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2.  Bariatric Surgery can Lead to Net Cost Savings to Health Care Systems: Results from a Comprehensive European Decision Analytic Model 
Obesity Surgery  2015;25(9):1559-1568.
The objective of the present study was to evaluate the cost-utility of bariatric surgery in a lifetime horizon from a Swedish health care payer perspective.
A decision analytic model using the Markov process was developed covering cardiovascular diseases, type 2 diabetes, and surgical complications. Clinical effectiveness and safety were based on the literature and data from the Scandinavian Obesity Surgery Registry. Gastric bypass, sleeve gastrectomy, and gastric banding were included in the analysis. Cost data were obtained from Swedish sources.
Bariatric surgery was cost saving in comparison with conservative management. It also led to a substantial reduction in lifetime risk of events: from a 16 % reduction in the risk of transient ischaemic attacks to a 62 % reduction in the incidence of type 2 diabetes. Over a lifetime, surgery led to savings of €8408 and generated an additional 0.8 years of life and 4.1 quality-adjusted life years (QALYs) per patient, which translates into gains of 32,390 quality-adjusted person-years and savings of €66 million for the cohort, operated in 2012. Analysis of the consequences of a 3-year delay in surgery provision showed that the overall lifetime cost of treatment may be increased in patients with diabetes or a body mass index >40 kg/m2. Delays in surgery may also lead to a loss of clinical benefits: up to 0.6 life years and 1.2 QALYs per patient over a lifetime.
Bariatric surgery, over a lifetime horizon, may lead to significant cost savings to health care systems in addition to the known clinical benefits.
Electronic supplementary material
The online version of this article (doi:10.1007/s11695-014-1567-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4522026  PMID: 25639648
Bariatric surgery; Cost-utility analysis; Cost-effectiveness analysis; Health economics; Cost; Sweden
3.  Clinical Indications, Utilization, and Funding of Bariatric Surgery in Europe 
Obesity Surgery  2014;25(8):1408-1416.
The objective of this study was to evaluate the current utilization, the level of endorsement by professional societies, and health technology assessment bodies, as well as the reimbursement levels for bariatric surgery in European countries.
Materials and Methods
We performed an analysis of the indications for bariatric surgery based on national clinical and commissioning guidelines, current utilization of surgery, characteristics of patients who underwent surgery, and reimbursement tariffs in Belgium, Denmark, England, France, Germany, Italy, and Sweden. Data were obtained from national patient registries, administrative databases, and published literature for the year 2012.
Despite clear consensus outlined in clinical guidelines, significant differences were found in the eligibility criteria for surgery. Patients with no significant comorbidities were deemed eligible if they had a body mass index (BMI) of 40 or 50 kg/m2 in Denmark. Irrespective of the country, patients with comorbidities were eligible if they had a BMI of 35 kg/m2. The highest utilization of bariatric surgery (number of surgeries per 1 M population) was observed in Belgium (928), Sweden (761), and France (571) while Italy (128), England (117), and Germany (72) had the lowest utilization. There was a strong negative correlation between utilization and average BMI level of the patient population (r = −.909, p = 0.005). The annual per capita spending on surgery differed significantly between countries, ranging from €0.54 in Germany to €4.33 in Belgium.
There are significant variations in the clinical indications, utilization, and funding of bariatric surgery in European countries.
Electronic supplementary material
The online version of this article (doi:10.1007/s11695-014-1537-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4498278  PMID: 25528567
Bariatric surgery; Clinical indication; Reimbursement; Utilization; Health care policy
4.  Lifestyle factors among proton pump inhibitor users and nonusers: a cross-sectional study in a population-based setting 
Clinical Epidemiology  2013;5:493-499.
Lifestyle factors may influence observed associations between proton pump inhibitor (PPI) usage and health outcomes. The aim of the study reported here was to examine characteristics and differences in lifestyle among PPI users and nonusers.
This cross-sectional study utilized data from a 2006 population-based health survey of 21,637 persons in the Central Danish Region. All persons using prescribed PPIs were identified through linkage to a population-based prescription database. Biometric measures and prevalence of smoking, excessive alcohol consumption, diet, and physical exercise were analyzed, comparing PPI users with nonusers.
