Publications by authors named "Arthur Revhaug"

58 Publications

Clinically relevant features for predicting the severity of surgical site infections.

IEEE J Biomed Health Inform 2021 Oct 19;PP. Epub 2021 Oct 19.

Surgical site infections are hospital-acquired infections resulting in severe risk for patients and significantly increased costs for healthcare providers. In this work, we show how to leverage irregularly sampled preoperative blood tests to predict, on the day of surgery, a future surgical site infection and its severity. Our dataset is extracted from the electronic health records of patients who underwent gastrointestinal surgery and developed either deep, shallow or no infection. We represent the patients using the concentrations of fourteen common blood components collected over the four weeks preceding the surgery partitioned into six time windows. A gradient boosting based classifier trained on our new set of features reports, respectively, an AUROC of 0:991 and 0:937 at predicting a postoperative infection and the severity thereof. Further analyses support the clinical relevance of our approach as the most important features describe the nutritional status and the liver function over the two weeks prior to surgery.
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http://dx.doi.org/10.1109/JBHI.2021.3121038DOI Listing
October 2021

Antenatal breastmilk expression for women with diabetes in pregnancy - a feasibility study.

Int Breastfeed J 2021 07 23;16(1):56. Epub 2021 Jul 23.

Department of Obstetrics and Gynecology, Division of Surgery, Oncology and Women's Health, University Hospital of North Norway, Tromsø, Norway.

Background: Mothers with diabetes are less likely to achieve successful breastfeeding. Antenatal breastmilk expression (ABE) may facilitate earlier breastfeeding, but feasibility of introducing ABE and its acceptance among Scandinavian women have previously not been investigated.

Methods: This observational trial was conducted between the 1 January 2019 and the 12 March 2020 in Tromsø, Norway. We aimed to determine the feasibility of ABE in terms of practicality and acceptability among women with medically (metformin or insulin) treated diabetes. Women were invited to participate during antenatal visits from 32 weeks gestation. Participants received instruction and started ABE from gestation week 37 + 0. Participants, and their infants, were followed until 6-8 weeks after birth. We collected data on breastfeeding rates, infant hypoglycemia, transfer to the neonatal unit, and the women's overall experience and satisfaction with antenatal breastmilk expression.

Results: Twenty-eight of 34 (82%) invited women consented to participate. All started ABE from week 37 + 0, and continued until hospital admission. No women reported any discomfort or side effects. Labor was induced at 38 weeks gestation. Twenty-four women brought harvested colostrum to the maternity ward, which was given to their infants during the first 24 h of life. Breastfeeding rates at discharge were 24/28 (86%) and 21/27 (78%) at 6-8 weeks after delivery. Seven (25%) infants were transferred to the neonatal unit; four because of hypoglycemia. Maternal satisfaction assessed 6-8 weeks after delivery revealed that all participants felt positive about the ABE, but one woman would not recommend it to other pregnant women.

Conclusions: Implementing a structured ABE guideline for women with medically treated diabetes was feasible. The intervention was associated with high level of satisfaction among study participants. No obvious side effects were observed, and breastfeeding rates at discharge and 6-8 weeks after delivery were higher than in comparable studies.

Trial Registration: The study was registered at the research study registry at the University Hospital of North Norway ( Nr 2018/7181 ).
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http://dx.doi.org/10.1186/s13006-021-00393-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299162PMC
July 2021

Uncertainty-Aware Deep Ensembles for Reliable and Explainable Predictions of Clinical Time Series.

IEEE J Biomed Health Inform 2021 07 27;25(7):2435-2444. Epub 2021 Jul 27.

Deep learning-based support systems have demonstrated encouraging results in numerous clinical applications involving the processing of time series data. While such systems often are very accurate, they have no inherent mechanism for explaining what influenced the predictions, which is critical for clinical tasks. However, existing explainability techniques lack an important component for trustworthy and reliable decision support, namely a notion of uncertainty. In this paper, we address this lack of uncertainty by proposing a deep ensemble approach where a collection of DNNs are trained independently. A measure of uncertainty in the relevance scores is computed by taking the standard deviation across the relevance scores produced by each model in the ensemble, which in turn is used to make the explanations more reliable. The class activation mapping method is used to assign a relevance score for each time step in the time series. Results demonstrate that the proposed ensemble is more accurate in locating relevant time steps and is more consistent across random initializations, thus making the model more trustworthy. The proposed methodology paves the way for constructing trustworthy and dependable support systems for processing clinical time series for healthcare related tasks.
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http://dx.doi.org/10.1109/JBHI.2020.3042637DOI Listing
July 2021

The effects of terlipressin and direct portacaval shunting on liver hemodynamics following 80% hepatectomy in the pig.

Clin Sci (Lond) 2019 01 15;133(1):153-166. Epub 2019 Jan 15.

Surgical Research Laboratory, Institute of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway.

