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Additional file 1: Supplementary information S1. Further details on dietary misreporting calculation. Supplementary information S2. Further details on sensitivity analyses. Supplementary information S3. Code used for employing reduced-rank regression in Stata (via SAS). Table S1. Food groups and their contents for the ‘obesogenic’ and ‘carb/fat balance’ dietary patterns. Table S2. Characteristics of all Early-ACTID participants compared with participants with complete covariate data for adjusted secondary analyses (periods 6-12m and 0-12m). Table S3. Explained nutrient variation and correlations for ‘carb/fat balance’ dietary patterns derived at 0, 6 and 12 months. Table S4. Explained nutrient variation and nutrient correlations for energy-dense, higher-fat, lower-fibre ‘obesogenic’ dietary patterns derived at 0, 6 and 12 months. Table S5. Descriptive dietary and sample characteristics in extreme quintiles of ‘carb/fat balance’ dietary pattern score change during 0-6m. Table S6. Descriptive dietary and sample characteristics in extreme quintiles of ‘obesogenic’ dietary pattern score change during 0-6m. Table S7. Relation between change in HbA1c and change in dietary pattern scores during study periods. Table S8. Relation between change in HbA1c and change in bodyweight during study periods. Table S9. Relation between change in bodyweight and change in dietary pattern score during study periods. Table S10. Relation between change in HbA1c and change in dietary pattern scores during study periods, with additional adjustment for trial arm in models 2-3. Fig. S1. Dietary pattern factor loading diagrams. Fig. S2. Associations between 1-SD increases in dietary pattern scores during 6-12 or 0-12 month periods and start-of-period-adjusted HbA1c at 12 months from multivariable linear regression. Fig. S3. Fitted lines by sex from simple linear regression analyses of end-of-period HbA1c on ‘carb/fat balance’ and ‘obesogenic’ dietary pattern change, to investigate potential interactions between dietary pattern change and sex. Fig. S4. Linear trend assessment.

Background Recruitment into surgical RCTs can be threatened if new interventions available outside the trial compete with those being evaluated. Adapting the trial to include the new intervention may overcome this issue, yet this is not often done in surgery. This paper describes the challenges, rationale and methods for adapting an RCT to include a new intervention. Methods The By‐Band study was designed in the UK in 2009–2010 to compare the effectiveness of laparoscopic adjustable gastric band and Roux‐en‐Y gastric bypass for severe obesity. It contained a pilot phase to establish whether recruitment was possible, and the grant proposal specified that an adaptation to include sleeve gastrectomy would be considered if practice changed and recruitment was successful. Information on changing obesity surgery practice, updated evidence and expert opinion about trial design were used to inform the adaptation. Results The pilot phase recruited over 13 months in 2013–2014 and randomized 80 patients (79 anticipated). During this time, major changes in obesity practice in the UK were observed, with gastric band reducing from 32·6 to 15·8 per cent and sleeve gastrectomy increasing from 9·0 to 28·1 per cent. The evidence base had not changed markedly. The British Obesity and Metabolic Surgery Society and study oversight committees supported an adaptation to include sleeve gastrectomy, and a proposal to do so was approved by the funder. Conclusion Adaptation of a two‐group surgical RCT can allow evaluation of a third procedure and maintain relevance of the RCT to practice. It also optimizes the use of existing trial infrastructure to answer an additional important research question. Registration number: ISRCTN00786323 (http://www.isrctn.com/)., Something to consider

This investigation examined the hypothesis that release of K(+) accounts for EDHF activity by comparing relaxant responses produced by ACh and KCl in human subcutaneous resistance arteries. Resistance arteries (internal diameter 244+/-12 microm, n=48) from human subcutaneous fat biopsies were suspended in a wire myograph. Cumulative concentration-response curves were obtained for ACh (10(-9) - 3x10(-5) M) and KCl (2.5 - 25 mM) following contraction with noradrenaline (NA; 0.1 - 3 microM). ACh (E(max) 99.07+/-9.61%; -LogIC(50) 7.03+/-0.22; n=9) and KCl (E(max) 74.14+/-5.61%; -LogIC(50) 2.12+/-0.07; n=10)-induced relaxations were attenuated (P0.0001) by removal of the endothelium (E(max) 8.21+/-5.39% and 11.56+/-8.49%, respectively; n=6 - 7). Indomethacin (10 microM) did not alter ACh-induced relaxation whereas L-NOARG (100 microM) reduced this response (E(max) 61.7+/-3.4%, P0.0001; n=6). The combination of ChTx (50 nM) and apamin (30 nM) attenuated the L-NOARG-insensitive component of ACh-induced relaxation (E(max): 15.2+/-10.5%, P0.002, n=6) although these arteries retained the ability to relax in response to 100 microM SIN-1 (E(max) 127.6+/-13.0%, n=3). Exposure to BaCl(2) (30 microM) and Ouabain (1 mM) did not attenuate the L-NOARG resistant component of ACh-mediated relaxation (E(max), 76.09+/-8.92, P=0.16; n=5). KCl-mediated relaxation was unaffected by L-NOARG+indomethacin (E(max); 68.1+/-5.6%, P=0.33; n=5) or the combination of L-NOARG/indomethacin/ChTx/apamin (E(max); 86.61+/-14.02%, P=0.35; n=6). In contrast, the combination of L-NOARG, indomethacin, ouabain and BaCl(2) abolished this response (E(max), 5.67+/-2.59%, P0.0001, n=6). The characteristics of KCl-mediated relaxation differed from those of the nitric oxide/prostaglandin-independent component of the response to ACh, and were endothelium-dependent, indicating that K(+) does not act as an EDHF in human subcutaneous resistance arteries.

