A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease.

Polymerization of deoxygenated hemoglobin S underlies the pathophysiology of sickle cell disease (SCD). In activating red blood cell pyruvate kinase and glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream precursor in glycolysis. Both changes have therapeutic potential for patients with SCD. Here, we evaluated the safety and tolerability of multiple ascending doses of mitapivat in adults with SCD with no recent blood transfusions or changes in hydroxyurea or l-glutamine therapy. Seventeen subjects were enrolled; 1 subject was withdrawn shortly after starting the study. Sixteen subjects completed 3 ascending dose levels of mitapivat (5, 20, and 50 mg, twice daily [BID]) for 2 weeks each; following a protocol amendment, the dose was escalated to 100 mg BID in 9 subjects. Mitapivat was well tolerated at all dose levels, with the most common treatment-emergent adverse events (AEs) being insomnia, headache, and hypertension. Six serious AEs (SAEs) included 4 vaso-occlusive crises (VOCs), non-VOC-related shoulder pain, and a preexisting pulmonary embolism. Two VOCs occurred during drug taper and were possibly drug related; no other SAEs were drug related. Mean hemoglobin increase at the 50 mg BID dose level was 1.2 g/dL, with 9 of 16 (56.3%) patients achieving a hemoglobin response of a ≥1 g/dL increase compared with baseline. Mean reductions in hemolytic markers and dose-dependent decreases in 2,3-DPG and increases in ATP were also observed. This study provides proof of concept that mitapivat has disease-modifying potential in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT04000165.

The impact of a weight reduction program with and without meal-replacement on health related quality of life in middle-aged obese females.

BACKGROUND: In addition to an increased risk for chronic illnesses, obese individuals suffer from social stigmatization and discrimination, and severely obese people may experience greater risk of impaired psychosocial and physical functioning. Lower health-related quality of life (HRQOL) has been reported among obese persons seeking intensive treatment for their disease. To aid in the treatment of obesity, meal replacements have been recommended as an effective therapeutic strategy for weight loss, particularly when consumed in the beginning of an intervention. Hence, the objective of this study was to assess the impact of two 12-month weight reduction interventions (one arm including a meal replacement) on changes in HRQOL among obese females. METHODS: This controlled trial compared two versions of a standardized 12-month weight reduction intervention: the weight-reduction lifestyle program without a meal replacement (LS) versus the same lifestyle program with the addition of a soy-based meal replacement product (LSMR). 380 women (LS: n = 190, LSMR: n = 190) were matched by age, gender, and weight (51.4 ± 7.0 yrs., 35.5 ± 3.03 kg/m2). This sample of women all completed the 12-month lifestyle intervention that was part of a larger study. The lifestyle intervention included instruction on exercise/sport, psychology, nutrition, and medicine in 18 theoretical and 40 practical units. Led by a sport physiologist, participants engaged in group-based exercise sessions once or twice a week. To evaluate HRQOL, all participants completed the SF-36 questionnaire pre- and post-intervention. Anthropometric, clinical, physical performance (ergometric stress tests), and self-reported leisure time physical activity (hours/day) data were collected. RESULTS: The LSMR sample showed lower baseline HRQOL scores compared to the LS sample in six of eight HRQOL dimensions, most significant in vitality and health perception (p < 0.01). After the intervention, body weight was reduced in both lifestyle intervention groups (LS: -6.6±6.6 vs. LSMR -7.6±7.9 kg), however, weight loss and HRQOL improvements were more pronounced in the LSMR sample (LSMR: seven of eight, LS: four of eight dimensions). CONCLUSIONS: Our results show that HRQOL may improve among middle-aged obese females during a standardized lifestyle weight reduction program and may be enhanced by consuming a soy-based meal replacement product. TRIAL REGISTRATION: ClinicalTrials.gov NCT00356785.

Two-year follow-up of an interdisciplinary cognitive-behavioral intervention program for obese adults.

Intervention programs for treating adiposity which focus on dietary change and physical exercise often do not lead to the desired long-term reduction in weight. This article reports on the effectiveness of M.O.B.I.L.I.S., a standardized theory-driven intervention program. Participants are taught cognitive-behavioral strategies of goal setting, action planning, barrier management, and self-monitoring. Persons with obesity (N=316) responded to a public advertisement to participate in the intervention program (IG) or comparison group (CG; quasi-experimental design). Assessments were conducted at four time points, with the last assessment being conducted two years after baseline. At the 24-month follow-up, the IG showed weight loss of 5.57%, whereas the CG lost 1.12% of their weight (t1-t4, p < .01). The results yielded significant interaction terms (group x time), indicating that the intervention had a substantial effect on food choice and level of physical exercise (p < .01). The IG showed significantly enhanced self-efficacy, stronger goal intentions, and more detailed implementation intentions than the CG at follow-ups. The intervention program has the potential to evoke enduring changes in the cognitions we hypothesized to be responsible for inducing obese adults to begin and continue regular exercise and healthy eating behavior, resulting in substantial weight loss.