Liver failure is the major cause of death following liver resection. Post-resection portal venous pressure (PVP) predicts liver failure, is implicated in its pathogenesis, and when PVP is reduced, rates of liver dysfunction decrease. The aim of the present study was to characterize the hemodynamic, biochemical, and histological changes induced by 80% hepatectomy in non-cirrhotic pigs and determine if terlipressin or direct portacaval shunting can modulate these effects. Pigs were randomized (=8/group) to undergo 80% hepatectomy alone (control); terlipressin (2 mg bolus + 0.5-1 mg/h) + 80% hepatectomy; or portacaval shunt (PCS) + 80% hepatectomy, and were maintained under terminal anesthesia for 8 h. The primary outcome was changed in PVP. Secondary outcomes included portal venous flow (PVF), hepatic arterial flow (HAF), and biochemical and histological markers of liver injury. Hepatectomy increased PVP (9.3 ± 0.4 mmHg pre-hepatectomy compared with 13.0 ± 0.8 mmHg post-hepatectomy, <0.0001) and PVF/g liver (1.2 ± 0.2 compared with 6.0 ± 0.6 ml/min/g, <0.0001) and decreased HAF (70.8 ± 5.0 compared with 41.8 ± 5.7 ml/min, =0.002). Terlipressin and PCS reduced PVP (terlipressin = 10.4 ± 0.8 mmHg, =0.046 and PCS = 8.3 ± 1.2 mmHg, =0.025) and PVF (control = 869.0 ± 36.1 ml/min compared with terlipressin = 565.6 ± 25.7 ml/min, <0.0001 and PCS = 488.4 ± 106.4 ml/min, =0.002) compared with control. Treatment with terlipressin increased HAF (73.2 ± 11.3 ml/min) compared with control (40.3 ± 6.3 ml/min, =0.026). The results of the present study suggest that terlipressin and PCS may have a role in the prevention and treatment of post-resection liver failure.
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http://dx.doi.org/10.1042/CS20180858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331658PMC
January 2019

Regional variation in hospitalizations and outpatient appointments for diverticular disease in Norway: a nationwide cross-sectional study.

Scand J Gastroenterol 2018 Oct - Nov;53(10-11):1228-1235. Epub 2018 Sep 28.

a Department of Clinical Medicine , UiT The Arctic University of Norway , Tromsø , Norway.

Objective: To investigate the use of specialized health care services for diverticular disease in different hospital referral regions in Norway.

Materials And Methods: Nationwide cross-sectional study with data from the Norwegian Patient Registry and Statistics Norway. All Norwegian inhabitants aged 40 years and older in the years 2012-16 (2,517,938) were included. We obtained the rates (n/100,000 population) for hospitalizations, outpatient appointments, and surgery for diverticular disease for the population in each hospital referral region. We also quantified the use of lower gastrointestinal (LGI) endoscopy in hospitalizations and outpatient appointments for diverticular disease and the use of LGI endoscopy performed on any indication.

Results: There were 131 hospitalizations and 381 outpatient appointments for diverticular disease per 100,000 population annually. Hospitalization rates varied 1.9-fold across regions from 94 to 175. Outpatient appointment rates varied 2.5-fold across regions from 258 to 655. Outpatient appointments were strongly correlated to hospitalizations (r=0.75, p < .001) and outpatient LGI endoscopy for any indication (r=0.67, p < .001). Hospitalization and surgery rates remained stable over the study period, while outpatient appointment rates increased by 37%. Concurrently, rates of outpatient LGI endoscopy performed on any indication increased by 35%.

Conclusion: There was considerable regional variation in both hospitalizations and outpatient appointments for diverticular disease. The extent of variation and the correlation with diagnostic intensity of LGI endoscopy indicate that the regional variation in health care utilization for diverticular disease to a large extent can be explained by regional differences in clinical practice rather than disease burden.
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http://dx.doi.org/10.1080/00365521.2018.1506047DOI Listing
April 2019

Extent, regional variation and impact of gynecologist payment models in routine pelvic examinations: a nationwide cross-sectional study.

BMC Womens Health 2017 Nov 21;17(1):114. Epub 2017 Nov 21.

Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Based on moderate quality evidence, routine pelvic examination is strongly recommended against in asymptomatic women. The aims of this study was to quantify the extent of routine pelvic examinations within specialized health care in Norway, to assess if the use of these services differs across hospital referral regions and to assess if the use of colposcopy and ultrasound differs with gynecologists' payment models.

Methods: Nationwide cross-sectional study including all women aged 18 years and older in Norway in the years 2014-16 (2,038,747). Data was extracted from the Norwegian Patient Registry and Statistics Norway. The main outcome measures were 1. The number of appointments per 1000 women with a primary diagnosis of "Encounter for gynecological examination without complaint, suspected or reported diagnosis." 2. The age-standardized number of these appointments per 1000 women in the 21 different hospital referral regions of Norway. 3. The use of colposcopy and ultrasound in routine pelvic examinations, provided by gynecologists with fixed salaries and gynecologists paid by a fee-for-service model.

Results: Annually 22.2 out of every 1000 women in Norway had a routine pelvic examination, with variation across regions from 6.6 to 43.9 per 1000. Gynecologists with fixed salaries performed colposcopy in 1.6% and ultrasound in 74.5% of appointments. Corresponding numbers for fee-for-service gynecologists were 49.2% and 96.2%, respectively.

Conclusions: Routine pelvic examinations are widely performed in Norway. The variation across regions is extensive. Our results strongly indicate that fee-for-service payments for gynecologists skyrocket the use of colposcopy and increase the use of ultrasound in pelvic examinations of asymptomatic women.
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http://dx.doi.org/10.1186/s12905-017-0471-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697055PMC
November 2017

Using anchors from free text in electronic health records to diagnose postoperative delirium.

Comput Methods Programs Biomed 2017 Dec 19;152:105-114. Epub 2017 Sep 19.

Department of Physics and Technology, UiT, Tromsø, Norway; Norwegian Centre for E-health Research, University Hospital of North Norway (UNN), Tromsø, Norway; UiT Machine Learning Group, Norway.

Objectives: Postoperative delirium is a common complication after major surgery among the elderly. Despite its potentially serious consequences, the complication often goes undetected and undiagnosed. In order to provide diagnosis support one could potentially exploit the information hidden in free text documents from electronic health records using data-driven clinical decision support tools. However, these tools depend on labeled training data and can be both time consuming and expensive to create.

