Predictors and outcomes of crossover to surgery from physical therapy for meniscal tear and osteoarthritis a randomized trial comparing physical therapy and surgery

BACKGROUND: Arthroscopic partial meniscectomy (APM) combined with physical therapy (PT) have yielded pain relief similar to that provided by PT alone in randomized trials of subjects with a degenerative meniscal tear. However, many patients randomized to PT received APM before assessment of the primary outcome. We sought to identify factors associated with crossing over to APM and to compare pain relief between patients who had crossed over to APM and those who had been randomized to APM. METHODS: We used data from the MeTeOR (Meniscal Tear in Osteoarthritis Research) Trial of APM with PT versus PT alone in subjects ≥45 years old who had mild-to-moderate osteoarthritis and a degenerative meniscal tear. We assessed independent predictors of crossover to APM among those randomized to PT. We also compared pain relief at 6 months among those randomized to PT who crossed over to APM, those who did not cross over, and those originally randomized to APM. RESULTS: One hundred and sixty-four subjects were randomized to and received APM and 177 were randomized to PT, of whom 48 (27%) crossed over to receive APM in the first 140 days after randomization. In multivariate analyses, factors associated with a higher likelihood of crossing over to APM among those who had originally been randomized to PT included a baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score of ≥40 (risk ratio [RR] = 1.99; 95% confidence interval [CI] = 1.00, 3.93) and symptom duration of <1 year (RR = 1.74; 95% CI = 0.98, 3.08). Eighty-one percent of subjects who crossed over to APM and 82% of those randomized to APM had an improvement of ≥10 points in their pain score at 6 months, as did 73% of those who were randomized to and received only PT. CONCLUSIONS: Subjects who crossed over to APM had presented with a shorter symptom duration and greater baseline pain than those who did not cross over from PT. Subjects who crossed over had rates of surgical success similar to those of the patients who had been randomized to surgery. Our findings also suggest that an initial course of rigorous PT prior to APM may not compromise surgical outcome. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence

Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity

New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances

The Post-Transcriptional Regulation of Antioxidant Enzymes

An excess in the levels of reactive oxygen species (ROS) can contribute to the development of cancer due to the oxidative damage to molecules such as DNA, protein and cellular membranes. Antioxidant proteins, including those that belong to the glutathione peroxidase (GPx), superoxide dismutase (SOD) and thioredoxin reductase (TrxR) families, contribute to the maintenance of the cellular redox balance by detoxification of ROS. Our attention was drawn to a report indicating that the non-receptor tyrosine kinase c-Abl could phosphorylate and activate the activity of GPx1 in tissue culture cells. To investigate this phenomenon further in humans, GPx activity were determined in samples obtained from patients with chronic myelogenous leukemia (CML), a disease initiated by the rearrangement of two different chromosomes and resulting in the Bcr-Abl oncogene. Samples were obtained before and after treatment with the Bcr-Abl inhibitor imatinib mesylate, and of the seven patient sample sets obtained, four exhibited elevated GPx activity following treatment, which was contrary to expectation. In order to expand upon this observation, the CML established cell lines KU812 and MEG-01 were treated with imatinib and the effect on several antioxidant proteins was determined. The levels of GPx1, manganese superoxide dismutase (MnSOD) and thioredoxin reductase 1 (TrxR1) were each significantly increased following treatment with imatinib. This increase was not due to altered steady-state mRNA levels, and appeared to be dependent on the expression of Bcr-Abl, as no increases were observed following imatinib treatment of cells that did not express the fusion protein. The nutrient-sensing signaling protein, mammalian target of rapamycin (mTOR), can be activated by Bcr-Abl and its activity regulates the translation of several proteins. Treatment of those same cells used in the imatinib studies with rapamycin, an inhibitor of mTOR, resulted in elevated GPx1, TrxR1 and GPx4 protein levels independent of Bcr-Abl expression. These proteins all belong to the selenoprotein family of peptides that contain the UGA-encoded amino acid selenocysteine. Collectively, these data provide evidence of a novel means of regulating antioxidants of the selenoprotein family via the mTOR pathway

Translational regulation of GPx-1 and GPx-4 by the mTOR pathway.