Cortisol is metabolized irreversibly by A-ring reductases (5α- and 5β-reductases) and reversibly (to cortisone) by 11β-hydroxysteroid dehydrogenases (11βHSDs). In rats, estradiol down-regulates 11βHSD1 expression. In humans, ratios of urinary cortisol/cortisone metabolites differ in men and women. In this study, urinary cortisol metabolites and hepatic 11βHSD1 activity were measured in healthy young men and women at different phases of the menstrual cycle. Ten men and 10 women with regular menstrual cycles collected a 24-h urine sample, took 250 μg oral dexamethasone at 2300 h, took 25 mg oral cortisone at 0900 h (after fasting), and had blood sampled for plasma cortisol estimation over the subsequent 150 min. Women repeated the tests in random order in menstrual, follicular, and luteal phases. Women excreted disproportionately less A-ring-reduced metabolites of cortisol [median 5α-tetrahydrocortisol, 1811 (interquartile range, 1391-2300) μg/day in menstrual phase vs. 2723 (interquartile range, 2454-3154) in men (P = 0.01); 5β-tetrahydrocortisol, 1600 (interquartile range, 1419 -1968) vs. 2197 (interquartile range, 1748-2995; P = 0.03)] but similar amounts of cortisol, cortisone, and tetrahydrocortisone. Analogous differences were observed in urinary excretion of androgen metabolites. Conversion of cortisone to cortisol on hepatic first pass metabolism was not different (peak plasma cortisol, 733 ± 60 nmol/L in women vs. 684 ± 53 nmol/L in men; mean ± SEM; P = 0.55). There were no differences in cortisol or androgen metabolism between phases of the menstrual cycle. We conclude that sexual dimorphism in cortisol metabolite excretion is attributable to less A-ring reduction of cortisol in women, rather than less reactivation of cortisone to cortisol by 11βHSD1. This difference is not influenced acutely by gonadal steroids. 11βHSD1 has been suggested to modulate insulin sensitivity and body fat distribution, but caution must be exercised in extrapolating inferences about its regulation from rodents to man. A-Ring reductases may have an equally important influence on metabolic clearance of cortisol and intracellular cortisol concentrations.

Cortisol is metabolized irreversibly by A-ring reductases (5α- and 5β-reductases) and reversibly (to cortisone) by 11β-hydroxysteroid dehydrogenases (11βHSDs). In rats, estradiol down-regulates 11βHSD1 expression. In humans, ratios of urinary cortisol/cortisone metabolites differ in men and women. In this study, urinary cortisol metabolites and hepatic 11βHSD1 activity were measured in healthy young men and women at different phases of the menstrual cycle. Ten men and 10 women with regular menstrual cycles collected a 24-h urine sample, took 250 μg oral dexamethasone at 2300 h, took 25 mg oral cortisone at 0900 h (after fasting), and had blood sampled for plasma cortisol estimation over the subsequent 150 min. Women repeated the tests in random order in menstrual, follicular, and luteal phases. Women excreted disproportionately less A-ring-reduced metabolites of cortisol [median 5α-tetrahydrocortisol, 1811 (interquartile range, 1391-2300) μg/day in menstrual phase vs. 2723 (interquartile range, 2454-3154) in men (P = 0.01); 5β-tetrahydrocortisol, 1600 (interquartile range, 1419 -1968) vs. 2197 (interquartile range, 1748-2995; P = 0.03)] but similar amounts of cortisol, cortisone, and tetrahydrocortisone. Analogous differences were observed in urinary excretion of androgen metabolites. Conversion of cortisone to cortisol on hepatic first pass metabolism was not different (peak plasma cortisol, 733 ± 60 nmol/L in women vs. 684 ± 53 nmol/L in men; mean ± SEM; P = 0.55). There were no differences in cortisol or androgen metabolism between phases of the menstrual cycle. We conclude that sexual dimorphism in cortisol metabolite excretion is attributable to less A-ring reduction of cortisol in women, rather than less reactivation of cortisone to cortisol by 11βHSD1. This difference is not influenced acutely by gonadal steroids. 11βHSD1 has been suggested to modulate insulin sensitivity and body fat distribution, but caution must be exercised in extrapolating inferences about its regulation from rodents to man. A-Ring reductases may have an equally important influence on metabolic clearance of cortisol and intracellular cortisol concentrations.