Methods: The recent learning with anchors framework resolves this problem by transforming key observations (anchors) into labels. This is a promising framework, but it is heavily reliant on clinicians knowledge for specifying good anchor choices in order to perform well. In this paper we propose a novel method for specifying anchors from free text documents, following an exploratory data analysis approach based on clustering and data visualization techniques. We investigate the use of the new framework as a way to detect postoperative delirium.

Results: By applying the proposed method to medical data gathered from a Norwegian university hospital, we increase the area under the precision-recall curve from 0.51 to 0.96 compared to baselines.

Conclusions: The proposed approach can be used as a framework for clinical decision support for postoperative delirium.
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http://dx.doi.org/10.1016/j.cmpb.2017.09.014DOI Listing
December 2017

Routine deferred computed tomography for patients with suspected urolithiasis is low-value healthcare.

Scand J Urol 2017 Feb 23;51(1):62-67. Epub 2016 Nov 23.

a Department of Clinical Medicine , UiT The Arctic University of Norway , Tromsø , Norway.

Objective: The aim of this study was to investigate the benefits of deferred routine computed tomography of the kidneys, ureters and bladder (CT KUB) for patients with a self-limiting episode of suspected urolithiasis.

Materials And Methods: The study comprised a case series of consecutive patients examined with deferred routine CT KUB for control of suspected urolithiasis. Patients examined with CT KUB at the University Hospital of North Norway, between 1 January 2010 and 31 December 2013, were included. The final analysis included 189 CT KUBs (response rate 48%). All data were extracted from the patient case files. The primary endpoint was the proportion of asymptomatic patients with a confirmed diagnosis of urolithiasis on CT KUB that led to surgical intervention within 1 year from the initial CT scan.

Results: At the time of CT KUB, 171 patients (90%) were asymptomatic, of whom three (1.8%) were treated. Urolithiasis was confirmed on CT KUB in 23% of asymptomatic patients.

Conclusion: Deferred CT KUB did not alter the clinical outcome for the great majority of asymptomatic patients. The majority of patients who received adequate pain relief in primary care remained asymptomatic, and did not need specialized healthcare. Refraining from CT KUB involves little risk. Deferred CT KUB for patients with suspected urolithiasis is a low-value healthcare service.
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http://dx.doi.org/10.1080/21681805.2016.1254680DOI Listing
February 2017

The impact of partial hepatectomy on oxidative state in the liver remnant - An in vivo swine model.

Redox Biol 2016 10 24;9:15-21. Epub 2016 May 24.

Laboratory of Surgical Research, Institute of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway; Department of Digestive Surgery, University Hospital North Norway, Tromsø, Norway.

Background: Previous studies on oxidative state after partial hepatectomy (PHx) report conflicting data on levels of glutathione (GSH) and are mainly presented in rodent models by methodology less sensitive than the present technologies. The current swine model presents GSH levels and the following genetic response post-PHx, utilizing an analytical platform more sensitive and precise than earlier available.

Method: Twelve pigs were randomized to a PHx- and a control group (n=6 in each). The PHx group had a 60% hepatectomy. Serial in vivo liver biopsies during 12h of anaesthesia post-PHx were analyzed for GSH by liquid chromatography mass spectrometry (LC-MS/MS). Transcriptional alterations of genes (GS, GCLM, GCLC, GR, HGF, NFE2L2, TGFβ1) regulating GSH synthesis were measured by real-time PCR.

Results: No difference was detected between the GSH levels in the PHx- and the control group during the experiment (P=0.247). Still, decreased gene expression of GS (P=0.026) and NFE2L2 (P=0.014) the first nine hours, and a decrease of TGFβ1 (P=0.029) the first seven hours post-PHx was seen in the liver remnant.

Conclusion: The results show that the liver has an extended capacity to maintain GSH homeostasis during major stress and parenchymal loss, even at the early onset of such trauma. This observation was not explained by increased expression of key genes in GSH pathways. Consequently, the results indicate an inherent compensatory capacity to maintain GSH homeostasis in the reduced organ.
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http://dx.doi.org/10.1016/j.redox.2016.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898964PMC
October 2016

Pulmonary vascular clearance of harmful endogenous macromolecules in a porcine model of acute liver failure.

Ann Hepatol 2016 May-Jun;15(3):427-35

Department of Digestive Surgery, University Hospital Northern Norway.

Background: Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake.

Results: As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups.

Conclusion: Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.
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http://dx.doi.org/10.5604/16652681.1198821DOI Listing
January 2017

Predicting colorectal surgical complications using heterogeneous clinical data and kernel methods.

J Biomed Inform 2016 06 12;61:87-96. Epub 2016 Mar 12.

Norwegian Centre for Integrated Care and Telemedicine, Norway; Dept. of Physics and Technology, UiT, Tromsø, Norway.

Objective: In this work, we have developed a learning system capable of exploiting information conveyed by longitudinal Electronic Health Records (EHRs) for the prediction of a common postoperative complication, Anastomosis Leakage (AL), in a data-driven way and by fusing temporal population data from different and heterogeneous sources in the EHRs.

Material And Methods: We used linear and non-linear kernel methods individually for each data source, and leveraging the powerful multiple kernels for their effective combination. To validate the system, we used data from the EHR of the gastrointestinal department at a university hospital.

Results: We first investigated the early prediction performance from each data source separately, by computing Area Under the Curve values for processed free text (0.83), blood tests (0.74), and vital signs (0.65), respectively. When exploiting the heterogeneous data sources combined using the composite kernel framework, the prediction capabilities increased considerably (0.92). Finally, posterior probabilities were evaluated for risk assessment of patients as an aid for clinicians to raise alertness at an early stage, in order to act promptly for avoiding AL complications.