Among 10,129 (46.8%) male and 11,508 (53.2%) female survey respondents, 1,356 (13.4%) males and 1,691 (14.7%) females reported ever use of PPIs. PPI users were more obese (16.7%) than nonusers (13.1%), with an age- and sex-standardized prevalence ratio (PR) of 1.3 (95% confidence interval [CI]: 1.2–1.4). The prevalence of smokers was also higher in the PPI group (26.2% vs 22.3% [PR =1.2, 95% CI: 1.1–1.3]), as was the prevalence of ex-smokers (41.0% vs 32.0% [PR =1.2, 95% CI: 1.1–1.2]). Unhealthy diet was slightly more common among PPI users than among nonusers (15.4% vs 13.0%), with a PR of 1.2 (95% CI: 1.1–1.3). Physical exercise level and alcohol consumption were similar in the two groups. Hospital-diagnosed comorbidity was observed in 35% of PPI users (a Charlson Comorbidity Index score of 1 or more) compared with only 15% among nonusers.
PPI users are more obese, smoke more, and have significantly more comorbidities than PPI nonusers. These data are important when evaluating unmeasured confounding in observational studies of PPI effects.
PMCID: PMC3857010  PMID: 24348070
PPI; obesity; smoking; reflux; population-based; gastroesophageal reflux
5.  Effects of ischemic pre- and postconditioning on HIF-1α, VEGF and TGF-β expression after warm ischemia and reperfusion in the rat liver 
Ischemic pre- and postconditioning protects the liver against ischemia/reperfusion injuries. The aim of the present study was to examine how ischemic pre- and postconditioning affects gene expression of hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor A (VEGF-A) and transforming growth factor β (TGF-β) in liver tissue.
28 rats were randomized into five groups: control; ischemia/reperfusion; ischemic preconditioning (IPC); ischemic postconditioning (IPO); combined IPC and IPO. IPC consisted of 10 min of ischemia and 10 min of reperfusion. IPO consisted of three cycles of 30 sec. reperfusion and 30 sec. of ischemia.
HIF-1α mRNA expression was significantly increased after liver ischemia compared to controls (p = 0.010). HIF-1α mRNA expression was significantly lower in groups subjected to IPC or combined IPC and IPO when compared to the ischemia/reperfusion group (p = 0.002). VEGF-A mRNA expression increased in the ischemia/reperfusion or combined IPC and IPO groups when compared to the control group (p < 0.05).
Ischemic conditioning seems to prevent HIF-1α mRNA induction in the rat liver after ischemia and reperfusion. This suggests that the protective effects of ischemic conditioning do not involve the HIF-1 system. On the other hand, the magnitude of the HIF-1α response might be a marker for the degree of I/R injuries after liver ischemia. Further studies are needed to clarify this issue.
PMCID: PMC3155899  PMID: 21771288
6.  Proximal and distal esophageal sensitivity is decreased in patients with Barrett’s esophagus 
AIM: To investigate sensations to multimodal pain stimulation in the metaplastic and normal parts of the esophagus in patients with Barrett’s esophagus (BE).
METHODS: Fifteen patients with BE and 15 age-matched healthy volunteers were subjected to mechanical, thermal and electrical pain stimuli of the esophagus. Both the metaplastic part and the normal part (4 and 14 cm, respectively, above the esophago-gastric junction) were examined. At sensory thresholds the stimulation intensity, referred pain areas, and evoked brain potentials were recorded.
RESULTS: Patients were hyposensitive to heat stimulation both in the metaplastic part [median stimulation time to reach the pain detection threshold: 15 (12-34) s vs 14 (6-23) s in controls; F = 4.5, P = 0.04] and the normal part of the esophagus [median 17 (6-32) s vs 13 (8-20) s in controls; F = 6.2, P = 0.02]. Furthermore, patients were hyposensitive in the metaplastic part of the esophagus to mechanical distension [median volume at moderate pain: 50 (20-50) mL vs 33 (13-50) mL in controls; F = 5.7, P = 0.02]. No indication of central nervous system abnormalities was present, as responses were comparable between groups to electrical pain stimuli in the metaplastic part [median current evoking moderate pain: 13 (6-26) mA vs 12 (9-24) mA in controls; F = 0.1, P = 0.7], and in the normal part of the esophagus [median current evoking moderate pain: 9 (6-16) mA, vs 11 (5-11) mA in controls; F = 3.4, P = 0.07]. Furthermore, no differences were seen for the referred pain areas (P-values all > 0.3) or latencies and amplitudes for the evoked brain potentials (P-values all > 0.1).
