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Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

Background: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study’s four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated “abnormal” laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors’ diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96–5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6–41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Gastroschisis is a congenital anomaly in which the intestines are exposed to amniotic fluid throughout fetal life. Previous studies in animal models have demonstrated smooth muscle thickening and decreased contractility, epithelial dysfunction, and submucosal thickening. The present studies were done to further define the mechanism of submucosal changes by investigating collagen deposition and gene expression in a rabbit model. Gastroschisis was surgically created in fetal rabbits at 24 days gestation (term is 31 days). Sham-operated and unoperated fetuses served as controls. Fetuses were sacrificed and bowels were harvested at 26, 28, and 31 days gestation. Animal weight and gross and histologic appearance were assessed. Submucosal collagen content was measured using the van Geison stain. In situ hybridization of the expression of alpha (1) procollagen RNA was done to determine the distribution and source of submucosal collagen. At term, submucosal thickening was present in animals with gastroschisis, associated with a significantly increased collagen content. Collagen distribution was also more diffuse in the gastroschisis animals than in controls. In situ hybridization revealed procollagen expression in round cells located in the submucosa and not in smooth muscle. These cells did not resemble fibroblasts, and their identity is uncertain. Experimental gastroschisis is characterized by submucosal thickening which is associated with changes in collagen, including increased deposition and more diffuse distribution in the submucosa. The cells responsible for production of procollagen are round, nonfibroblast cells which are located in the submucosa and not in the smooth muscle layer. These findings may have some importance in understanding the mechanisms responsible for intestinal malfunction in infants with gastroschisis.

The hysteroscopic approach to the correction of congenital anomalies in utero may be helped by the temporary introduction of clear, electrically neutral fluids (liquids or gases) into the amniotic cavity. Accordingly, the authors determined the effects of three candidate fluids (helium, carbon dioxide, and water) on the oxygenation, acid-base balance, electrolyte concentrations, and hemodynamic function of nine sheep fetuses at 120 days' gestation (full term 145 days). Each fetus was exposed, in random order, to each of the three fluids, at an intraamniotic pressure of 15 mm Hg. The authors found that helium produced no changes in any of the measurements and was well tolerated by the fetus and the mother. Carbon dioxide decreased fetal arterial pH, and increased both arterial PCO2 and PO2. Although the decrease in pH was explained entirely by the increase in PCO2, the increase in arterial PO2 may have resulted from vasodilatation of the placental circulation or vasoconstriction of the fetal circulation with a redistribution of blood flow to the placenta. Water caused mild fetal hyponatremia and hypochloremia, without significant changes in acid-base balance or oxygenation. The results suggest that both helium and water may represent viable alternatives for amniotic fluid replacement during hysteroscopic surgery.

Although jejunal atresia occasionally may occur with a familial pattern, an association with renal disease has not been described. The authors report on three family members treated over two generations, all of whom had both proximal jejunal atresia and renal dysplasia. This association was most likely inherited as an autosomal dominant trait.

The objective of this study was to describe recent trends in the management of mild-to-moderate gallstone pancreatitis and assess patient outcomes. Acute gallstone pancreatitis has traditionally been managed with open cholecystectomy and intraoperative cholangiography during the initial hospitalization. The popularization of endoscopic retrograde cholangiopancreatography (ERCP) and laparoscopic cholecystectomy has made a reassessment necessary. Two consecutive time periods were retrospectively analyzed: prior to laparoscopic cholecystectomy (prelaparoscopic era [PLE]) and after the diffusion of laparoscopic cholecystectomy (laparoscopic cholectomy era [LCE]). There were 35 patients in the PLE group and 58 in the LCE group. LCE patients waited 37.1 +/- 63 days from admission until cholecystectomy, compared to 9.8 +/- 14.8 days in the PLE group (P = 0.04). Biliary-pancreatic complications occurred in 24% of LCE patients and only 6% of PLE patients (P = 0.05), nearly always while they were awaiting cholecystectomy (P = 0.009). Patients in either time period who underwent cholecystectomy with intraoperative cholangiography developed less pancreatic-biliary complications than those who underwent ERCP prior to cholecystectomy, with or without sphincterotomy. Delaying the interval from pancreatitis to laparoscopic cholecystectomy beyond historical values is associated with a greater risk of recurrent biliary-pancreatic complications, which are not prevented by the use of ERCP. Early cholecys tectomy with intraoperative ductal evaluation is still the approach of choice.