Discussion: Machine-learning statistical model from EHR data can be useful to predict surgical complications. The combination of EHR extracted free text, blood samples values, and patient vital signs, improves the model performance. These results can be used as a framework for preoperative clinical decision support.
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http://dx.doi.org/10.1016/j.jbi.2016.03.008DOI Listing
June 2016

Tissue Remodelling following Resection of Porcine Liver.

Biomed Res Int 2015 9;2015:248920. Epub 2015 Jul 9.

Laboratory of Surgical Research, Institute of Clinical Medicine, University of Tromsø, 9037 Tromsø, Norway.

Aim: To study genes regulating the extracellular matrix (ECM) and investigate the tissue remodelling following liver resection in porcine.

Methods: Four pigs with 60% partial hepatectomy- (PHx-) induced liver regeneration were studied over six weeks. Four pigs underwent sham surgery and another four pigs were used as controls of the normal liver growth. Liver biopsies were taken upon laparotomy, after three and six weeks. Gene expression profiles were obtained using porcine-specific oligonucleotide microarrays. Immunohistochemical staining was performed and a proliferative index was assessed.

Results: More differentially expressed genes were associated with the regulation of ECM in the resection group compared to the sham and control groups. Secreted protein acidic and rich in cysteine (SPARC) and collagen 1, alpha 2 (COL1A2) were both upregulated in the early phase of liver regeneration, validated by immunopositive cells during the remodelling phase of liver regeneration. A broadened connective tissue was demonstrated by Masson's Trichrome staining, and an immunohistochemical staining against pan-Cytokeratin (pan-CK) demonstrated a distinct pattern of migrating cells, followed by proliferating cell nuclear antigen (PCNA) positive nuclei.

Conclusions: The present study demonstrates both a distinct pattern of PCNA positive nuclei and a deposition of ECM proteins in the remodelling phase of liver regeneration.
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http://dx.doi.org/10.1155/2015/248920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512564PMC
April 2016

Food at will after pancreaticoduodenectomies. Re. "Perioperative nutritional support of patients undergoing pancreatic surgery in the age of ERAS".

Nutrition 2015 Jul-Aug;31(7-8):1057-8. Epub 2015 Mar 20.

Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

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http://dx.doi.org/10.1016/j.nut.2015.02.013DOI Listing
September 2015

Preoperative carbohydrate supplementation attenuates post-surgery insulin resistance via reduced inflammatory inhibition of the insulin-mediated restraint on muscle pyruvate dehydrogenase kinase 4 expression.

Clin Nutr 2015 Dec 11;34(6):1177-83. Epub 2014 Dec 11.

Department of Digestive Surgery, University Hospital of North Norway, Tromsø, Norway; Laboratory of Surgical Research, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.

Background & Aims: We hypothesized that the so far poorly understood improvement in postoperative insulin sensitivity, when surgery is preceded by a carbohydrate (CHO) drink, occurs via attenuation of skeletal muscle inflammatory responses to surgery, improved insulin signaling and attenuated expression of muscle pyruvate dehydrogenase kinase (PDK) 4.

Methods: Vastus lateralis muscle biopsies, collected before and after major abdominal surgery and during postoperative hyperinsulinaemic-euglycaemic clamping from 16 pigs randomized to either 200 ml of a CHO-supplemented drink 2 h before surgery (CHO, 25 g; n = 8), or preoperative overnight fasting (fasted; n = 8), were analyzed by fast qRT-PCR and IR-Western blotting.

Results: During clamping, expression of IKKβ, SOCS3 and the ratio of phosphorylated/total JNK2 proteins were lower in the CHO group than in the fasted group (-1.0 vs. 2.9-fold, P < 0.001; -0.6 vs. 3.2-fold, P < 0.01; and -0.5 vs. 1.1-fold, P < 0.02, respectively). Furthermore, the ratio of Ser(307)-phosphorylated (inhibition)/total IRS1 protein was reduced only in the CHO group (-2.4 fold, P < 0.02), whereas FOXO1 phosphorylation (inactivation), which correlated negatively with PDK4 mRNA (r(2) = 0.275, P < 0.05), was lower in the CHO group than in the fasted group (-1.1-fold, P > 0.05 vs. -2.3-fold, P = 0.05). Post-surgery, PDK4 mRNA increased ∼20-fold (P < 0.01) in both groups, but was reversed to a greater extent by insulin in the CHO group (-40.5 vs. -22.7-fold, P < 0.05), resulting in 5-fold lower PDK4 protein levels, which correlated negatively with insulin-stimulated whole-body glucose disposal rates (r(2) = -0.265, P < 0.05).

Conclusions: Preoperative carbohydrate supplementation was found to ameliorate postoperative insulin sensitivity by reducing muscle inflammatory responses and improved insulin inhibition of FOXO1-mediated PDK4 mRNA and protein expression after surgery.
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http://dx.doi.org/10.1016/j.clnu.2014.12.004DOI Listing
December 2015

Support Vector Feature Selection for Early Detection of Anastomosis Leakage From Bag-of-Words in Electronic Health Records.

IEEE J Biomed Health Inform 2016 09 8;20(5):1404-15. Epub 2014 Oct 8.

