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Background: Laparoscopic cholecystectomy (LCC) carries a 0.3-1.8% risk of bile duct injury (BDI). This study investigated if intraoperative photo documentation of the critical view of safety (CVS) is related to lower rates of BDIs and postoperative complications in LCC. Methods: Surgeons were instructed to take photos of the view before clipping the cystic duct and artery. Two independent raters scored the photos 0-6 using predefined criteria for CVS. Mean scores of >= 4.5 were satisfactory. Results: The study consisted of 1532 patients undergoing LCC between April 2018 and October 2019. CVS was satisfactory in 354 (23.1%), unsatisfactory in 823 (53.7%), and photos were missing in 355 (23.2%) patients. Patients with satisfactory CVS had the lowest BDI rate compared with unsatisfactory CVS or missing photos (0.3% vs. 1.0% vs. 2.3%, p = 0.012). Four major BDIs (Strasberg D-E) occurred, but none in patients with satisfactory CVS. Patients with satisfactory CVS had the lowest postoperative complication rate compared with patients with unsatisfactory CVS or without photos (4.8% vs. 7.9 vs. 9.9%, p = 0.011). Of patients with acute cholecystitis, 15.7% had satisfactory CVS, whereas 26.8% without cholecystitis had satisfactory CVS (p < 0.001). Conclusion: Intraoperative photo documentation of satisfactory CVS is associated with lower rates of BDIs and complications.

Background Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. Methods We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. Discussion This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. Systematic review registration PROSPERO CRD42021234119

Background Longer duration from symptom onset is associated with increased risk of perforation in appendicitis. In previous studies, in-hospital delay to surgery has had conflicting effects on perforation rates. Although preoperative antibiotics have been shown to reduce postoperative infections, there are no data showing that administration of antibiotics while waiting for surgery has any benefits. The aims of this study are to evaluate the role of both in-hospital delay to surgery and antibiotic treatment while waiting for surgery on the rate of appendiceal perforation. Methods This prospective, open-label, randomized, controlled non-inferiority trial compares the in-hospital delay to surgery of less than 8 hours versus less than 24 hours in adult patients with predicted uncomplicated acute appendicitis. Additionally, participants are randomized either to receive or not to receive antibiotics while waiting for surgery. The primary study endpoint is the rate of perforated appendicitis discovered during appendicectomy. The aim is to randomize 1800 patients, that is estimated to give a power of 90 per cent (χ2) for the non-inferiority margin of 5 percentage points for both layers (urgency and preoperative antibiotic). Secondary endpoints include length of hospital stay, 30-day complications graded using Clavien–Dindo classification, preoperative pain, conversion rate, histopathological diagnosis and Sunshine Appendicitis Grading System classification. Discussion There are no previous randomized controlled studies for either in-hospital delay or preoperative antibiotic treatment. The trial will yield new level 1 evidence. EU Clinical Trials Register, EudraCT Number: 2019–002348-26; registration number: NCT04378868 (http://www.clinicaltrials.gov), Study protocol for a randomized non-inferiority trial (PERFECT). The aims of this study are to evaluate the role of in-hospital delay to surgery and antibiotic treatment whilst waiting for surgery on the rate of appendiceal perforation.

OBJECTIVES The aim of the study was to evaluate health-related quality of life (HRQoL) and parental distress in a national cohort of children with biliary atresia (BA) with their native livers in relation to BA complications and HRQoL of normal population controls. METHODS We invited all Finnish children with BA surviving with their native livers at age 2 to 18 years to participate in 2009 and in 2014. Parents filled the Pediatric Quality of Life Inventory (PedsQL) proxy questionnaire, a survey of their child's health and evaluated parental distress on a visual-analog scale from 0 to 7. Overall participation rates were 80% (12/15) for the longitudinal and 83% (20/24) for the cross-sectional assessment. A control population of 324 children matched for age and sex was randomly picked, and 108 (33%) participated. RESULTS Overall, patients and controls had comparable HRQoL. Patients reported significantly lower scores for school functioning (P = 0.004) as depicted by missing school or day care due to hospital visits. Eighty-five percent of parents reported extreme worry (7.0) when hearing their child's BA diagnosis. At 6 years after diagnosis, parents reported significantly less worry: median score 3.8 (interquartile range 3.0-5.4, P