CONCLUSION: Patients with BE are hyposensitive both in the metaplastic and normal part of esophagus likely as a result of abnormalities affecting peripheral nerve pathways.
PMCID: PMC3027019  PMID: 21274382
Barrett’s esophagus; Heat; Multimodal; Pain; Sensitivity
7.  Internal gallbladder drainage prevents development of acute cholecystitis in a pig model: a randomized study 
Acute cholecystitis can be the result of retention of bile in the gallbladder with possible secondary infection and ischaemia. The aim of the present study was to investigate whether internal drainage of the gallbladder could protect against the development of acute cholecystitis in a pig model.
Materials and methods
Twenty pigs were randomized to either internal drainage (drained) or not (undrained). Day 0 acute cholecystitis was induced by ligation of the cystic artery and duct together with inoculation of bacteria. Four days later the pigs were killed and the gallbladders were removed and histologically scored for the presence of cholecystitis. Bile and blood samples were collected for bacterial culturing and biochemical analyses.
The histological examination demonstrated statistical significant differences in acute cholecystitis development between groups, the degree of inflammation being highest in undrained pigs. There were no differences in bacterial cultures between the two groups.
Internal drainage of the gallbladder protected against the development of acute cholecystitis in the present pig model. These findings support the theory that gallstone impaction of the cystic duct plays a crucial role as a pathogenetic mechanism in the development of acute cholecystitis and suggest that internal drainage may be a way to prevent and treat acute cholecystitis.
PMCID: PMC2890535  PMID: 20504296
8.  Increased liver regeneration rate and decreased liver function after synchronous liver and colon resection in rats 
The surgical strategy for the treatment of colorectal cancer and synchronous liver metastases remains controversial. The aim of the present study was to investigate the effects of colonic resection on liver function and regeneration in a rat model.
Ninety-six Sprague-Dawley rats were block-randomized into six groups: Group I had a laparotomy performed. Group II had 1 cm colon resected and anastomosed. Group III and V had 40% or 70% of the liver resected, respectively. Additionally Group IV and VI had 1 cm colon resected and anastomosed, respectively. Body weight was recorded on postoperative day 0, 3, 5 and 7. Rats were sacrificed on postoperative day 7 by rapid collection of blood from the inferior vena cava, and endotoxin levels were measured. Remnant liver function was evaluated by means of branched amino acids to tyrosine ratio. Liver regeneration was calculated by (liver weight per 100 g of the body weight at sacrifice/preoperative projected liver weight per 100 g of the body weight) × 100.
The total number of complications was significantly higher in Group VI than Group I, III, IV, and V. Body weight and branched amino acids to tyrosine ratio were both significantly lower in rats that had simultaneous colonic and liver resection performed. Hepatic regeneration rate was significantly higher in the simultaneous colectomy group. Systemic endotoxin levels were unaffected by simultaneous colectomy on postoperative day 7.
In our model morbidity seems to be related to the extent of hepatic resection. In rats undergoing liver resection, simultaneous colectomy induced a higher degree of hepatic regeneration rate. Body weight changes and branched amino acids to tyrosine ratio were negatively affected by simultaneous colectomy.
PMCID: PMC2806264  PMID: 20034379
9.  Axial force measurement for esophageal function testing 
The esophagus serves to transport food and fluid from the pharynx to the stomach. Manometry has been the “golden standard” for the diagnosis of esophageal motility diseases for many decades. Hence, esophageal function is normally evaluated by means of manometry even though it reflects the squeeze force (force in radial direction) whereas the bolus moves along the length of esophagus in a distal direction. Force measurements in the longitudinal (axial) direction provide a more direct measure of esophageal transport function. The technique used to record axial force has developed from external force transducers over in-vivo strain gauges of various sizes to electrical impedance based measurements. The amplitude and duration of the axial force has been shown to be as reliable as manometry. Normal, as well as abnormal, manometric recordings occur with normal bolus transit, which have been documented using imaging modalities such as radiography and scintigraphy. This inconsistency using manometry has also been documented by axial force recordings. This underlines the lack of information when diagnostics are based on manometry alone. Increasing the volume of a bag mounted on a probe with combined axial force and manometry recordings showed that axial force amplitude increased by 130% in contrast to an increase of 30% using manometry. Using axial force in combination with manometry provides a more complete picture of esophageal motility, and the current paper outlines the advantages of using this method.