The free text in electronic health records (EHRs) conveys a huge amount of clinical information about health state and patient history. Despite a rapidly growing literature on the use of machine learning techniques for extracting this information, little effort has been invested toward feature selection and the features' corresponding medical interpretation. In this study, we focus on the task of early detection of anastomosis leakage (AL), a severe complication after elective surgery for colorectal cancer (CRC) surgery, using free text extracted from EHRs. We use a bag-of-words model to investigate the potential for feature selection strategies. The purpose is earlier detection of AL and prediction of AL with data generated in the EHR before the actual complication occur. Due to the high dimensionality of the data, we derive feature selection strategies using the robust support vector machine linear maximum margin classifier, by investigating: 1) a simple statistical criterion (leave-one-out-based test); 2) an intensive-computation statistical criterion (Bootstrap resampling); and 3) an advanced statistical criterion (kernel entropy). Results reveal a discriminatory power for early detection of complications after CRC (sensitivity 100%; specificity 72%). These results can be used to develop prediction models, based on EHR data, that can support surgeons and patients in the preoperative decision making phase.
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http://dx.doi.org/10.1109/JBHI.2014.2361688DOI Listing
September 2016

Multidisciplinary team conferences promote treatment according to guidelines in rectal cancer.

Acta Oncol 2015 Apr 7;54(4):447-53. Epub 2014 Oct 7.

Department of Surgical and Perioperative Sciences, Umeå University , Sweden.

Background: Multidisciplinary team (MDT) conferences have been introduced into standard cancer care, though evidence that it benefits the patient is weak. We used the national Swedish Rectal Cancer Register to evaluate predictors for case discussion at a MDT conference and its impact on treatment.

Material And Methods: Of the 6760 patients diagnosed with rectal cancer in Sweden between 2007 and 2010, 78% were evaluated at a MDT. Factors that influenced whether a patient was discussed at a preoperative MDT conference were evaluated in 4883 patients, and the impact of MDT evaluation on the implementation of preoperative radiotherapy was evaluated in 1043 patients with pT3c-pT4 M0 tumours, and in 1991 patients with pN+ M0 tumours.

Results: Hospital volume, i.e. the number of rectal cancer surgical procedures performed per year, was the major predictor for MDT evaluation. Patients treated at hospitals with < 29 procedures per year had an odds ratio (OR) for MDT evaluation of 0.15. Age and tumour stage also influenced the chance of MDT evaluation. MDT evaluation significantly predicted the likelihood of being treated with preoperative radiotherapy in patients with pT3c-pT4 M0 tumours (OR 5.06, 95% CI 3.08-8.34), and pN+ M0 (OR 3.55, 95% CI 2.60-4.85), even when corrected for co-morbidity and age.

Conclusion: Patients with rectal cancer treated at high-volume hospitals are more likely to be discussed at a MDT conference, and that is an independent predictor of the use of adjuvant radiotherapy. These results indirectly support the introduction into clinical practice of discussing all rectal cancer patients at MDT conferences, not least those being treated at low-volume hospitals.
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http://dx.doi.org/10.3109/0284186X.2014.952387DOI Listing
April 2015

A sensitive method for the analysis of glutathione in porcine hepatocytes.

Scand J Gastroenterol 2014 Nov 3;49(11):1359-66. Epub 2014 Oct 3.

Laboratory of Surgical Research, Institute of Clinical Medicine, University of Tromsø , Tromsø , Norway.

Background: Reduced glutathione (γ-glutamylcysteinylglycine), GSH, is essential when protecting cells from oxidative stress and also an indicator of disease risk. Reported concentrations of GSH and its oxidized form, glutathione disulfide (GSSG), varies considerably, primarily due to the instability of GSH and various analytical methods.

Methods: We designed a sensitive method to analyze GSH and GSSG in porcine hepatocytes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) after stabilization with N-ethylmaleimide (NEM). This method includes stable isotope labeled internal standards and simple synthesis of labeled GSSG which commercial sources rarely offer. GSH and GSSG were analyzed in porcine liver biopsies giving a reference interval based on a large number of samples (26 pigs; 3 parallels).

Results: The LC-MS/MS results revealed excellent linearity for both GSH and GSSG, with interday coefficient of variation (%CV) for GSH-NEM and GSSG <10 %. Accuracy for recovery tests was between 95.6% and 106.7% (n = 3) for GSH and between 92.3% and 107.7% (n = 3) for GSSG. The limits of quantification were 0.1 μM for GSH-NEM and 0.08 μM for GSSG. The mean concentration of GSH was 3.5 (95% CI = 1.5-8.1) mmol/liter and of GSSG 0.0023 (95% CI = 0.0003-0.019) mmol/liter.

Conclusion: For the first time GSH and GSSG are analyzed in porcine hepatocytes by LC-MS/MS yielding a reference level of GSH and GSSG. The method is reproducible in any laboratory with LC-MS/MS service and will probably be applicable in all soft tissues and cell suspensions, essentially with no modification.
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http://dx.doi.org/10.3109/00365521.2014.964757DOI Listing
November 2014

L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.

Am J Physiol Gastrointest Liver Physiol 2014 Nov 25;307(10):G1024-31. Epub 2014 Sep 25.

Department of Anesthesiology, University Hospital of North Norway and UiT The Arctic University of Norway, Tromsø, Norway;

Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: (1) sham operated + vehicle, (2) ALF + vehicle, and (3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF (P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals (P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 ± 106 μmol/l; ALF + OP: 27,625 ± 2,670 μmol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.
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http://dx.doi.org/10.1152/ajpgi.00244.2014DOI Listing
November 2014

Implementation of an electronic surgical referral service. Collaboration, consensus and cost of the surgeon - general practitioner Delphi approach.

J Multidiscip Healthc 2014 9;7:371-80. Epub 2014 Sep 9.

Department of Gastrointestinal Surgery, University Hospital North Norway, Tromsø, Norway ; Department of Colorectal Surgery, University Hospitals Case Medical Center, Cleveland, Ohio, USA.

Background: Poor coordination between levels of care plays a central role in determining the quality and cost of health care. To improve patient coordination, systematic structures, guidelines, and processes for creating, transferring, and recognizing information are needed to facilitate referral routines.