Glutathione peroxidase activity was previously determined to be elevated in lymphocytes obtained from patients treated with the Bcr-Abl kinase inhibitor imatinib mesylate. In order to expand upon this observation, the established chronic myelogenous leukemia cell lines KU812 and MEG-01 were treated with imatinib and the effect on several anti-oxidant proteins was determined. The levels of GPx-1 were significantly increased following treatment with imatinib. This increase was not due to altered steady-state mRNA levels, and appeared to be dependent on the expression of Bcr-Abl, as no increases were observed following imatinib treatment of cells that did not express the fusion protein. The nutrient-sensing signaling protein, mammalian target of rapamycin (mTOR), can be activated by Bcr-Abl and its activity regulates the translation of many different proteins. Treatment of those same cells used in the imatinib studies with rapamycin, an inhibitor of mTOR, resulted in elevated GPx-1 and GPx-4 protein levels independent of Bcr-Abl expression. These proteins all belong to the selenoprotein family of peptides that contain the UGA-encoded amino acid selenocysteine. Collectively, these data provide evidence of a novel means of regulating anti-oxidants of the selenoprotein family via the mTOR pathway

COVID\u27S CONSTITUTIONAL CONUNDRUM: ASSESSING INDIVIDUAL RIGHTS IN PUBLIC HEALTH EMERGENCIES

Considerable legal challenges alleging infringements of constitutional rights have arisen against governments imposing social distancing or other restrictive measures to quell the COVID-19 pandemic. Courts assess these claims largely under two approaches. Consistent with constitutional re-balancing, judges weigh the application of rights against governments\u27 compelling interests to protect public health and safety in emergencies. Alternatively, a minority of courts temporarily set aside existing rights to effectuate emergency responses. Both approaches insufficiently account for the flexible nature of rights and freedoms in exigencies pursuant to the Constitution\u27s cohesive design. In public health emergencies, courts should engage in guided assessments focused on the execution, efficacy, and purpose of public health interventions as a constitutional prerogative rather than examining alleged rights infringements framed outside crisis contexts

Rapamycin increases levels of GPx-4, MnSOD and pS6 protein levels in cell lines.

<p>The effect of 1 ng/mL rapamycin on GPx-4 and MnSOD and pS6 protein levels in KU812a, MEG-01, GM10832 and MDA-MB-231 is shown. GPx-4 by 3-day 1 ng/mL rapamycin treatment in KU812a and MEG-01 (<i>P</i> > 0.2), but was increased 3-fold in GM10832 (<i>P</i> = 0.05) and 6-fold in MDA-MB-231 cells (<i>P</i> = 0.02). The disappearance of pS6 signal following rapamycin treatment indicates inhibition of mTOR. Data shown is representative of three independent experiments.</p

Rapamycin enhances GPx-1 protein and enzyme activity levels in all cell lines investigated.

<p>The effect of rapamycin on GPx-1 activity (A) and protein levels (B) in KU812a, MEG-01 GM10832 or MDA-MB-231 is shown. The effect of rapamycin on steady-state GPx-1 transcript levels as determined by RT-qPCR and normalization of GPx-1 Ct values to Ct values for 18s RNA (C). Rapamycin significantly increased protein respectively 3-fold and 1.3-fold in KU812a and MEG-01 (<i>P</i> = 0.05). Steady state transcript levels for GPx-1 were unaffected by treatment with rapamycin in KU812a. Data shown is representative of three independent experiments. * = <i>P</i><0.001, ** = <i>P</i><0.01. † = <i>P</i><0.05. Error bars indicate S.D.</p

GPx-1 levels are enhanced in a dose- and time-dependent manner following imatinib treatment.

<p>The dose- and time-dependent increases in GPx activity following 100 nM and 150 nM imatinib treatment of KU812a cells for 7 days (A) or 150 nM imatinib treatment for 3 or 7 days (B). The effect of imatinib treatment on GPx1 protein levels. Data shown is representative of thee independent experiments were performed (C). * = <i>P</i><0.001, † = <i>P</i><0.05, compared to 100 nM or 3-day imatinib treatment. Error bars indicate S.D.</p