Introduction:
Clinical trial designs based on the assumption of independent observations are well established. Clustered clinical trial designs, where all observational units belong to a cluster and ...outcomes within clusters are expected to be correlated, have also received considerable attention. However, many clinical trials involve partially clustered data, where only some observational units belong to a cluster. Examples of such trials occur in neonatology, where participants include infants from both singleton and multiple births, and ophthalmology, where one or two eyes per participant may need treatment. Partial clustering can also arise in trials of group-based treatments (e.g. group education or counselling sessions) or treatments administered individually by a discrete number of health care professionals (e.g. surgeons or physical therapists), when this is compared to an unclustered control arm. Trials involving partially clustered data have received limited attention in the literature and the current lack of standardised terminology may be hampering the development and dissemination of methods for designing and analysing these trials.
Methods and examples:
In this article, we present an overarching definition of partially clustered trials, bringing together several existing trial designs including those for group-based treatments, clustering due to facilitator effects and the re-randomisation design. We define and describe four types of partially clustered trial designs, characterised by whether the clustering occurs pre-randomisation or post-randomisation and, in the case of pre-randomisation clustering, by the method of randomisation that is used for the clustered observations (individual randomisation, cluster randomisation or balanced randomisation within clusters). Real life examples are provided to highlight the occurrence of partially clustered trials across a variety of fields. To assess how partially clustered trials are currently reported, we review published reports of partially clustered trials.
Discussion:
Our findings demonstrate that the description of these trials is often incomplete and the terminology used to describe the trial designs is inconsistent, restricting the ability to identify these trials in the literature. By adopting the definitions and terminology presented in this article, the reporting of partially clustered trials can be substantially improved, and we present several recommendations for reporting these trial designs in practice. Greater awareness of partially clustered trials will facilitate more methodological research into their design and analysis, ultimately improving the quality of these trials.
The family food environment is an important influence in the development of children's dietary habits. Research suggests that influences of current dietary behaviour and behaviour change may differ. ...The aims of this paper were to: (1) investigate the association between the food environment at baseline and change in children's saturated fat intake; and (2) to explore whether a change in the food environment was associated with a change in children's saturated fat intake.
Secondary analysis of a 12 week cluster randomised controlled trial in 133 4-13 year old children. Families were randomly allocated to parental education regarding changing to reduced-fat dairy foods or a comparison non-dietary behaviour. The interventions were family focused. Parents received education from a dietitian in 3x30 minute sessions to facilitate behaviour change. Parents completed a comprehensive questionnaire capturing three domains of the food environment--Parent knowledge and attitudes; shaping practices; and behaviours and role modelling. Children's dietary intake was assessed via multiple 24-hour recalls at baseline and week 12. Changes in the family food environment and primary outcome (saturated fat) were calculated. Hierarchical linear regression models were performed to explore the association between baseline and change in food environment constructs and change in saturated fat intake. Standardised Beta are presented (p<0.05).
After adjustments for child and family demographics, higher levels of perceived food availability (β=-0.2) at baseline was associated with greater reduction in saturated fat intake, where as higher perceived responsibility (β=0.2), restriction (β=0.3) and pressure to eat (β=0.3) were associated with lesser change in saturated fat. An increase in nutrition knowledge (β=-0.2), perceived responsibility (β=-0.3) and restriction (β=-0.3) from baseline to week 12 were associated with greater reduction in saturated fat intake.
The present study was one of the first to quantify changes in the family food environment, and identify a number of factors which were associated with a positive dietary change. Because interventions focus on behaviour change, the findings may provide specific targets for intervention strategies in the future.
Australia New Zealand Clinical Trials Registry ACTRN12609000453280.