Methods: Prospective observational survey of implementation of electronic medical record (EMR)-supported guidelines for surgical treatment.

Results: One university clinic, two local hospitals, 31 municipalities, and three EMR vendors participated in the implementation project. Surgical referral guidelines were developed using the Delphi method; 22 surgeons and seven general practitioners (GPs) needed 109 hours to reach consensus. Based on consensus guidelines, an electronic referral service supported by a clinical decision support system, fully integrated into the GPs' EMR, was developed. Fifty-five information technology personnel and 563 hours were needed (total cost 67,000 £) to implement a guideline supported system in the EMR for 139 GPs. Economical analyses from a hospital and societal perspective, showed that 504 (range 401-670) and 37 (range 29-49) referred patients, respectively, were needed to provide a cost-effective service.

Conclusion: A considerable amount of resources were needed to reach consensus on the surgical referral guidelines. A structured approach by the Delphi method and close collaboration between IT personnel, surgeons and primary care physicians were needed to reach consensus.
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http://dx.doi.org/10.2147/JMDH.S66693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167028PMC
September 2014

Functional recovery is considered the most important target: a survey of dedicated professionals.

Perioper Med (Lond) 2014 30;3. Epub 2014 Jul 30.

Department of GI and HPB Surgery, University Hospital Northern Norway, Breivika, Tromsø, Norway ; Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.

Background: The aim of this study was to survey the relative importance of postoperative recovery targets and perioperative care items, as perceived by a large group of international dedicated professionals.

Methods: A questionnaire with eight postoperative recovery targets and 13 perioperative care items was mailed to participants of the first international Enhanced Recovery After Surgery (ERAS) congress and to authors of papers with a clear relevance to ERAS in abdominal surgery. The responders were divided into categories according to profession and region.

Results: The recovery targets 'To be completely free of nausea', 'To be independently mobile' and 'To be able to eat and drink as soon as possible' received the highest score irrespective of the responder's profession or region of origin. Equally, the care items 'Optimizing fluid balance', 'Preoperative counselling' and 'Promoting early and scheduled mobilisation' received the highest score across all groups.

Conclusions: Functional recovery, as in tolerance of food without nausea and regained mobility, was considered the most important target of recovery. There was a consistent uniformity in the way international dedicated professionals scored the relative importance of recovery targets and care items. The relative rating of the perioperative care items was not dependent on the strength of evidence supporting the items.
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http://dx.doi.org/10.1186/2047-0525-3-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118075PMC
August 2014

Single-dose carbohydrate treatment in the immediate preoperative phase diminishes development of postoperative peripheral insulin resistance.

Clin Nutr 2015 Feb 6;34(1):156-64. Epub 2014 Mar 6.

Department of Digestive Surgery, University Hospital of North Norway, Tromsø, Norway; Laboratory of Surgical Research, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.

Background & Aims: Preoperative oral carbohydrate (CHO) treatment is known to reduce postoperative insulin resistance, but the necessity of a preoperative evening dose is uncertain. We investigated the effect of single-dose CHO treatment two hours before surgery on postoperative insulin sensitivity.

Methods: Thirty two pigs (∼ 30 kg) were randomized to 4 groups (n = 8) followed by D-[6,6-(2)H2] glucose infusion and hyperinsulinemic-euglycemic step clamping. Two groups received a morning drink of 25 g carbohydrate (CHO/surgery and CHO/control). Animals in the other two groups were fasted overnight (fasting/surgery and fasting/control). Counter-regulatory hormones, free fatty acids (FFA) and liver and muscle glycogen content were measured serially.

Results: Glucose infusion rates needed to maintain euglycemia were higher after CHO/surgery than fasting/surgery during low (8.54 ± 0.82 vs. 6.15 ± 0.27 mg/kg/min, P < 0.05), medium (17.26 ± 1.08 vs. 14.02 ± 0.56 mg/kg/min, P < 0.02) and high insulin clamping (19.83 ± 0.95 vs. 17.16 ± 0.58 mg/kg/min, P < 0.05). The control groups exhibited identical insulin sensitivity. Compared to their respective controls, insulin-stimulated whole-body glucose disposal was significantly reduced after fasting/surgery (-41%, P < 0.001), but not after CHO/surgery (-16%, P = 0.180). CHO reduced FFA perioperatively (P < 0.05) and during the clamp procedures (P < 0.02), but did not affect hepatic insulin sensitivity, liver and muscle glycogen content or counter-regulatory hormone profiles. A strong negative correlation between peripheral insulin sensitivity and mean cortisol levels was seen in fasted (R = -0.692, P = 0.003), but not in CHO loaded pigs.

Conclusions: Single-dose preoperative CHO treatment is sufficient to reduce postoperative insulin resistance, possibly due to the antilipolytic effects and antagonist properties of preoperative hyperinsulinemia on the suppressant actions of cortisol on carbohydrate oxidation.
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http://dx.doi.org/10.1016/j.clnu.2014.02.010DOI Listing
February 2015

Guidelines for perioperative care after radical cystectomy for bladder cancer: Enhanced Recovery After Surgery (ERAS(®)) society recommendations.

Clin Nutr 2013 Dec 17;32(6):879-87. Epub 2013 Oct 17.

Dept of Urology, University Hospital of Lausanne, Switzerland.

Purpose: Enhanced recovery after surgery (ERAS) pathways have significantly reduced complications and length of hospital stay after colorectal procedures. This multimodal concept could probably be partially applied to major urological surgery.

Objectives: The primary objective was to systematically assess the evidence of ERAS single items and protocols applied to cystectomy patients. The secondary objective was to address a grade of recommendation to each item, based on the evidence and, if lacking, on consensus opinion from our ERAS Society working group.