IntroductionCT is the primary imaging option for acute abdominal pain in adults. Intravenous (IV) contrast media use improves CT quality but may cause post-contrast acute kidney injury (PC-AKI). Retrospective studies show no association between reduced baseline renal function and IV contrast CT, but, to our knowledge, no data from randomised controlled trials exist.Methods and analysisThe INCARO (INtravenous Contrast computed tomography versus native computed tomography in patients with acute Abdomen and impaired Renal functiOn) trial is a multicentre, open-label, parallel group, superiority, individually randomised controlled trial comparing IV contrast-enhanced CT to native CT in patients requiring emergency abdominal or body CT with impaired renal function defined as an estimated glomerular filtration rate (eGFR) of 15 to 45 mL/min/1.73 m2. The primary outcome is a composite of all-cause mortality or renal replacement therapy (RRT) within 90 days from CT. Secondary outcomes are AKI measured by KDIGO (The Kidney Disease: Improving Global Outcomes) criteria within 72 hours from CT, organ dysfunction defined by mSOFA (modified Sequential Organ Failure Assessment) criteria after 48 hours from CT, alive and hospital-free days within 90 days after CT, and time from imaging to definitive treatment. All-cause mortality, need for RRT and renal transplant in long-term follow-up are also measured. The calculated sample size is 994 patients. Patient recruitment is estimated to take 3 years.Ethics and disseminationThe Ethics Committee of Helsinki University Hospital approved the study. The findings will be disseminated in peer-reviewed academic journals.Trial registration numberNCT04196244

Background. In biliary atresia mechanisms of progressive liver injury leading to need of liver transplantation after successful portoenterostomy remain unknown. A better understanding is a prerequisite for development of novel therapies to extend native liver survival, and we aimed to unravel molecular characteristics of liver injury after successful portoenterostomy. Methods. Liver biopsies obtained from 28 biliary atresia children during successful portoenterostomy and at median age 3.0 years were studied. Biopsies were analyzed for histology and immunohistochemical expression of collagen 1, myofibroblast marker alpha-smooth muscle actin, and cytokeratin-7 positive ductal reactions. Hepatic ribonucleic acid (RNA) expression of growth factors and inflammatory cytokines was evaluated. Intestinal failure patients with comparable liver fibrosis and nonfibrotic gallstone patients and donor livers were controls. Results. After successful portoenterostomy, histologic cholestasis resolved and portal inflammation reduced, while fibrosis along with ductal reactions and overexpression of collagen and alpha-smooth muscle actin persisted. At follow-up, liver RNA expression of collagen and platelet-derived growth factor was increased, whereas RNA expression of various inflammatory cytokines remained low. Disappearance of periductal alpha-smooth muscle actin expression after successful portoenterostomy (36% of patients) associated with contracted ductal reactions and reduced progression of fibrosis, collagen accumulation, platelet-derived growth factor RNA expression, and serum levels of bile acids and bilirubin. Fibrosis progressed less rapidly in syndromic than in isolated biliary atresia patients. Conclusion. These findings suggest that instead of inflammation, molecular signature of active fibrogenesis in association with ductal reactions prevails in long-term native liver survivors with biliary atresia. Patients should be stratified for isolated and syndromic disease forms in interventional studies.

Evidence-based recommendations on endoscopic screening and prophylactic treatment of esophageal varices in patients with biliary atresia (BA) are scarce. We assessed the efficiency of endoscopic surveillance and risk factors of esophageal varices and associated upper gastrointestinal bleeding.A total of 47 consecutive children with BA and portoenterostomy underwent yearly endoscopies and prophylactic injection sclerotherapy of esophageal varices between 1987 and 2009. The median follow-up was 1.7 years (range 0.5-18.9) and overall 2-year survival 71%. Disease characteristics, clearance of jaundice, laboratory tests reflecting liver function and hypersplenism, as well as sonographic signs of portal hypertension were related to endoscopic findings and bleeding episodes.Grade 2 to 3 varices developed with similar frequency after failed (18/28, 64%) and successful portoenterostomy (10/19, 53%) in 28 patients. Following failed portoenterostomy, esophageal varices were encountered significantly earlier (8 [4-23] vs. 19 [4-165] months, P = 0.004), and they reappeared after eradication more often (16/16 vs. 4/10, P = 0.001). Varices bled only after failed portoenterostomy (13/28 vs. 0/19, P 0.001). Increased serum bilirubin concentration40 μmol/L at 3 months after portoenterostomy was a risk factor of upper gastrointestinal bleeding (odds ratio [OR] 17, 95% confidence interval [CI] 1.7-175, P = 0.017).In future studies as well as clinical surveillance of BA patients' varices, successful and failed portoenterostomy patients should be approached as separate groups with divergent prognoses. After failed portoenterostomy, surveillance should start early, for example, at 6 months.