Intraduodenal quinine, in the dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1), cholecystokinin and insulin; slows gastric emptying (GE); and lowers post-meal glucose in men. Oral ...sensitivity to bitter substances may be greater in women than men. We, accordingly, evaluated the dose-related effects of quinine on GE, and the glycaemic responses to, a mixed-nutrient drink in females, and compared the effects of the higher dose with those in males. A total of 13 female and 13 male healthy volunteers received quinine-hydrochloride (600 mg (‘QHCl-600’) or 300 mg (‘QHCl-300’, females only) or control (‘C’), intraduodenally (10 mL bolus) 30 min before a drink (500 kcal, 74 g carbohydrates). Plasma glucose, insulin, C-peptide, GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin were measured at baseline, for 30 min after quinine alone, and then for 2 h post-drink. GE was measured by 13C-acetate breath-test. QHCl-600 alone stimulated insulin, C-peptide and GLP-1 secretion compared to C. Post-drink, QHCl-600 reduced plasma glucose, stimulated C-peptide and GLP-1, and increased the C-peptide/glucose ratio and oral disposition index, while cholecystokinin and GIP were less, in females and males. QHCl-600 also slowed GE compared to C in males and compared to QHCl-300 in females (p < 0.05). QHCl-300 reduced post-meal glucose concentrations and increased the C-peptide/glucose ratio, compared to C (p < 0.05). Magnitudes of glucose lowering and increase in C-peptide/glucose ratio by QHCl-600 were greater in females than males (p < 0.05). We conclude that quinine modulates glucoregulatory functions, associated with glucose lowering in healthy males and females. However, glucose lowering appears to be greater in females than males, without apparent differential effects on GI functions.
Postprandial hypotension (PPH) occurs frequently in older people >65 years old. Protein-rich supplements, particularly whey protein (WP), are increasingly used by older people for various health ...benefits. We have reported that 70 g WP drinks cause significant, and in some cases marked, falls in blood pressure (BP) in older men. The effects of lower, more widely used, doses (~30 g) on systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) are not known. In a randomized order, eight older men (age: 72 ± 1 years; body mass index (BMI): 25 ± 1 kg/m2) after overnight fast ingested a drink containing (i) a non-caloric control (~2 kcal), (ii) 30 g of whey protein (120 kcal; ‘WP30’), or (iii) 70 g of whey protein (280 kcal; ‘WP70’). The BP and HR were measured in this pilot study with an automated device before and at 3-min intervals for 180 min following drink ingestion. Drink condition effects were determined by repeated-measures ANOVA. The SBP decreased after both WP drinks compared to the control (p = 0.016), particularly between 120 and 180 min, with no difference in the effects of WP30 and WP70. The SBP decreased by ≥20 mmHg in more than 50% of people after both WP drinks (WP30: 63%; WP70: 75%) compared to 38% after the control. The maximum fall in the SBP occurred during the third hour, with the nadir occurring latest after WP70. The DBP decreased non-significantly by several mmHg more after the WP drinks than after the control. The maximum HR increases occurred during the third hour, with the greatest increase after WP70. The SBP decreased after both WP drinks compared to the control, with the effects most evident between 120 and 180 min. Accordingly, ingestion of even relatively modest protein loads in older men has the potential to cause PPH.
Abdominal obesity and type 2 diabetes mellitus are associated with sexual and endothelial dysfunction, lower urinary tract symptoms (LUTS), and chronic systemic inflammation.
To determine the effects ...of diet‐induced weight loss and maintenance on sexual and endothelial function, LUTS, and inflammatory markers in obese diabetic men.
Weight, waist circumference (WC), International Index of Erectile Function (IIEF‐5) score, Sexual Desire Inventory (SDI) score, International Prostate Symptom Scale (IPSS) score, plasma fasting glucose and lipids, testosterone, sex hormone binding globulin (SHBG), inflammatory markers (high‐sensitivity C‐reactive protein CRP and interleukin‐6 IL‐6) and soluble E‐selectin, and brachial artery flow‐mediated dilatation (FMD) were measured at baseline, 8 weeks, and 52 weeks.
Over 8 weeks, 31 abdominally obese (body mass index ≥ 30 kg/m2, WC ≥ 102 cm), type 2 diabetic men (mean age 59.7 years) received either a meal replacement‐based low‐calorie diet (LCD) ∼1,000 kcal/day (N = 19) or low‐fat, high‐protein, reduced‐carbohydrate (HP) diet (N = 12) prescribed to decrease intake by ∼600 kcal/day. Subjects continued on, or were switched to, the HP diet for another 44 weeks.
At 8 weeks, weight and WC decreased by ∼10% and ∼5% with the LCD and HP diet, respectively. Both diets significantly improved plasma glucose, low‐density lipoprotein (LDL), SHBG, IIEF‐5, SDI and IPSS scores, and endothelial function (increased FMD, reduced soluble E‐selectin). Erectile function, sexual desire, and urinary symptoms improved by a similar degree with both diets. CRP and IL‐6 decreased with the HP diet. At 52 weeks, reductions in weight, WC, and CRP were maintained. IIEF‐5, SDI, and IPSS scores improved further.