Evidence Acquisition: A systematic literature review was performed on ERAS for cystectomy by searching EMBASE and Medline. Relevant articles were selected and quality-assessed by two independent reviewers using the GRADE approach. If no study specific to cystectomy was available for any of the 22 given items, the authors evaluated whether colorectal guidelines could be extrapolated.

Evidence Synthesis: Overall, 804 articles were retrieved from electronic databases. Fifteen articles were included in the present systematic review and 7 of 22 ERAS items were studied. Bowel preparation did not improve outcomes. Early nasogastric tube removal reduced morbidity, bowel recovery time and length of hospital stay. Doppler-guided fluid administration allowed for reduced morbidity. A quicker bowel recovery was observed with a multimodal prevention of ileus, including gum chewing, prevention of PONV and minimally invasive surgery.

Conclusions: ERAS has not yet been widely implemented in urology and evidence for individual interventions is limited or unavailable. The experience in other surgical disciplines encourages the development of an ERAS protocol for cystectomy.
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http://dx.doi.org/10.1016/j.clnu.2013.09.014DOI Listing
December 2013

Enhanced recovery after surgery: are we ready, and can we afford not to implement these pathways for patients undergoing radical cystectomy?

Eur Urol 2014 Feb 22;65(2):263-6. Epub 2013 Oct 22.

Academic Urology Unit, University of Sheffield, Sheffield, UK.

Enhanced recovery after surgery (ERAS) for radical cystectomy seems logical, but our study has shown a paucity in the level of clinical evidence. As part of the ERAS Society, we welcome global collaboration to collect evidence that will improve patient outcomes.
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http://dx.doi.org/10.1016/j.eururo.2013.10.011DOI Listing
February 2014

The genetic regulation of the terminating phase of liver regeneration.

Comp Hepatol 2012 Nov 20;11(1). Epub 2012 Nov 20.

Department of Digestive Surgery, University Hospital of Northern-Norway, Tromsø 9038, Norway.

Unlabelled:

Background: After partial hepatectomy (PHx), the liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5% has been re-established. To investigate the genetic regulation of the terminating phase of liver regeneration, we performed a 60% PHx in a porcine model. Liver biopsies were taken at the time of resection, after three weeks and upon termination the sixth week. Gene expression profiles were obtained using porcine oligonucleotide microarrays. Our study reveals the interactions between genes regulating the cell cycle, apoptosis and angiogenesis, and the role of Transforming Growth Factor-β (TGF-β) signalling towards the end of liver regeneration.

Results: Microarray analysis revealed a dominance of genes regulating apoptosis towards the end of regeneration. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was up-regulated six weeks after PHx, suggesting the involvement of the caspase system at this time. Zinc Finger Protein (ZNF490) gene, with a potential negative effect on cell cycle progression, was only up-regulated at three and six weeks after PHx indicating a central role at this time. TGF-β regulation was not found to be significantly affected in the terminating phase of liver regeneration. Vasohibin 2 (VASH2) was down-regulated towards the end of regeneration, and may indicate a role in preventing a continued vascularization process.

Conclusions: CARD11, ZNF490 and VASH2 are differentially expressed in the termination phase of liver regeneration. The lack of TGF-β up-regulation suggests that signalling by TGF-β is not required for termination of liver regeneration.
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http://dx.doi.org/10.1186/1476-5926-11-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558440PMC
November 2012

Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure.

Am J Physiol Gastrointest Liver Physiol 2012 Aug 15;303(3):G435-41. Epub 2012 Mar 15.

UCL Institute of Hepatology, Royal Free Campus, University College London, London, UK.

In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N = 8) or hepatic devascularization ALF (N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h (P < 0.001), whereas citrulline and ornithine progressively increased in ALF (P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.
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http://dx.doi.org/10.1152/ajpgi.00268.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774247PMC
August 2012

Neuropathological changes in the brain of pigs with acute liver failure.

Scand J Gastroenterol 2010 Aug;45(7-8):935-43

Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, Sykehusveien, Tromsø, Norway.

Objective: Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF.

Materials And Methods: Sixteen female Norwegian Landrace pigs weighing 27-35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy.

Results: Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal.

Conclusions: Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.
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http://dx.doi.org/10.3109/00365521003675047DOI Listing
August 2010

Hyperinsulinemic euglycemic step clamping with tracer glucose infusion and labeled glucose infusate for assessment of acute insulin resistance in pigs.

Am J Physiol Endocrinol Metab 2010 Jun 6;298(6):E1305-12. Epub 2010 Apr 6.

Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.

The present study aimed to establish hyperinsulinemic euglycemic step clamping with tracer glucose infusion and labeled glucose infusate (step hot-GINF HEC) for assessment of acute insulin resistance in anesthetized pigs and to arrange for combination with invasive investigative methods. Tracer enrichment was measured during D-[6,6-(2)H(2)]glucose infusion before and after surgical instrumentation (n = 8). Insulin dose-response characteristics were determined by two step hot-GINF HEC procedures, with accordingly labeled glucose infusates performed at a total of six insulin infusion rates ranging from 0.2 to 2.0 mU kg(-1) min(-1) (n = 8). Finally, three-step hot-GINF HEC (0.4, 1.2, and 2.0 mU kg(-1) min(-1)) was performed subsequent to major surgical trauma (n = 8). Tracer enrichment, basal glucose kinetics, and circulating levels of C-peptide, cortisol, glucagon, and catecholamines were not influenced by surgical instrumentation. Mean intraindividual coefficient of variance levels for glucose infusion rates and repeatedly measured insulin, glucose, and tracer enrichment indicated stable clamping conditions. Basal and maximal insulin-stimulated glucose utilization was twice as high as in humans at approximately 5.5 and 21 mg kg(-1) min(-1). Surgical trauma elicited pronounced peripheral and moderate hepatic insulin unresponsiveness (45% lower whole body glucose disposal and 19% less suppressed endogenous glucose release) and apparently diminished metabolic insulin clearance. Step hot-GINF HEC seems suitable for assessment of acute insulin resistance in anesthetized pigs, and combination with invasive investigative methods requiring surgical instrumentation can be accomplished without the premises for utilization of the technique being altered, but attention must be paid to alterations in metabolic insulin clearance.
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http://dx.doi.org/10.1152/ajpendo.00701.2009DOI Listing
June 2010

Increased sinusoidal flow is not the primary stimulus to liver regeneration.