Liver transplantation (LT) predisposes to metabolic derangements and increases the risk for cardiovascular disease. We conducted a national cross-sectional study of all pediatric recipients who underwent LT between 1987 and 2007. We measured serum levels of noncholesterol sterols (surrogate markers of cholesterol synthesis and intestinal absorption) and fibroblast growth factor 21 (FGF21) in 49 patients (74% of survivors) at a median of 10 years posttransplant and in 93 controls matched for age and gender. Although serum cholesterol levels were similar in patients and controls, patients displayed increased whole-body synthesis and decreased intestinal absorption of cholesterol compared with controls (lathosterol to cholesterol ratio 129 ± 55 vs. 96 ± 41, respectively, p < 0.001; campesterol to cholesterol ratio 233 ± 91 vs. 316 ± 107, respectively; p < 0.001). Azathioprine (r =–0.383, p = 0.007) and low-dose methylpredisolone (r =–0.492, p < 0.001) were negatively associated with lathosterol/sitosterol ratio reflecting a favorable effect on cholesterol metabolism. FGF21 levels were higher in patients than in controls (248 pg/mL vs. 77 pg/mL, p < 0.001). In healthy controls, FGF21 was associated with cholesterol metabolism, an association missing in LT recipients. Normal serum lipids are achievable in long-term survivors of pediatric LT, but changes in cholesterol metabolism and increased FGF21 levels may explicate later cardiovascular risk.

BACKGROUND AND OBJECTIVE Plant sterols (PS) in parenteral nutrition (PN) may contribute to intestinal failure-associated liver disease. We investigated interrelations between serum PS, liver function and histology, cholesterol metabolism, and characteristics of PN. PATIENTS AND METHODS Eleven patients with intestinal failure (mean age 6.3 years) receiving long-term PN were studied prospectively (mean 254 days) and underwent repeated measurements of serum lipids, noncholesterol sterols, including PS, and liver enzymes. PS contents of PN were analyzed. Liver biopsy was obtained in 8 patients. Twenty healthy children (mean age 5.7 years) served as controls. RESULTS Median percentage of parenteral energy of total daily energy (PN%) was 48%, including 0.9 g · kg(-1) · day(-1) of lipids. Respective amounts of PN sitosterol, campesterol, avenasterol, and stigmasterol were 683, 71, 57, and 45 μg · kg(-1) · day(-1). Median serum concentrations of sitosterol (48 vs 7.5 μmol/L, P < 0.001), avenasterol (2.9 vs 1.9, P < 0.01), stigmasterol (1.9 vs 1.2, P < 0.005), but not that of campesterol (9.8 vs 12, P = 0.22), were increased among patients in relation to controls, and correlated with PN% (r = 0.81-0.88, P < 0.005), but not with PN fat. Serum cholesterol precursors were higher in patients than in controls. Serum liver enzymes remained close to normal range. Glutamyl transferase correlated with serum PS (r = 0.61-0.62, P < 0.05). Liver fibrosis in 5 patients reflected increased serum PS (r = 0.55-0.60, P = 0.16-0.12). CONCLUSIONS Serum PS moderately increase during olive oil-based PN, and correlate positively with PN% and glutamyl transferase. Despite well-preserved liver function, histology often revealed significant liver damage.

AIM: To study the relation between collagen 1, α-smooth muscle actin (α-SMA) and CD34 expression and the most essential portoenterostomy (PE) outcomes. METHODS: Liver specimens were obtained at PE from 33 biliary atresia (BA) patients for immunohistochemical analysis of collagen 1, α-SMA and CD34. Liver biopsies from 35 organ donors were used as controls. Expression patterns were related to clinical data including age at PE, serum total and conjugated bilirubin concentration at the time of PE and during follow-up, incidence of esophageal varices in follow-up upper gastrointestinal endoscopies, and native liver survival as well as to detailed histopathological findings. RESULTS: Collagen 1 (16.4% vs 4.5%, P < 0.0001), α-SMA (17.9% vs 4.6%, P < 0.0001) and CD34 (4.9% vs 3.8%, P = 0.017) were markedly overexpressed in BA patients compared with controls. Patients who underwent liver transplantation by age of two years had significantly higher expression of collagen 1 (18.6% vs 13.7%, P = 0.024), α-SMA (20.4% vs 15.4%, P = 0.009) and CD34 (5.9% vs 4.0%, P = 0.029) at PE compared with native liver survivors. CD34-positive microvessels were identified in the centrizonal region close to central vein in every BA patient. In majority of BA cases (56%) neovascularization was frequent as CD34-positive microvessels were observed in over half of the hepatic lobules. In controls, the CD34-positive microvessels were rare as they were completely absent in 40 % and were found in less than 5 % of the hepatic lobules in the rest. The difference between BA patients and controls was significant (P < 0.0001). Patients who developed esophageal varices by two years had significantly higher expression of CD34 at PE compared with patients without varices (5.6% vs 4.0%, P = 0.019). Expression of α-SMA (r = 0.758, P < 0.0001) and collagen 1 (r = 0.474, P = 0.016), and the amount of CD34-positive microvessels (r = 0.356, P = 0.047) were related to patient age at PE. CONCLUSION: Hepatic myofibroblastic cell activation, fibrogenesis and neovascularization are enhanced in BA, progress with increasing PE age and relate to native liver survival and development of esophageal varices.

