An expanded access protocol of RT001 in amyotrophic lateral sclerosis-Initial experience with a lipid peroxidation inhibitor.

INTRODUCTION/AIMS: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA). METHODS: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88 g/day, which was increased to to 8.64 g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3 months after RT001 initiation. RESULTS: Sixteen participants received RT001 (5.6 ± 1.6 g/day; dose range, 1.92 to 8.64 g/day) for a mean period of 10.8 ± 7.1 months. After 3 months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001. DISCUSSION: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS.

Surgery versus physical therapy for a meniscal tear and osteoarthritis.

BACKGROUND: Whether arthroscopic partial meniscectomy for symptomatic patients with a meniscal tear and knee osteoarthritis results in better functional outcomes than nonoperative therapy is uncertain. METHODS: We conducted a multicenter, randomized, controlled trial involving symptomatic patients 45 years of age or older with a meniscal tear and evidence of mild-to-moderate osteoarthritis on imaging. We randomly assigned 351 patients to surgery and postoperative physical therapy or to a standardized physical-therapy regimen (with the option to cross over to surgery at the discretion of the patient and surgeon). The patients were evaluated at 6 and 12 months. The primary outcome was the difference between the groups with respect to the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical-function score (ranging from 0 to 100, with higher scores indicating more severe symptoms) 6 months after randomization. RESULTS: In the intention-to-treat analysis, the mean improvement in the WOMAC score after 6 months was 20.9 points (95% confidence interval [CI], 17.9 to 23.9) in the surgical group and 18.5 (95% CI, 15.6 to 21.5) in the physical-therapy group (mean difference, 2.4 points; 95% CI, -1.8 to 6.5). At 6 months, 51 active participants in the study who were assigned to physical therapy alone (30%) had undergone surgery, and 9 patients assigned to surgery (6%) had not undergone surgery. The results at 12 months were similar to those at 6 months. The frequency of adverse events did not differ significantly between the groups. CONCLUSIONS: In the intention-to-treat analysis, we did not find significant differences between the study groups in functional improvement 6 months after randomization; however, 30% of the patients who were assigned to physical therapy alone underwent surgery within 6 months. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; METEOR ClinicalTrials.gov number, NCT00597012.).

The AViKA (Adding Value in Knee Arthroplasty) postoperative care navigation trial: rationale and design features.

BACKGROUND: Utilization of total knee arthroplasty is increasing rapidly. A substantial number of total knee arthroplasty recipients have persistent pain after surgery. Our objective was to design a randomized controlled trial to establish the efficacy of a motivational-interviewing-based telephone intervention aimed at improving patient outcomes and satisfaction following total knee arthroplasty. METHODS/DESIGN: The study was conducted at Brigham and Women's Hospital in Boston, Massachusetts. The study focused on individuals 40 years or older with a primary diagnosis of osteoarthritis who were scheduled for total knee arthroplasty. The study compared two management strategies over the first six months postoperatively: 1) enhanced postoperative care with frequent follow-up by a care navigator; 2) usual postoperative care. Those who were randomized into the enhanced postoperative care arm received ten calls from a trained non-clinician care navigator over the first six postoperative months. The navigator used motivational interviewing techniques to engage patients in discussions related to their rehabilitation goals, including patient's plans for and confidence in achieving those goals. Patients in the usual care arm received standard postoperative management and received no navigator phone calls. Patients in both arms were assessed at baseline, three months, and six months postoperatively. DISCUSSION: The primary outcome of the study was improvement in function as measured by the difference in Western Ontario and McMaster Universities Osteoarthritis Index function score between preoperative (baseline) status and six months postoperatively. Data were collected to identify factors that may be related to total knee arthroplasty outcomes, including preoperative pain, pain catastrophizing, self-efficacy, and depression. A formal economic analysis is also planned to determine the cost-effectiveness of the care navigator as a component of total knee arthroplasty care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01540851.

The MeTeOR trial (Meniscal Tear in Osteoarthritis Research): rationale and design features.

This paper presents the rationale and design features of the MeTeOR Trial (Meniscal Tear in Osteoarthritis Research; Clinical Trials.gov NCT00597012). MeTeOR is an NIH-funded seven-center prospective randomized controlled trial (RCT) designed to establish the efficacy of arthroscopic partial meniscectomy combined with a standardized physical therapy program as compared with a standardized physical therapy program alone in patients with a symptomatic meniscal tear in the setting of mild to moderate knee osteoarthritic change (OA). The design and execution of a trial that compares surgery with a nonoperative treatment strategy presents distinctive challenges. The goal of this paper is to provide the clinical rationale for MeTeOR and to highlight salient design features, with particular attention to those that present clinical and methodologic challenges.

Simultaneous electroencephalography and functional magnetic resonance imaging of general anesthesia.

It has been long appreciated that anesthetic drugs induce stereotyped changes in electroencephalogram (EEG), but the relationships between the EEG and underlying brain function remain poorly understood. Functional imaging methods including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have become important tools for studying how anesthetic drugs act in the human brain to induce the state of general anesthesia. To date, no investigation has combined functional MRI with EEG to study general anesthesia. We report here a paradigm for conducting combined fMRI and EEG studies of human subjects under general anesthesia. We discuss the several technical and safety problems that must be solved to undertake this type of multimodal functional imaging and show combined recordings from a human subject. Combined fMRI and EEG exploits simultaneously the high spatial resolution of fMRI and the high temporal resolution of EEG. In addition, combined fMRI and EEG offers a direct way to relate established EEG patterns induced by general anesthesia to changes in neural activity in specific brain regions as measured by changes in fMRI blood oxygen level dependent (BOLD) signals.

Risk factors for cardiovascular complications following total joint replacement surgery.

OBJECTIVE: To determine risk factors for cardiac complications following total joint replacement (TJR) surgery. METHODS: We performed a case-control study of patients who had undergone a primary or revision total knee or total hip replacement surgery. Cases consisted of those who received a TJR and experienced a cardiac complication during the surgical admission period (myocardial infarction [MI], congestive heart failure [CHF], unstable angina, arrhythmia, symptomatic hypotension, or pulmonary embolus). Controls consisted of those who received a TJR and did not experience a cardiac complication during the surgical admission period. Controls were matched to the cases for age at surgery, year of surgery, and surgeon. Case and control status and identification of potential risk factors were ascertained by review of medical records. Conditional logistic regression analysis was used to identify independent predictors of cardiac complications. RESULTS: The sample included 209 cases and 209 controls. Factors associated with a higher risk of cardiac complications included a history of arrhythmia (adjusted odds ratio [OR] 2.6 [95% confidence interval (95% CI) 1.5-4.3]), a history of coronary artery disease, MI, CHF, or valvular heart disease (OR 1.6 [95% CI 0.9-2.6]), revision surgery (OR 2.2 [95% CI 1.2-3.9]), and bilateral surgery (adjusted OR 3.5 [95% CI 1.6-8.0]). Even though controls were matched for age (within age brackets), age was still associated with a higher risk of cardiac complications (OR 1.7 [95% CI 0.9-3.4]). CONCLUSION: This case-control study identified 2 new risk factors for cardiac complications following TJR: bilateral and revision surgery. The study also confirmed previously documented risk factors, including older age at surgery and a history of arrhythmia and of other cardiac problems. These findings should help clinicians anticipate and prevent cardiac complications following TJR surgery.