Effect of meal replacement on metabolic risk factors in overweight and obese subjects.

AIM: Our objective was to assess alterations in metabolic risk factors, body weight, fat mass and hormonal parameters following 6 weeks of lifestyle intervention with increased physical activity and either a meal-replacement regimen or a low calorie diet. RESEARCH METHODS AND PROCEDURES: 90 overweight or obese subjects (age 47 +/- 7.5 years, weight 90.6 +/- 11.3 kg, BMI 31.5 +/- 2.3) were included in this randomized controlled clinical trial. Subjects in the fat-restricted low-calorie-diet group (LCD-G; n = 30) received 2 dietary counseling sessions and instructions on how to increase physical activity. Subjects in the meal-replacement-diet group (MRD-G; n = 60) received the same lifestyle education and were instructed to replace 2 daily meals by a low-calorie high soy-protein drink. RESULTS: Subjects in the MRD-G lost significantly more weight (6.4 vs. 3.1 kg, p < 0.01) and fat mass (5.1 vs. 2.8 kg, p < 0.01) than the LCD-G. Most metabolic risk parameters were reduced in both the MRD-G and the LCD-G; however, subjects in the MRD-G showed a higher reduction in waist circumference (6.1 vs. 1.8 cm, p < 0.01) and a larger decrease in triglycerides (-19.6 vs. +12.5 mg/dl, p < 0.01). The prevalence of the metabolic syndrome was reduced in subjects in the MRD-G only (-12%, p < 0.05) compared to an unchanged risk score in the LCD-G. The reductions in leptin (18.2 vs. 6.97 ng/ml) and insulin (4.92 vs. 0.58 microU/ml) were only significant in the MRD-G (p < 0.01). DISCUSSION: Our data suggest that even over a short period of time, a meal-replacement diet is more effective in reducing metabolic risk factors, insulin, and leptin, and in improving anthropometric measures than a fat-restricted low-calorie diet.

Exercise based lifestyle intervention in obese adults: results of the intervention study m.o.B.I.L.I.s.

INTRODUCTION: Obesity is one of the greatest public health challenges of the 21st century. A combination of diet and exercise interventions have been shown to deliver stable weight reduction. M.O.B.I.L.I.S. is an interdisciplinary lifestyle modification program, aimed at lasting modification of exercise levels and diet with a view to an energy balanced lifestyle and healthy living skills. METHODS: Lifestyle changes are to be achieved via a 12-month exercise based intervention. This standardized training program is to be followed up at predetermined time intervals in a planned sample size of 4000 to 5000 obese adults (BMI 30 to 40 kg/m(2)). As target variables body weight, body mass index, and waist circumference were defined. RESULTS: One year results are now available for 32 groups and 454 obese participants. The results clearly demonstrate that lifestyle changes in obese individuals are possible and lead to an average weight reduction of 6.4 kg at 12 months. DISCUSSION: M.O.B.I.L.I.S. constitutes an effective, economic, and non-pharmacological therapy option for obese adults.

Effect of a weight loss intervention on anthropometric measures and metabolic risk factors in pre- versus postmenopausal women.

BACKGROUND: The present study examines changes in body weight, fat mass, metabolic and hormonal parameters in overweight and obese pre- and postmenopausal women who participated in a weight loss intervention. METHODS: Seventy-two subjects were included in the analysis of this single arm study (premenopausal: 22 women, age 43.7 +/- 6.4 years, BMI 31.0 +/- 2.4 kg/m2; postmenopausal: 50 women, age 58.2 +/- 5.1 years, BMI 32.9 +/- 3.7 kg/m2). Weight reduction was achieved by the use of a meal replacement and fat-reduced diet. In addition, from week 6 to 24 participants attended a guided exercise program. Body composition was analyzed with the Bod Pod(R). Blood pressures were taken at every visit and blood was collected at baseline and closeout of the study to evaluate lipids, insulin, cortisol and leptin levels. RESULTS: BMI, fat mass, waist circumference, systolic blood pressure, triglycerides, glucose, leptin and cortisol were higher in the postmenopausal women at baseline. Both groups achieved a substantial and comparable weight loss (pre- vs. postmenopausal: 6.7 +/- 4.9 vs 6.7 +/- 4.4 kg; n.s.). However, in contrast to premenopausal women, weight loss in postmenopausal women was exclusively due to a reduction of fat mass (-5.3 +/- 5.1 vs -6.6 +/- 4.1 kg; p < 0.01). In premenopausal women 21% of weight loss was attributed to a reduction in lean body mass. Blood pressure, triglycerides, HDL-cholesterol, and glucose improved significantly only in postmenopausal women whereas total cholesterol and LDL-cholesterol were lowered significantly in both groups. CONCLUSION: Both groups showed comparable weight loss and in postmenopausal women weight loss was associated with a pronounced improvement in metabolic risk factors thereby reducing the prevalence of metabolic syndrome.