PMCID: PMC2653304  PMID: 19132762
Axial force; Traction force; Manometry; Motility; Peristalsis; Esophageal function
10.  The influence of preconditioning on metabolic changes in the pig liver before, during, and after warm liver ischemia measured by microdialysis 
Hepatology International  2008;3(1):310-315.
Ischemia-reperfusion injury induced by the Pringle maneuver is a well-known problem after liver surgery. The aim of this study was to monitor metabolic changes in the pig liver during warm ischemia and the following reperfusion preceded by ischemic preconditioning (IPC).
Eight Landrace pigs underwent laparotomy. Two microdialysis catheters were inserted in the liver, one in the left lobe and another in the right lobe. A reference catheter was inserted in the right biceps femoris muscle. Microdialysis samples were collected every 30 min during the study. After 2 h of baseline measurement, IPC was performed by subjecting pigs to 10 min of ischemia, followed by 10 min of reperfusion. Total ischemia for 60 min was followed by 3 h of reperfusion. The samples were analyzed for glucose, lactate, pyruvate, and glycerol. Blood samples were drawn three times to determine standard liver parameters.
All parameters remained stable during baseline. Glycerol and glucose levels increased significantly during ischemia, followed by a decrease from the start of reperfusion. During the ischemic period, lactate levels increased significantly and decreased during reperfusion. The lactate–pyruvate ratio increased significantly during ischemia and decreased rapidly during reperfusion. Only minor changes were observed in standard liver parameters.
The present study demonstrated profound metabolic changes before, during, and after warm liver ischemia under the influence of IPC. Compared with a similar study without IPC, the metabolic changes seem to be unaffected by preconditioning.
PMCID: PMC2712317  PMID: 19669382
Warm liver ischemia; Portal triad clamping; Preconditioning; Metabolic changes; Microdialysis
11.  Unexplained chest/epigastric pain in patients with normal endoscopy as a predictor for ischemic heart disease and mortality: A Danish 10-year cohort study 
BMC Gastroenterology  2008;8:28.
Normal upper endoscopy may be a marker of ischemic heart disease in patients with unexplained chest/epigastric pain.
We examined the 10-year risk of ischemic heart disease and mortality in a cohort of 386 Danish patients with chest/epigastric pain, normal upper endoscopy, and no prior hospital discharge diagnosis of ischemic heart disease (defined as patients with unexplained chest/epigastric pain), compared with 3,793 population controls matched by age, gender, and residence. Outcome data were obtained from population-based health registries. Cox regression analysis was used to estimate the relative risk of hospitalization for ischemic heart disease and the adjusted mortality rate ratio (MRR).
The 10-year relative risk of hospitalization for ischemic heart disease following a normal upper endoscopy among patients with unexplained chest/epigastric pain was 1.6 (95% CI, 1.1–2.2), compared with controls. The 10-year MRR was 1.1 (95% CI, 0.9–1.5). Within the first year after the upper endoscopy the MRR was 2.4 (95% CI, 1.3–4.5). The cause-specific MRR among patients with unexplained chest/epigastric pain compared with controls was up to threefold higher for deaths related to alcohol dependence, pneumonia, and lung cancer.
Unexplained chest/epigastric pain in patients with normal endoscopy is a strong marker for ischemic heart disease and increased mortality.
PMCID: PMC2490769  PMID: 18627631
12.  Is the pain in chronic pancreatitis of neuropathic origin? Support from EEG studies during experimental pain 
AIM: To prove the hypothesis that patients with chronic pancreatitis would show increased theta activity during painful visceral stimulation.
METHODS: Eight patients and 12 healthy controls underwent an experiment where the esophagus was electrically stimulated at the pain threshold using a nasal endoscope. The electroencephalogram (EEG) was recorded from 64 surface electrodes and “topographic matching pursuit” was used to extract the EEG information in the early brain activation after stimulation.
RESULTS: A major difference between controls and patients were seen in delta and theta bands, whereas there were only minor differences in other frequency bands. In the theta band, the patients showed higher activity than controls persisting throughout the 450 ms of analysis with synchronous brain activation between the channels. The main theta components oscillated with 4.4 Hz in the patients and 5.5 Hz in the controls. The energy in the delta (0.5-3.5 Hz) band was higher in the controls, whereas the patients only showed scattered activity in this band.
