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Responsiveness and convergent validity of QLU-C10D and EQ-5D-3L in assessing short-term quality of life following esophagectomy.
Bulamu, NB, Vissapragada, R, Chen, G, Ratcliffe, J, Mudge, LA, Smithers, BM, Isenring, EA, Smith, L, Jamieson, GG, Watson, DI, et al
Health and quality of life outcomes. 2021;(1):233
Abstract
AIM: This study assessed the responsiveness and convergent validity of two preference-based measures; the newly developed cancer-specific EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D) relative to the generic three-level version of the EuroQol 5 dimensions (EQ-5D-3L) in evaluating short-term health related quality of life (HRQoL) outcomes after esophagectomy. METHODS Participants were enrolled in a multicentre randomised controlled trial to determine the impact of preoperative and postoperative immunonutrition versus standard nutrition in patients with esophageal cancer. HRQoL was assessed seven days before and 42 days after esophagectomy. Standardized Response Mean and Effect Size were calculated to assess responsiveness. Ceiling effects for each dimension were calculated as the proportion of the best level responses for that dimension at follow-up/post-operatively. Convergent validity was assessed using Spearman's correlation and the level of agreement was explored using Bland-Altman plots. RESULTS Data from 164 respondents (mean age: 63 years, 81% male) were analysed. HRQoL significantly reduced on both measures with large effect sizes (> 0.80), and a greater mean difference (0.29 compared to 0.16) on QLU-C10D. Both measures had ceiling effects (> 15%) on all dimensions at baseline. Following esophagectomy, ceiling effects were observed with self-care (86%), mobility (67%), anxiety/depression (55%) and pain/discomfort (19%) dimensions on EQ-5D-3L. For QLU-C10D ceiling effects were observed with emotional function (53%), physical function (16%), nausea (35%), sleep (31%), bowel problems (21%) and pain (20%). A strong correlation (r = 0.71) was observed between EQ-5D-3L anxiety and QLU-C10D emotional function dimensions. Good agreement (3.7% observations outside the limits of agreement) was observed between the utility scores. CONCLUSION The QLU-C10D is comparable to the more widely applied generic EQ-5D-3L, however, QLU-C10D was more sensitive to short-term utility changes following esophagectomy. Cognisant of requirements by policy makers to apply generic utility measures in cost effectiveness studies, the disease-specific QLU-C10D should be used alongside the generic measures like EQ-5D-3L. TRIAL REGISTRATION The trial was registered with the Australian New Zealand Clinical Trial Registry (ACTRN12611000178943) on the 15th of February 2011.
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Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer.
Mudge, LA, Watson, DI, Smithers, BM, Isenring, EA, Smith, L, Jamieson, GG, ,
The British journal of surgery. 2018;(10):1262-1272
Abstract
BACKGROUND Preoperative immunonutrition has been proposed to reduce the duration of hospital stay and infective complications following major elective surgery in patients with gastrointestinal malignancy. A multicentre 2 × 2 factorial RCT was conducted to determine the impact of preoperative and postoperative immunonutrition versus standard nutrition in patients with oesophageal cancer. METHODS Patients were randomized before oesophagectomy to immunonutrition (IMPACT® ) versus standard isocaloric/isonitrogenous nutrition, then further randomized after operation to immunonutrition versus standard nutrition. Clinical and quality-of-life outcomes were assessed at 14 and 42 days after operation on an intention-to-treat basis. The primary outcome was the occurrence of infective complications. Secondary outcomes were other complications, duration of hospital stay, mortality, nutritional and quality-of-life outcomes (EuroQol EQ-5D-3 L™, European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-OES18). Patients and investigators were blinded until the completion of data analysis. RESULTS Some 278 patients from 11 Australian sites were randomized; two were excluded and data from 276 were analysed. The incidence of infective complications was similar for all groups (37 per cent in perioperative standard nutrition group, 51 per cent in perioperative immunonutrition group, 34 per cent in preoperative immunonutrition group and 40 per cent in postoperative immunonutrition group; P = 0·187). There were no significant differences in any other clinical or quality-of-life outcomes. CONCLUSION Use of immunonutrition before and/or after surgery provided no benefit over standard nutrition in patients undergoing oesophagectomy. Registration number: ACTRN12611000178943 ( https://www.anzctr.org.au).
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Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naïve to enzyme replacement therapy or previously treated with imiglucerase.
Smith, L, Rhead, W, Charrow, J, Shankar, SP, Bavdekar, A, Longo, N, Mardach, R, Harmatz, P, Hangartner, T, Lee, HM, et al
Molecular genetics and metabolism. 2016;(2):164-71
Abstract
BACKGROUND Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). METHODS Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30-60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. RESULTS The study included 24 pediatric patients. Fifteen patients were naïve to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naïve patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. CONCLUSION The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults.
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Evaluation overview for the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project.