The introduction of family presence evidence-based practice into a baccalaureate nursing curriculum.

The topic of family presence (FP) during cardiopulmonary resuscitation or invasive procedures has recently received attention and debate among healthcare professionals due to pioneering research in this field. Studies completed have included family perspectives on family presence, patients' feelings on family presence, and healthcare providers' views on family presence. Two key areas found to correlate with family presence acceptance among healthcare providers are education and experience. Senior nursing students in one baccalaureate program were introduced to this topic during a 3-hour class on death and dying. Comparisons between pretest and posttest scores revealed an increase in the acceptance of family presence as a priority in nursing care of the critically ill.

Fasting serum insulin and the homeostasis model of insulin resistance (HOMA-IR) in the monitoring of lifestyle interventions in obese persons.

OBJECTIVES: Lifestyle changes with increased physical activity and balanced energy intake are recognized as the principal interventions in obesity and insulin resistance. Only few prospective studies, however, have so far addressed the potential role of routine biochemical markers of insulin sensitivity in the monitoring of respective interventions. DESIGN AND METHODS: Fasting insulin and glucose was measured in 33 obese individuals undergoing a lifestyle modification program (MOBILIS) at baseline and after 1 year. The HOMA-IR index (homeostasis model of insulin resistance) was calculated as [fasting serum glucose*fasting serum insulin/22.5], with lower values indicating a higher degree of insulin sensitivity. RESULTS: While the median body mass index (BMI) and waist circumference decreased by 10% and 11%, respectively, the HOMA-IR index decreased in an over-proportional manner by 45% within 1 year (BMI baseline, median 35.7, interquartile range (IQR) 33.7-37.7; after 1 year, median 32.2, IQR 29.6-35.1. HOMA-IR baseline, median 2.9, IQR 1.5-4.6; after 1 year 1.6, IQR 0.9-2.7). In contrast to HOMA-IR and fasting serum insulin, no significant changes in fasting serum glucose were observed. Baseline and post-intervention HOMA-IR showed a high degree of inter-individual variation with eight individuals maintaining high HOMA-IR values despite weight loss after 1 year of intervention. CONCLUSIONS: Individual changes in the carbohydrate metabolism achieved by a lifestyle intervention program were displayed by fasting serum insulin concentrations and the HOMA-IR but not by fasting glucose measurement alone. Therefore, assessment of the HOMA-IR may help to individualize lifestyle interventions in obesity and to objectify improvements in insulin sensitivity after therapeutic lifestyle changes.

Increased Velocity Exercise Specific to Task (InVEST) training: a pilot study exploring effects on leg power, balance, and mobility in community-dwelling older women.

OBJECTIVES: To evaluate a dynamic form of weighted vest exercise suitable for home use and designed to enhance muscle power, balance, and mobility. DESIGN: A single-blind, randomized, controlled trial. SETTING: Outpatient exercise research facility situated within an academic long-term care center. PARTICIPANTS: Twenty-one community-dwelling women aged 70 and older with a Short Physical Performance Battery (SPPB) score between 4 and 10 (out of 12). INTERVENTIONS: Subjects were randomized into a progressive resistance-training program using weighted vests for resistance with exercises designed to be specific to mobility tasks and have a component performed at the fastest possible velocity (Increased Velocity Exercise Specific to Task (InVEST), n=11) or a control exercise group (control, n=10), which performed slow-velocity, low-resistance exercise. Both groups exercised three times a week for 12 weeks. MEASUREMENTS: Changes in muscle power, balance, and physical performance were compared. RESULTS: In comparison to control group, InVEST group manifested significant improvements (P<.05) in leg power across measurements obtained at 75% to 90% of the one-repetition maximum. Both groups demonstrated significant improvements in chair stand and SPPB score from baseline, and the InVEST group showed significant improvements in gait speed and chair stand from baseline (P<.05). InVEST produced significantly greater changes in chair stand time than control (P<.05). CONCLUSION: InVEST training appears be an effective means of enhancing leg power and chair rise in this population and is worthy of further investigation as a means of enhancing balance and mobility.