparib group versus 4.2 months in the placebo group HR, 0.72; 95% confidence interval (CI), 0.45-1.15;
= 0.17). Median overall survival (OS) was 11.7 and 9.1 months in the veliparib and placebo groups, respectively (HR, 0.80; 95% CI, 0.54-1.18;
= 0.27). In patients with squamous histology, median PFS (HR, 0.54; 95% CI, 0.26-1.12;
= 0.098) and OS (HR, 0.73; 95% CI, 0.43-1.24;
= 0.24) favored veliparib treatment. Objective response rate was similar between groups (veliparib: 32.4%; placebo: 32.1%), but duration of response favored veliparib treatment (HR, 0.47; 95% CI, 0.16-1.42;
= 0.18). Grade III/IV neutropenia, thrombocytopenia, and anemia were comparable between groups.
Veliparib combination with carboplatin and paclitaxel was well-tolerated and demonstrated a favorable trend in PFS and OS versus chemotherapy alone. Patients with squamous histology had the best outcomes with veliparib combination.
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