To test the hypothesis that increased airway strain resulting from lung denervation initiates a fibroproliferative response in the airways, we compared the transcriptional expressions of alpha1(I)-procollagen and tropoelastin in the lungs of rats subjected to unilateral vagal denervation, unilateral vagal denervation combined with ipsilateral phrenectomy, or thoracotomy without denervation (controls). We found increases in alpha1(I)-procollagen messenger ribonucleic acids (mRNAs) in the submucosa of the airways and the adventitia of airways and pulmonary vessels of the denervated lungs in 31% of the rats subjected to unilateral denervation (with and without phrenectomy), and in none of the controls. The increased transcripts were associated with collagen deposition in the peribronchial and perivascular tissue, and occasionally with cell proliferation leading to occlusion of the airway and vascular lumina. Unilateral phrenectomy did not decrease the frequency with which production of Type I procollagen was upregulated, suggesting that the upregulation was not entirely dependent on airway strain. Tropoelastin expression was not influenced by denervation. Our results indicate that the autonomic nervous system has a previously unsuspected trophic influence on collagen synthesis in the airways and pulmonary vessels. Abolition of this influence by denervation may lead to structural changes analogous to those observed in bronchiolitis obliterans after lung transplantation.

Gastroschisis is a congenital anomaly in which exposure of the intestines to amniotic fluid throughout fetal life results in nutrient malabsorption. To begin to understand the molecular basis underlying epithelial changes in this condition, we investigated enterocytic gene expression during fetal development. Gastroschisis was surgically created at 24 days gestation (term = 31 days) in fetal rabbits; sham-operated and unoperated fetuses served as controls. Bowel was harvested at 28 and 31 days gestation. Cellular lactase expression was detected using immunohistochemistry, and apolipoprotein A-I and cellular retinol binding protein II (CRBPII) mRNA levels were quantitated using Northern blot analysis. Despite absence of gross histological changes in the mucosa, lactase protein expression and apolipoprotein A-I and CRBPII mRNA expression were decreased in intestine from gastroschisis compared to sham-operated animals. Expression of GAPDH (a housekeeping gene) increased over the same period, suggesting that the changes in enterocytic absorptive gene expression associated with gastroschisis were relatively specific. In conclusion, a decrease in expression of a variety of genes involved in nutrient absorption and trafficking within the enterocyte may contribute to the absorptive defects seen in this gastroschisis.

Several investigators have reported good results after a one-stage Soave procedure without a stoma for infants with Hirschsprung's disease. The authors reviewed their concurrent experience with the one- and two-stage approaches, comparing the two groups with respect to rate of complications and clinical outcome. Over a 3-year period, 36 infants with colonic Hirschsprung's disease presenting in the first year of life were treated with a Soave pull-through. Thirteen had a one-stage pull-through, and 23 had a two-stage procedure using an initial stoma. There was no difference with respect to median age at time of diagnosis, median follow-up period, length of aganglionosis, or male:female ratio between the groups. The incidences of major complications such as small bowel obstruction, segmental or acquired aganglionosis, anastomotic leak, and malabsorption were equal between the two groups. However, 13% of the two-stage patients required revision of the stoma. All major complications in the one-stage group were in those who weighed less than 4 kg at the time of surgery. Minor complications such as wound infection, perianal excoriation, and need for repeated dilatation were similar between the groups, but minor stoma-related complications (prolapse or retraction) occurred in 26% of the two-stage infants. When complications were stratified using a more sophisticated scale of severity, no significant difference was found between the groups. The overall complication rate was 1.5 events per patient in the one-stage group and 2.0 events per patient in the two-stage group. This small difference was related to the presence of a stoma in the two-stage group. Overall, 10 of 12 survivors in the one-stage group and 22 of 23 in the two-stage group were doing well, with normal bowel function noted on long-term follow-up (mean period, of 14 and 19 months, respectively). Both one- and two-stage approaches were associated with a significant complication rate, although long-term outcome was excellent in both groups. The higher complication rate in the two-stage group was attributable to the presence of a stoma. For small infants, it may be beneficial to delay the one-stage pull-through until weight exceeds 4 kg.

We studied the outcome in 94 infants less than 1 year of age who had an incarcerated inguinal hernia reduced in the emergency room. Fifty-six were admitted and 38 were sent home. Of the 56 infants admitted, 12 (21%) reincarcerated prior to surgery, whereas 28 (74%) of the 38 sent home reincarcerated. The incidence of reincarcinated was not affected by age or weight. Mean time to surgery was 2 days in the admission group and 10 days in the outpatient group. The cumulative reincarceration rate 72 h after the initial reduction was similar in the two groups, and the majority of reincarcerations in those sent home occured later than 72 h after the initial reduction. The wound infection rate was slighty higher in the admission group, but other early and late complications were not affected by either admission or the presence of reincarceration. Although it is safe to send infants home after emergency room reduction of an incarcerated inguinal hernia, definitive repair should be done within 72 h to avoid an increased risk of reincarceration.