Diet‐induced weight loss induces rapid improvement of sexual, urinary, and endothelial function in obese diabetic men. A high‐protein, carbohydrate‐reduced, low‐fat diet also reduces systemic inflammation and sustains these beneficial effects to 1 year. Khoo J, Piantadosi C, Duncan R, Worthley SG, Jenkins A, Noakes M, Worthley MI, Lange K, and Wittert GA. Comparing effects of a low‐energy diet and a high‐protein low‐fat diet on sexual and endothelial function, urinary tract symptoms and inflammation in obese diabetic men. J Sex Med 2011;8:2868–2875.
(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain ...amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using 13C-acetate breath-testing. (3) Results: Amino acids alone did not affect plasma glucose or C-peptide, while isoleucine and valine, but not leucine, stimulated glucagon (p < 0.05), compared with control. After the drink, isoleucine and leucine reduced peak plasma glucose compared with both control and valine (all p < 0.05). Neither amino acid affected early (t = 0–30 min) postprandial C-peptide or glucagon. While there was no effect on overall gastric emptying, plasma glucose at t = 30 min correlated with early gastric emptying (p < 0.05). (4) Conclusion: In healthy individuals, leucine and isoleucine lower postprandial blood glucose, at least in part by slowing gastric emptying, while valine does not appear to have an effect, possibly due to glucagon stimulation.
Protein-rich supplements are used commonly to increase energy intake in undernourished older people. This study aimed to establish age effects on energy intake, appetite, gastric emptying, blood ...glucose, and gut hormones in response to protein-rich drinks. In a randomized double-blind, order, 13 older men (age: 75 ± 2 yrs, body mass index (BMI): 26 ± 1 kg/m
) and 13 younger (23 ± 1 yrs, 24 ± 1 kg/m
) men consumed (i) a control drink (~2 kcal) or drinks (450 mL) containing protein/fat/carbohydrate: (ii) 70 g/0 g/0 g (280 kcal/'P
), (iii) 14 g/12.4 g/28 g (280 kcal/'M
), (iv) 70 g/12.4 g/28 g (504 kcal/'M
), on four separate days. Appetite (visual analog scales), gastric emptying (3D ultrasonography), blood glucose, plasma insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) concentrations (0-180 min), and ad-libitum energy intake (180-210 min) were determined. Older men, compared to younger men, had higher fasting glucose and CCK concentrations and lower fasting GLP-1 concentrations (all
< 0.05). Energy intake by P
compared to control was less suppressed in older men (increase: 49 ± 42 kcal) than it was in younger men (suppression: 100 ± 54 kcal,
= 0.038). After the caloric drinks, the suppression of hunger and the desire to eat, and the stimulation of fullness was less (
< 0.05), and the stimulation of plasma GLP-1 was higher (
< 0.05) in older men compared to younger men. Gastric emptying, glucose, insulin, ghrelin, and CCK responses were similar between age groups. In conclusion, ageing reduces the responses of caloric drinks on hunger, the desire to eat, fullness, and energy intake, and protein-rich nutrition supplements may be an effective strategy to increase energy intake in undernourished older people.
Background: Critically ill patients typically receive ∼60% of estimated calorie requirements.Objectives: We aimed to determine whether the substitution of a 1.5-kcal/mL enteral nutrition solution for ...a 1.0-kcal/mL solution resulted in greater calorie delivery to critically ill patients and establish the feasibility of conducting a multicenter, double-blind, randomized trial to evaluate the effect of an increased calorie delivery on clinical outcomes.Design: A prospective, randomized, double-blind, parallel-group, multicenter study was conducted in 5 Australian intensive care units. One hundred twelve mechanically ventilated patients expected to receive enteral nutrition for ≥2 d were randomly assigned to receive 1.5 (n = 57) or 1.0 (n = 55) kcal/mL enteral nutrition solution at a rate of 1 mL/kg ideal body weight per hour for 10 d. Protein and fiber contents in the 2 solutions were equivalent.Results: The 2 groups had similar baseline characteristics (1.5 compared with 1.0 kcal/mL). The mean (±SD) age was 56.4 ± 16.8 compared with 56.5 ± 16.1 y, 74% compared with 75% were men, and the Acute Physiology and Chronic Health Evaluation II score was 23 ± 9.1 compared with 22 ± 8.9. The groups received similar volumes of enteral nutrition solution 1221 mL/d (95% CI: 1120, 1322 mL/d) compared with 1259 mL/d (95% CI: 1143, 1374 mL/d); P = 0.628, which led to a 46% increase in daily calories in the group given the 1.5-kcal/mL solution 1832 kcal/d (95% CI: 1681, 1984 kcal/d) compared with 1259 kcal/d (95% CI: 1143, 1374 kcal/d); P < 0.001. The 1.5-kcal/mL solution was not associated with larger gastric residual volumes or diarrhea. In this feasibility study, there was a trend to a reduced 90-d mortality in patients given 1.5 kcal/mL 11 patients (20%) compared with 20 patients (37%); P = 0.057.Conclusions: The substitution of a 1.0- with a 1.5-kcal/mL enteral nutrition solution administered at the same rate resulted in a 46% greater calorie delivery without adverse effects. The results support the conduct of a large-scale trial to evaluate the effect of increased calorie delivery on clinically important outcomes in the critically ill. This trial was registered at Australian New Zealand Clinical Trials (http://www.anzctr.org.au/) as ACTRN 12611000793910.
