Train High Eat Low for Osteoarthritis study (THE LO study): protocol for a randomized controlled trial.

INTRODUCTION: Osteoarthritis (OA) is one of the most prevalent chronic conditions among older adults, with the medial tibio-femoral joint being most frequently affected. The knee adduction moment is recognized as a surrogate measure of the medial tibio-femoral compartment joint load and therefore represents a valid intervention target. This article provides the rationale and methodology for THE LO study (Train High, Eat Low for Osteoarthritis), which is a randomized controlled trial that is investigating the effects of a unique, targeted lifestyle intervention in overweight/obese adults with symptomatic medial knee OA. RESEARCH QUESTION: Compared to a control group given only lifestyle advice, do the effects of the following interventions result in significant reductions in the knee adduction moment: (1) gait retraining; and (2) combined intervention (which involves a combination of three interventions: (a) gait retraining, (b) high-intensity progressive resistance training, and (c) high-protein/low-glycaemic-index energy-restricted diet)? It is hypothesized that the combined intervention group will be superior to the isolated interventions of the high-protein/low-glycaemic-index diet group and the progressive resistance training group. Finally, it is hypothesized that the combined intervention will result in a greater range of improvements in secondary outcomes, including: muscle strength, functional status, body composition, metabolic profile, and psychological wellbeing, compared to any of the isolated interventions or control group. DESIGN: Single-blinded, randomized controlled trial adhering to the CONSORT guidelines on conduct and reporting of non-pharmacological clinical trials. PARTICIPANTS: One hundred and twenty-five community-dwelling people are being recruited. Inclusion criteria include: medial knee OA, low physical activity levels, no current resistance training, body mass index ≥ 25kg/m(2) and age ≥ 40 years. INTERVENTION AND CONTROL: The participants are stratified by sex and body mass index, and randomized into one of five groups: (1) gait retraining; (2) progressive resistance training; (3) high-protein/low-glycaemic-index energy-restricted diet (25 to 30% of energy from protein, 45% of energy from carbohydrates, < 30% of energy from fat, and glycaemic index diet value < 50); (4) a combination of these three active interventions; or (5) a lifestyle-advice control group. All participants receive weekly telephone checks for health status, adverse events and optimisation of compliance. MEASUREMENTS: Outcomes are measured at baseline, 6 and 12 months. The primary outcome is the peak knee adduction moment during the early stance phase of gait. The secondary outcome measures are both structural (radiological), with longitudinal reduction in medial minimal joint space width at 12 months, and clinical, including: change in body mass index; joint pain, stiffness and function; body composition; muscle strength; physical performance/mobility; nutritional intake; habitual physical activity and sedentary behaviour; sleep quality; psychological wellbeing and quality of life. DISCUSSION: THE LO study will provide the first direct comparison of the long-term benefits of gait retraining, progressive resistance training and a high-protein/low-glycaemic-index energy-restricted diet, separately and in combination, on joint load, radiographic progression, symptoms, and associated co-morbidities in overweight/obese adults with OA of the knee.

Safety and efficacy of ranirestat in patients with mild-to-moderate diabetic sensorimotor polyneuropathy.

We examined the efficacy and safety of ranirestat in patients with diabetic sensorimotor polyneuropathy (DSPN). Patients (18-75 years) with stable type 1/2 diabetes mellitus and DSPN were eligible for this global, double-blind, phase II/III study (ClinicalTrials.gov NCT00927914). Patients (n = 800) were randomized 1 : 1 : 1 to placebo, ranirestat 40 mg/day or 80 mg/day (265 : 264 : 271). Change in peroneal motor nerve conduction velocity (PMNCV) from baseline to 24 months was the primary endpoint with a goal improvement vs. placebo ≥1.2 m/s. Other endpoints included symptoms, quality-of-life, and safety. Six hundred thirty-three patients completed the study. The PMNCV difference from placebo was significant at 6, 12, and 18 months in both ranirestat groups, but <1.2 m/s. The mean improvement from baseline at 24 months was +0.49, +0.95, and +0.90 m/s for placebo, ranirestat 40 mg and 80 mg, respectively (NS). The treatment difference vs. placebo reached significance when ranirestat groups were combined in a post hoc analysis (+0.44 m/s; p = 0.0237). There was no effect of ranirestat on safety assessments, secondary or exploratory endpoints vs. placebo. Ranirestat was well tolerated and improved PMNCV, but did not achieve any efficacy endpoints. The absence of PMNCV worsening in the placebo group underscores the challenges of DSPN studies in patients with well-controlled diabetes.