Biliary atresia is a rare, neonatal, progressive cholestatic liver disease caused by fibroinflammatory obstruction of the biliary tree. Typical symptoms include prolonged neonatal jaundice, pale stools, and conjugated hyperbilirubinemia. Treatment starts with portoenterostomy, where fibrotic remnants of the extra hepatic bile ducts are replaced with small intestine. Best operative results are achieved among the youngest patients treated in specialized centres. Despite clearance of jaundice after a successful operation, fibrotic change of the liver continues in most. Liver transplantation serves as a salvage procedure if the portoenterostomy fails, or complications of liver cirrhosis develop after an initially successful portoenterostomy. In Finland, biliary atresia treatment was centralized in 2005. Of the patients treated thereafter, 90% are alive and over 80% with their native livers.

In children, optimal timing of liver transplantation (LT) is crucial, but reliable prognostic tools for chronic liver diseases are scarce. We assessed the predictive value of galactose half-life (Gal½) for LT or death. A retrospective search of hospital database 2003-2010 revealed 92 consecutive children with chronic liver disease (36 biliary atresia) whose liver function was assessed with Gal½ measurement. Gal½, follow-up data, and liver biochemistry were recorded and pediatric/model for end-stage liver disease (P/MELD) scores calculated. Patients listed for LT or those who died within 1 year of the Gal½ measurement (Group 1) were compared to those surviving without listing (Group 2). Predictive value of Gal½ and P/MELD for listing for LT was assessed with area under the receiver operating characteristic curve (AUROC) analysis. Group 1 had markedly increased median Gal½ [17.0 (interquartile range 12.5-28.5) min] and higher P/MELD [13 (-1-23)] compared with group 2, [10.5 (9.5-12.5) min and -1 (-8-8); P0.001 for both]. Both Gal½ and P/MELD (P0.001) predicted listing or death with respective AUROCs of 0.808 (95% CI 0.704-0.913) and 0.780 (0.676-0.890), and 85% sensitivity and 69% specificity for Gal½≥12.0 min. Gal½ is a useful tool when evaluating 1-year prognosis in children with chronic liver disease.

Controversy remains about the role of protocol liver biopsy for symptom-free recipients and about the long-term use of low-dose steroids after pediatric liver transplantation (LT). We conducted a national cross-sectional study of pediatric recipients who underwent LT between 1987 and 2007. Liver biopsy samples were taken from 54 patients (82% of survivors) after a median posttransplant follow-up of 11 years, and they were reviewed by 2 pathologists blinded to the clinical data. Biopsy samples from 18 patients (33%) showed nearly normal histology with no inflammation, fibrosis, or steatosis. Portal inflammation was detected in 14 samples (26%), showed no correlation with anti-nuclear antibodies, and was less frequent in the 35 patients whose immunosuppression included steroids (14% versus 47% of patients not using steroids, P = 0.008). Fibrosis was present in 21 biopsy samples (39%). According to the Metavir classification, 16 were stage 1, 3 were stage 2, and 2 were stage 3. The fibrosis stage correlated negatively with serum prealbumin levels (r = -0.364, P = 0.007) and positively with chronic cholestasis (cytokeratin 7 staining; r = 0.529, P0.001) and portal inflammation (r = 0.350, P = 0.01). Microvesicular steatosis was found in 23 biopsy samples (43% of patients in 5%-80% of hepatocytes), and it correlated with the body mass index (r = 0.458, P0.001) but not with steroid use. The age of the allograft (donor age plus follow-up time) correlated with higher serum gamma-glutamyltransferase (r = 0.472, P0.001) and conjugated bilirubin levels (r = 0.420, P = 0.002) as well as chronic cholestasis (r = 0.299, P = 0.03). The biopsy findings led to treatment changes in 10 patients (19%), whereas only 1 complication (subcapsular hematoma) was encountered. In conclusion, continuing low-dose steroids indefinitely after pediatric LT may have a positive effect on the long-term histological state of the liver graft. Allograft aging may lead to chronic cholestasis and thus contribute to the development of liver fibrosis.