Whey protein, when ingested on its own, load-dependently slows gastric emptying and stimulates gut hormone concentrations in healthy young men. The aim of this study was to determine the effects of ...substitution, and addition, of carbohydrate (dextrose) and fat (olive oil) to whey protein. In randomized, double-blind order, 13 healthy young men (age: 23 ± 1 years, body mass index: 24 ± 1 kg/m²) ingested a control drink (450 mL; ~2 kcal/'control') or iso-volumetric drinks containing protein/carbohydrate/fat: (i) 14 g/28 g/12.4 g (280 kcal/'M
), (ii) 70 g/28 g/12.4 g (504kcal/'M
), and (iii) 70 g/0 g/0 g (280 kcal/'P
), on 4 separate study days. Gastric emptying (
= 11, 3D-ultrasonography), blood glucose, plasma insulin, ghrelin, cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) concentrations (0⁻180 min), appetite (visual analogue scales), and ad-libitum buffet-meal energy intake (180⁻210 min) were determined. Substitution of protein with carbohydrate and fat was associated with faster gastric emptying (lower 50% emptying time (T50)), reduced suppression of ghrelin, and stimulation of GLP-1 (all
< 0.001); while the addition of carbohydrate and fat to protein did not affect gastric emptying or gut hormone responses significantly. Total energy intake (i.e., drink plus meal) was greater after all caloric drinks than control (
< 0.001). In conclusion, substitution of whey protein with dextrose and olive oil accelerated gastric emptying. Higher protein content of a mixed macronutrient drink increased gut hormone and insulin responses.
Abstract
Background
Caloric supplements are increasingly used by older people, aiming to increase their daily protein intake. These high caloric drinks, rich in glucose and whey-protein in ...particular, may result in potential harmful decreases in blood pressure (BP). The effect of ingesting whey-protein with glucose and fat on BP is unknown. It has also been assumed that the maximum fall in systolic blood pressure occurs within 2 h of a meal.
Methods
This study aimed to determine in older men, the effects of whey-protein, alone and mixed with other macronutrients, on systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) in older men for 3 h. Thirteen older men (age 75 ± 2yrs; body mass index (BMI) 25.6 ± 0.6 kg/m
2
) ingested a drink on separate study days: (i) 70 g whey-protein (P
280
)
;
(ii) 14 g whey-protein, 28 g carbohydrate, 12.4 g fat (M
280
); (iii) 70 g whey-protein, 28 g carbohydrate, 12.4 g fat (M
504
); or (iv) a non-caloric control drink (C).
Results
SBP decreased after all three nutrient drinks compared to the C, with the greatest reduction after the M
504
drink (
P
= 0.008). Maximal decreases in SBP (C: -14 ± 2 mmHg, P
280
: -22 ± 2 mmHg, M
280
: -22 ± 4 mmHg, M
504
: -24 ± 3 mmHg) occurred about 2 h after drink ingestion and this fall was sustained thereafter (120-180 min: P
280
and M
504
vs. C
P
< 0.05). Maximum DBP decreases and HR increases occurred after M
504
, with no differences between the effects of the P
280
and M
280
drinks.
Conclusions
The effects of whey-protein containing drinks to lower BP and increase HR appear to be primarily dependent on their energy content rather than macronutrient composition and may persist for at least 3 h after ingestion,. Pure whey-protein drinks may represent the best approach to maximize protein intake without increasing the potential for deleterious BP falls in older people.
Trial registration
ACTRN12614000846628
, 14/03/2019.
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