Sexual orientation change efforts through psychotherapy for LGBQ individuals affiliated with the Church of Jesus Christ of Latter-day Saints.

This study reports the results of a comprehensive online survey of 1,612 current or former members of the Church of Jesus Christ of Latter-day Saints, many of whom engaged in psychotherapy to cope with (i.e., understand, accept, or change) their same-sex attractions. Data obtained from written and quantitative responses showed that therapy was initiated over a very wide age range and continued for many years. However, counseling was largely ineffective; less than 4% reported any modification of core same-sex erotic attraction. Moreover, 42% reported that their change-oriented therapy was not at all effective, and 37% found it to be moderately to severely harmful. In contrast, affirming psychotherapeutic strategies were often found to be beneficial in reducing depression, increasing self-esteem, and improving family and other relationships. Results suggest that the very low likelihood of a modification of sexual orientation and the ambiguous nature of any such change should be important considerations for highly religious sexual minority individuals considering reorientation therapy.

Adjunctive zonisamide therapy in the long-term treatment of children with partial epilepsy: results of an open-label extension study of a phase III, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate the safety/tolerability and efficacy of long-term adjunctive zonisamide and its impact on growth and development in children (6-18 years) with partial epilepsy. METHODS: Open-label extension of a phase III, placebo-controlled trial. Started with double-blind transition period (2-11 weeks), during which patients on zonisamide continued at the same dose and those on placebo switched to zonisamide 1 mg/kg/day, up-titrated to 8 mg/kg/day (maximum 500 mg/day). During the subsequent open-label period (45-57 weeks), zonisamide dosing could be adjusted according to tolerability/response. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters, and vital signs. Efficacy assessments included responder rate (primary assessment) and seizure freedom rate during the open-label period. Growth and development assessments comprised Tanner stages, hand x-rays, Child Behavior Checklist (CBCL 6/18), School Performance questionnaire, Physician and Parent/Guardian Global Impression of Change, and Controlled Oral Word Association Test (COWAT). RESULTS: One hundred forty-four children entered the study; 99 (68.8%) of 144 children completed it, and 108 (75.0%) of 144 received zonisamide for ≥1 year. TEAEs occurred in 39 (27.1%) of 144 patients. There were low incidences of serious TEAEs (2.1%) and TEAEs leading to discontinuation (2.8%). Bicarbonate level decreases >3.5 mm occurred in 64 patients (44.4%), and 24 patients (16.7%) had a weight decrease of ≥10% from baseline. During the open-label period, 81 (56.3%) of 144 patients were responders and 16 (11.1%) of 144 achieved seizure freedom. Tanner staging and skeletal development were as expected for the study population. Changes were minimal for CBCL 6/18 and School Performance scores. Most patients were "much improved"/"very much improved" on Physician (73.8%) and Parent/Guardian (75.4%) Global Impressions of Change. Median changes in COWAT Category and Letter Fluency scores were 2.0 and 0.5, respectively. SIGNIFICANCE: Adjunctive zonisamide was well tolerated and efficacious over a period of at least 1 year in children with partial epilepsy, with no unexpected safety concerns and no consistent detrimental effects on growth and development. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy.

PURPOSE: To assess the efficacy and safety/tolerability of adjunctive zonisamide treatment in pediatric patients with partial epilepsy. METHODS: In this phase III, double-blind, randomized, placebo-controlled, multicenter trial, 207 patients (age 6-17 years) with partial epilepsy, receiving one or two antiepileptic drugs, were randomized to receive adjunctive zonisamide or placebo. Zonisamide was initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over 8 weeks (one down-titration permitted), and maintained for 12 weeks. The primary efficacy end point was the proportion of responders (≥ 50% seizure frequency reduction from baseline) during the 12-week maintenance period. Safety/tolerability assessments included the incidence of treatment-emergent adverse events (TEAEs). KEY FINDINGS: In total, 93 (86.9%) of 107 patients randomized to zonisamide and 90 (90.0%) of 100 patients randomized to placebo completed the trial. Responder rates were 50% for zonisamide versus 31% for placebo (p = 0.0044; intention-to-treat population, last observation carried forward). The overall incidence of TEAEs was similar for zonisamide (55.1%) versus placebo (50.0%), with low rates of serious TEAEs with zonisamide and placebo (3.7% vs. 2.0%) and TEAEs leading to withdrawal (0.9% vs. 3.0%). TEAEs reported more frequently with zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%). SIGNIFICANCE: Adjunctive zonisamide treatment was shown to be effective and well tolerated in pediatric patients with partial epilepsy. No new or unexpected safety findings emerged.