Comp Hepatol 2010 Jan 20;9. Epub 2010 Jan 20.

Surgical Research Laboratory, Institute of Clinical Medicine, University of Tromsoe, Tromsoe, Norway.

Background: Hemodynamic changes in the liver remnant following partial hepatectomy (PHx) have been suggested to be a primary stimulus in triggering liver regeneration. We hypothesized that it is the increased sinusoidal flow per se and hence the shear-stress stimulus on the endothelial surface within the liver remnant which is the main stimulus to regeneration. In order to test this hypothesis we wanted to increase the sinusoidal flow without performing a concomitant liver resection. Accordingly, we constructed an aorto-portal shunt to the left portal vein branch creating a standardized four-fold increase in flow to segments II, III and IV. The impact of this manipulation was studied in both an acute model (6 animals, 9 hours) using a global porcine cDNA microarray chip and in a chronic model observing weight and histological changes (7 animals, 3 weeks).

Results: Gene expression profiling from the shunted segments does not suggest that increased sinusoidal flow per se results in activation of genes promoting mitosis. Hyperperfusion over three weeks results in the whole liver gaining a supranormal weight of 3.9% of the total body weight (versus the normal 2.5%). Contrary to our hypothesis, the weight gain was observed on the non-shunted side without an increase in sinusoidal flow.

Conclusions: An isolated increase in sinusoidal flow does not have the same genetic, microscopic or macroscopic impact on the liver as that seen in the liver remnant after partial hepatectomy, indicating that increased sinusoidal flow may not be a sufficient stimulus in itself for the initiation of liver regeneration.
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http://dx.doi.org/10.1186/1476-5926-9-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819042PMC
January 2010

Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) Group recommendations.

Arch Surg 2009 Oct;144(10):961-9

Department of Gastrointestinal Surgery, University Hospital Northern Norway, 9038 Tromsø, Norway.

Objectives: To describe a consensus review of optimal perioperative care in colorectal surgery and to provide consensus recommendations for each item of an evidence-based protocol for optimal perioperative care.

Data Sources: For every item of the perioperative treatment pathway, available English-language literature has been examined.

Study Selection: Particular attention was paid to meta-analyses, randomized controlled trials, and systematic reviews.

Data Extraction: A consensus recommendation for each protocol item was reached after critical appraisal of the literature by the group.

Data Synthesis: For most protocol items, recommendations are based on good-quality trials or meta-analyses of such trials.

Conclusions: The Enhanced Recovery After Surgery (ERAS) Group presents a comprehensive evidence-based consensus review of perioperative care for colorectal surgery. It is based on the evidence available for each element of the multimodal perioperative care pathway.
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http://dx.doi.org/10.1001/archsurg.2009.170DOI Listing
October 2009

Porcine liver sinusoidal endothelial cells contribute significantly to intrahepatic ammonia metabolism.

Hepatology 2009 Sep;50(3):900-8

Department of Digestive Surgery, University Hospital Northern Norway and Institute of Clinical Medicine, Norway.

Unlabelled: Ammonia metabolism in the liver has been largely credited to hepatocytes (HCs). We have shown that liver nonparenchymal cells that include liver sinusoidal endothelial cells (LSECs) produce ammonia. To address the limited knowledge regarding a role for LSECs in ammonia metabolism, we investigated the ammonia metabolism of isolated LSECs and HCs under three different conditions: (1) bioreactors containing LSECs (LSEC-bioreactors), (2) bioreactors containing HCs (HC-bioreactors), and (3) separate bioreactors containing LSECs and HCs connected in sequence (Seq-bioreactors). Our results showed that LSEC-bioreactors released six-fold more ammonia (22.2 nM/hour/10(6) cells) into the growth media than HC-bioreactors (3.3 nM/hour/10(6) cells) and Seq-bioreactors (3.8 nM/hour/10(6) cells). The glutamate released by LSEC-bioreactors (32.0 nM/hour/10(6) cells) was over four-fold larger than that released by HC-bioreactors and Seq-bioreactors (<7 nM/hour/10(6) cells). LSEC-bioreactors and HC-bioreactors consumed large amounts of glutamine (>25 nM/hour/10(6) cells). Glutaminase is known for catalyzing glutamine into glutamate and ammonia. To determine if this mechanism may be responsible for the large levels of glutamate and ammonia found in LSEC-bioreactors, immunolabeling of glutaminase and messenger RNA expression were tested. Our results demonstrated that glutaminase was present with colocalization of an LSEC-specific functional probe in lysosomes of LSECs. Furthermore, using a nucleotide sequence specific for kidney-type glutaminase, reverse-transcription polymerase chain reaction revealed that this isoform of glutaminase was expressed in porcine LSECs.

Conclusion: LSECs released large amounts of ammonia, perhaps due to the presence of glutaminase in lysosomes. The ammonia and glutamate released by LSECs in Seq-bioreactors were used by hepatocytes, suggesting an intrahepatic collaboration between these two cell types.
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http://dx.doi.org/10.1002/hep.23076DOI Listing
September 2009
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