Davison, KK, Falbe, J, Taveras, EM, Gortmaker, S, Kulldorff, M, Perkins, M, Blaine, RE, Franckle, RL, Ganter, C, Woo Baidal, J, et al
Childhood obesity (Print). 2015;(1):23-36
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BACKGROUND The Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project is a 2-year, multilevel, multisector community intervention to prevent and control obesity among children 2-12 years of age from two predominantly low-income communities in Massachusetts. MA-CORD includes evidence-based interventions in multiple sectors, including community health centers, early care and education centers, schools, afterschool programs, the Special Supplemental Nutrition Program for Women, Infants and Children, and the broader community. Currently, implementation of MA-CORD is complete and the final year of data collection is in progress. Here, the MA-CORD evaluation plan is described and baseline data are presented. METHODS/DESIGN The impact of MA-CORD on children's BMI, lifestyle behaviors, obesity-related care, and quality of life will be assessed using sector-specific, pre/post, time-series, and quasi-experimental designs. Change in the primary outcomes will be compared for intervention and comparison communities. Additionally, change in mean BMI and obesity prevalence in intervention school districts will be compared to similar districts throughout the state. RESULTS At baseline in 2012, approximately 16% of preschool-aged and 25% of school-aged children were obese. Moreover, 15-40% of children consumed no vegetables on the previous day, 25-75% drank a sugar-sweetened beverage on the previous day, up to 87% had insufficient physical activity, 50-75% had a television in the room where they slept, and 50-80% obtained insufficient sleep. CONCLUSIONS There is ample room for improvement in BMI and health behaviors in children in MA-CORD communities. If successful, MA-CORD may serve as a model for multilevel, multisector approaches to childhood obesity prevention and control.
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Design of the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) study.
Taveras, EM, Blaine, RE, Davison, KK, Gortmaker, S, Anand, S, Falbe, J, Kwass, JA, Perkins, M, Giles, C, Criss, S, et al
Childhood obesity (Print). 2015;(1):11-22
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BACKGROUND Childhood obesity is highly prevalent, is associated with both short- and long-term adverse outcomes, disproportionately affects racial/ethnic minority and economically deprived children, and represents a major threat to public health. Among the most promising approaches for its prevention and management are multilevel, multisector strategies. METHODS/DESIGN The Massachusetts Childhood Obesity Research Demonstration (MA-CORD) Study was a comprehensive, systematic intervention to prevent and reduce childhood obesity among low-income children ages 2-12 years in two selected cities in Massachusetts. Building on the Obesity Chronic Care Model, MA-CORD expanded a state public health department community-level obesity prevention initiative that incorporated evidence-based interventions in primary healthcare, the Women, Infants, and Children program, early care and education, schools/afterschool programs, as well as community-wide programs to improve food, beverage, physical activity (PA), and messaging environments. The study used a combination of pre- and post-time series and quasi-experimental designs to examine the extent to which the intervention resulted in changes in BMI, individual-level lifestyle behaviors, satisfaction with healthcare services, and quality of life among children, as well as changes in health policies, programs, and environments in the two intervention cities, compared to a comparison city. The intervention period was 2 years. CONCLUSIONS MA-CORD will determine the extent to which a multisetting, multilevel intervention that integrates activities in primary care with broader public health interventions in schools, early care and education, and the community at large can improve children's dietary and PA behaviors and ultimately reduce obesity in low-income children.
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Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding.
Stanley, AJ, Dickson, S, Hayes, PC, Forrest, EH, Mills, PR, Tripathi, D, Leithead, JA, MacBeth, K, Smith, L, Gaya, DR, et al
Journal of hepatology. 2014;(5):1014-9
Abstract
BACKGROUND & AIMS Rebleeding after an initial oesophageal variceal haemorrhage remains a significant problem despite therapy with band ligation, non-selective β-blockers or a combination of these. Carvedilol is a vasodilating non-selective β-blocker with alpha-1 receptor and calcium channel antagonism. A recent study has suggested it is effective in the prevention of a first variceal bleed. Our aim was to compare oral carvedilol with variceal band ligation (VBL) in the prevention of rebleeding following a first variceal bleed. METHODS Patients who were stable 5 days after presentation with a first oesophageal variceal haemorrhage and had not been taking β-blockers were randomised to oral carvedilol or VBL. Patients were followed-up after one week, monthly, then every 3 months. The primary end point was variceal rebleeding on intention-to-treat analysis. RESULTS 64 patients were randomised, 33 to carvedilol and 31 to VBL. 58 (90.6%) patients had alcohol related liver disease. Age and Child-Pugh score were similar in both groups at baseline. Median follow-up was 26.3 (interquartile range [IQR] 10.2-46.6)months. Compliance was 68% and 65% for carvedilol and VBL respectively (p=0.993) and serious adverse events between the two groups were similar (p=0.968). Variceal rebleeding occurred during follow-up in 12 (36.4%) and 11 (35.5%) patients in the carvedilol and VBL groups, respectively (p=0.857), with 9 (27.3%) and 16 (51.6%) deaths in each group, respectively (p=0.110). CONCLUSIONS Carvedilol is not superior to VBL in the prevention of variceal rebleeding. The trend to a survival benefit for patients taking this drug compared with those undergoing banding requires further exploration.