Effects of caseload and organization of care on outcomes of biliary atresia (BA) remain unclear. We compared outcomes before and after national centralization of BA treatment in Finland with a population of 5.4 million people and 60,000 live births/year.All children born in Finland from 1987 to 2010 with BA were included. Complete patient identification was ascertained from the national Register of Congenital Malformations. Hospital records were reviewed for confirmation of the diagnosis, treatment, and follow-up data. Clearance of jaundice (serum bilirubin ≤ 20 μmol/l) and survival modalities were compared before and after centralization from five centers to Helsinki.The incidence of BA was 1 in 20,100 live births. A total of 72 BA patients of whom 64 had undergone surgery for BA were identified. After centralization, the median caseload per center increased from 0 (range, 0-3) to 4 (2-5) patients/year (p0.001), clearance of jaundice rate increased from 27% to 75% (p = 0.001), 2-year jaundice-free native liver survival from 25% to 75% (p = 0.002), transplant-free survival from 27% to 75% (p = 0.005), and overall survival from 64% to 92% (p = 0.082). Baseline patient characteristics including type of BA and age at portoenterostomy remained unaltered. In a logistic regression analysis including treatment era, operating center, BA splenic malformation syndrome, and age at portoenterostomy as variables, only treatment in Helsinki after centralization predicted clearance of jaundice (odds ratio 4.2; 95% confidence interval 1.05-16.5; p = 0.043).In small countries, BA treatment should be centralized to appointed multidisciplinary teams allowing high quality results with a median of four cases/year.

The long-term impact of pediatric liver transplantation (LT) and its complications on general health, health-related quality of life (HRQoL) and sexual health were assessed. We conducted a national cross-sectional study of all pediatric recipients who underwent LT between 1987 and 2007. Of 66 survivors, 57 participants (86%) were compared to randomly chosen healthy controls (n = 141) at 10.7 ± 6.6 years posttransplant. PedsQL4.0, SF-36, DISF-SR and AUDIT questionnaires for appropriate age groups were used. Patients and controls

Biliary atresia is the most common indication for childhood liver transplantation. The effects of successful portoenterostomy (PE) on native liver histology remain unclear.We assessed changes in native liver histology after a successful PE in relation to liver function and clinical outcomes.In total, 70 native liver biopsies of 44 biliary atresia patients were obtained at PE (n=30), 4.2 years after successful PE (n=23) and 1.1 years after failed PE (n=17), and reviewed for cholestasis, fibrosis, inflammation, and cytokeratin 7 (CK7) immunopositivity (chronic cholestasis). Ten transplant donor livers served as controls.After a successful PE [serum bilirubin 11 (2 to 35) μmol/L at biopsy], histologic native liver cholestasis completely resolved in 83% of the patients and portal inflammation significantly decreased. Nevertheless, enhanced fibrosis [Metavir stage 2 (1-4) vs. 4 (1-4)], bile duct proliferation [grade 2 (1-2) vs. 1 (0-2)], and periportal CK7 immunostaining [grade 1 (0-2) vs. 1 (0-4)] persisted in 100%, 87%, and 61% of subjects, respectively. Metavir fibrosis stage corresponded cirrhosis (stage 4) in 52% of the patients, associated with the presence of portal hypertension, and correlated with serum-conjugated bilirubin (r=0.601, P=0.002), bile duct proliferation (r=0.657, P=0.001), and CK7 positivity (r=0.657, P=0.001). Aspartate transferase to platelet ratio index predicted native liver fibrosis and development of esophageal varices. The degree of fibrosis and portal inflammation at PE were unrelated to native liver survival.Despite resolution of cholestasis and decreasing inflammation, bile duct proliferation, periportal CK7 immunostaining, and fibrosis persist after successful PE. Fibrosis is associated with biochemical cholestasis, bile duct proliferation, CK7 immunopositivity (chronic cholestasis), and development of portal hypertension.