A randomized controlled trial of mycophenolate mofetil in patients with IgA nephropathy [ISRCTN62574616]

BACKGROUND: IgAN is the most common type of glomerulonephritis in the world. Between 15 and 40 percent of adults and children diagnosed with IgAN eventually progress to ESRD. Despite the need for effective treatment strategies, very few RCTs for IgAN have been performed. The most effective therapies for IgAN appear to be corticosteroids, ACEi, and FOS that contain a high concentration of omega 3 fatty acids. While ACEi and FOS are generally well tolerated with minimal side effects, the use of high dose steroids over a long course of therapy is often associated with significant morbidity. OBJECTIVE OF THE STUDY: The objective of the study is to test the hypothesis that treatment with the immunosuppressive agent, MMF, will lead to significant and sustained improvement in urinary protein excretion in patients with IgAN who have been pre-treated (and continue to be treated) with ACE(i )and FOS compared to a placebo control group of patients receiving comparable doses of ACEi and FOS without MMF. DESIGN: After a three month treatment period with the ACEi, lisinopril and the FOS, Omacor(®), 100 (2 × 50) patients with IgAN and a urinary P/C ratio ≥ 0.6 (males) and ≥ 0.8 (females) and an estGFR ≥ 40 ml/min/1.73 m2 will be randomized to treatment with either MMF or placebo for one year. All patients will be followed off study drug for a second year, but will continue treatment with lisinopril and Omacor(® )for the two year duration of the study. The primary outcome measure of change in urine P/C ratio will be assessed at the end of years one and two

2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

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Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Determining the Trough-to-Peak Ratio in Parallel-Group Trials

We explored how in parallel-group trials interindividual variability, correction for placebo effects, and smoothing of blood pressure profiles can be handled in measuring the trough-to-peak ratio in 244 individuals with isolated systolic hypertension (greater than or equal to 60 years) enrolled in the placebo-controlled Systolic Hypertension in Europe Trial. Net treatment effects were computed by subtracting the mean changes from baseline during placebo (n=133) from those during active treatment (n=111). At entry, systolic/diastolic pressures averaged 176/86 mm Hg in the clinic and 149/80 mm Hg on 24-hour ambulatory monitoring. With corrections applied for baseline and placebo, nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d), reduced (P<.001) these blood pressure values by 16.6/7.3 and 9.8/4.7 mm Hg, respectively. The net trough-to-peak ratios were first determined from blood pressure profiles (12 hours) with I-hour precision, synchronized by the morning and evening doses of the double-blind medication. According to the usual approach, disregarding interindividual variability, the systolic/diastolic net trough-to-peak ratios were 0.46/0.40 in the morning and 0.77/0.99 in the evening. In individual subjects, the baseline-adjusted trough-to-peak ratios were nonnormally distributed. We therefore used a nonparametric technique to calculate the net trough-to-peak ratios from the results in individual subjects. In the morning, these ratios averaged 0.25 systolic (95% confidence interval, 0.09 to 0.41) and 0.15 diastolic (95% confidence interval, 0.00 to 0.31) and in the evening, 0.19 and 0.36 (95% confidence intervals, 0.00 to 0.38 and 0.14 to 0.56), respectively. When the blood pressure profiles were smoothed by substituting the 1-hour averages by moving or fixed 2-hour averages or by Fourier modeling, the trough-to-peak ratios remained unchanged after-the morning dose (0.20/0.13, 0.20/0.14, and 0.16/0.21, respectively) but tended to increase in the evening (0.32/0.38, 0.28/0.40, and 0.48/0.49). In conclusion, the parallel-group analysis proposed makes it possible for one to correct the trough-to-peak ratio for baseline as well as placebo, to account for interindividual variability, and to calculate a confidence interval for the net trough-to-peak ratio. Accounting for interindividual variability reduces the trough-to-peak ratio. Smoothing affects the individualized net trough-to-peak ratios in an unpredictable way and should therefore be avoided

Determining the trough-to-peak ratio in parallel-group trials

We explored how in parallel-group trials interindividual variability, correction for placebo effects, and smoothing of blood pressure profiles can be handled in measuring the trough-to-peak ratio in 244 individuals with isolated systolic hypertension (greater than or equal to 60 years) enrolled in the placebo-controlled Systolic Hypertension in Europe Trial. Net treatment effects were computed by subtracting the mean changes from baseline during placebo (n=133) from those during active treatment (n=111). At entry, systolic/diastolic pressures averaged 176/86 mm Hg in the clinic and 149/80 mm Hg on 24-hour ambulatory monitoring. With corrections applied for baseline and placebo, nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d), reduced (P<.001) these blood pressure values by 16.6/7.3 and 9.8/4.7 mm Hg, respectively. The net trough-to-peak ratios were first determined from blood pressure profiles (12 hours) with I-hour precision, synchronized by the morning and evening doses of the double-blind medication. According to the usual approach, disregarding interindividual variability, the systolic/diastolic net trough-to-peak ratios were 0.46/0.40 in the morning and 0.77/0.99 in the evening. In individual subjects, the baseline-adjusted trough-to-peak ratios were nonnormally distributed. We therefore used a nonparametric technique to calculate the net trough-to-peak ratios from the results in individual subjects. In the morning, these ratios averaged 0.25 systolic (95% confidence interval, 0.09 to 0.41) and 0.15 diastolic (95% confidence interval, 0.00 to 0.31) and in the evening, 0.19 and 0.36 (95% confidence intervals, 0.00 to 0.38 and 0.14 to 0.56), respectively. When the blood pressure profiles were smoothed by substituting the 1-hour averages by moving or fixed 2-hour averages or by Fourier modeling, the trough-to-peak ratios remained unchanged after-the morning dose (0.20/0.13, 0.20/0.14, and 0.16/0.21, respectively) but tended to increase in the evening (0.32/0.38, 0.28/0.40, and 0.48/0.49). In conclusion, the parallel-group analysis proposed makes it possible for one to correct the trough-to-peak ratio for baseline as well as placebo, to account for interindividual variability, and to calculate a confidence interval for the net trough-to-peak ratio. Accounting for interindividual variability reduces the trough-to-peak ratio. Smoothing affects the individualized net trough-to-peak ratios in an unpredictable way and should therefore be avoided