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Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.
Castro, M, King, TS, Kunselman, SJ, Cabana, MD, Denlinger, L, Holguin, F, Kazani, SD, Moore, WC, Moy, J, Sorkness, CA, et al
JAMA. 2014;(20):2083-91
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IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.
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The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C.
Schwarz, KB, Gonzalez-Peralta, RP, Murray, KF, Molleston, JP, Haber, BA, Jonas, MM, Rosenthal, P, Mohan, P, Balistreri, WF, Narkewicz, MR, et al
Gastroenterology. 2011;(2):450-458.e1
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BACKGROUND & AIMS Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C. METHODS HCV RNA-positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m(2) body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy). RESULTS SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log(10) IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups. CONCLUSIONS The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.
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Diabetes Medication Assistance Service Stage 1: impact and sustainability of glycaemic and lipids control in patients with Type 2 diabetes.
Krass, I, Mitchell, B, Song, YJ, Stewart, K, Peterson, G, Hughes, J, Smith, L, White, L, Armour, C
Diabetic medicine : a journal of the British Diabetic Association. 2011;(8):987-93
Abstract
AIMS: To investigate (i) optimal intensity (four visits vs. six visits) and duration (6 vs. 12 months) of the Diabetes Medication Assistance Service in community pharmacy and (ii) sustainability of improvements in patients' diabetes control associated with differing intensities of intervention. METHODS A national quota sample of 90 community pharmacies in Australia were randomly assigned into group 1 (6-month Diabetes Medication Assistance Service) or group 2 (12-month Diabetes Medication Assistance Service) and subsequently recruited a total of 524 patients. A wide range of clinical (HbA(1c) , blood pressure, lipids) and quality-of-life outcome measures were assessed. RESULTS The 6- and 12-month Diabetes Medication Assistance Service resulted in significant and similar reductions in HbA(1c) (-0.9 mmol/mol; 95% CI -0.7 to -1.1) -, total cholesterol (-0.3 mmol/l; 95% CI -0.1 to -0.4) and triglycerides (-0.3 mmol/l; 95% CI -0.1 to -0.5). There was also a significant reduction in the number of patients who were at risk of having a cardiovascular event in the next 10 years. For the subset of patients for whom data were available at baseline, completion and 18 months, improvements in HbA(1c) and total cholesterol were sustained at 18 months and triglycerides showed a further improvement at 18 months. CONCLUSIONS The Diabetes Medication Assistance Service resulted in significant improvements in diabetes control that were independent of intensity and duration of the service and showed evidence of being sustained at 18 months. The extent and sustainability of clinical improvements achieved by the Diabetes Medication Assistance Service, together with the resulting reduction in cardiovascular risk, should translate into future cost savings to healthcare systems by delaying and reducing diabetes-related complications.
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A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077.
Britten, CD, Rowinsky, EK, Baker, SD, Weiss, GR, Smith, L, Stephenson, J, Rothenberg, M, Smetzer, L, Cramer, J, Collins, W, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2000;(1):42-9
Abstract
This Phase I study was performed to evaluate the tolerability and pharmacokinetic behavior of MKT-077, a water soluble rhodacyanine dye analogue, which partitions into tumor cell mitochondria where it is thought to act as a metabolic poison, leading to G1 arrest and apoptosis. Thirteen patients with advanced solid malignancies were treated with MKT-077 administered as a 30-min i.v. infusion weekly for 4 weeks every 6 weeks at doses ranging from 42 to 126 mg/m2/week. The principal toxicity was renal magnesium wasting, which was dose-limiting (grade 3) in one patient at each of the 84- and 126-mg/m2 dose levels. The other three patients at the 126-mg/m2 dose level developed grade 2 hypomagnesemia, which was cumulative in nature, improved with i.v. magnesium supplementation, and was controlled in two patients by the administration of prophylactic magnesium before and after treatment with MKT-077. Given the requirement for extensive monitoring of serum magnesium levels, dose escalation >126 mg/m2 was not considered feasible. Thus, the recommended dose for disease-oriented studies with this schedule of MKT-077 is 126 mg/m2/week. Pharmacokinetic studies revealed a prolonged terminal half-life (37 +/- 17 h) and a large volume of distribution (685 +/- 430 liters/m2). Clearance averaged 39 +/- 13 liters/h/m2. Peak MKT-077 plasma concentrations (1.2 +/-0.31 to 6.3 +/- 5.3 microg/ml) exceeded the IC50 concentrations required for human CX-1 colon, MCF-breast, CRL-1420 pancreas, EJ bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 microg/ml). These results indicate that at the recommended dose level of 126 mg/m2/week of MKT-077, the toxicity profile was consistent with the preferential accumulation of the agent within tumor cell mitochondria, and biologically relevant plasma concentrations were achieved.