CONCLUSION: The differences in the theta band indicate that neuropathic pain mechanisms are involved in chronic pancreatitis. This has important implications for the understanding and treatment of pain in these patients, which should be directed against drugs with effects on neuropathic pain disorders.
PMCID: PMC2725341  PMID: 18609686
Chronic Pancreatitis; Neuropathic pain; Esophagus; Thalamocortical system; Electroencephalography
13.  Impaired contractility and remodeling of the upper gastrointestinal tract in diabetes mellitus type-1 
AIM: To investigate that both the neuronal function of the contractile system and structural apparatus of the gastrointestinal tract are affected in patients with longstanding diabetes and auto mic neuropathy.
METHODS: The evoked esophageal and duodenal contractile activity to standardized bag distension was assessed using a specialized ultrasound-based probe. Twelve type-1 diabetic patients with autonomic neuropathy and severe gastrointestinal symptoms and 12 healthy controls were studied. The geometry and biomechanical parameters (strain, tension/stress, and stiffness) were assessed.
RESULTS: The diabetic patients had increased frequency of distension-induced contractions (6.0 ± 0.6 vs 3.3 ± 0.5, P < 0.001). This increased reactivity was correlated with the duration of the disease (P = 0.009). Impaired coordination of the contractile activity in diabetic patients was demonstrated as imbalance between the time required to evoke the first contraction at the distension site and proximal to it (1.5 ± 0.6 vs 0.5 ± 0.1, P = 0.03). The esophageal wall and especially the mucosa-submucosa layer had increased thickness in the patients (P < 0.001), and the longitudinal and radial compressive stretch was less in diabetics (P < 0.001). The esophageal and duodenal wall stiffness and circumferential deformation induced by the distensions were not affected in the patients (all P > 0.14).
CONCLUSION: The impaired contractile activity with an imbalance in the distension-induced contractions likely reflects neuronal abnormalities due to autonomic neuropathy. However, structural changes and remodeling of the gastrointestinal tract are also evident and may add to the neuronal changes. This may contribute to the pathophysiology of diabetic gut dysfunction and impact on future management of diabetic patients with gastrointestinal symptoms.
PMCID: PMC4611767  PMID: 17828820
Diabetes; Autonomic Neuropathy; Bio-mechanics; Contractility; Ultrasound; Esophagus; Duodenum; Deformation; Stress
14.  Reversibility of central neuronal changes in patients recovering from gallbladder stones or acute cholecystitis 
AIM: To investigate the referred pain area in patients 2-7 years after cholecystectomy in order to test the hypothesis that neuroplastic changes could give rise to post cholecystectomy pain.
METHODS: Forty patients were tested. Twenty five were cholecystectomized due to uncomplicated gallbladder stones and 15 because of acute cholecystitis. Sensitivity to pinprick, heat, cold, pressure and single and repeated electrical stimulation was studied both in the referred pain area and in the control area on the contra lateral side of the abdomen.
RESULTS: Five patients still intermittently suffered from pain. But in the objective test of the 40 patients, no statistical significant difference was found between the referred pain area and the control area.
CONCLUSION: This study does not support the hypothesis that de novo neuroplastic changes could develop several years after cholecys-tectomy.
PMCID: PMC4087601  PMID: 17167844
Referred pain; Hyperalgesia; Cholecystitis; Post cholecystectomy syndrome
15.  Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain 
Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy.
PMCID: PMC4087795  PMID: 16718803
Pain; Gut; Experimental; Chest pain; Esophagitis
16.  Evaluation of the biliary tract in patients with functional biliary symptoms 
The aim of this paper was to describe functional biliary syndromes and methods for evaluation of the biliary tract in these patients. Functional biliary symptoms can be defined as biliary symptoms without demonstrable organic substrate. Two main syndromes exist: Gallbladder dysfunction and sphincter of Oddi dysfunction. The most important investigative tools are cholescintigraphy and endoscopic sphincter of Oddi manometry. In gallbladder dysfunction a scintigraphic gallbladder ejection fraction below 35% can select patients who will benefit from cholecystectomy. Endoscopic sphincter of Oddi manometry is considered the gold standard in sphincter of Oddi dysfunction but recent development in scintigraphic methods is about to change this. Thus, calculation of hilum-to-duodenum transit time and duodenal appearance time on cholescintigraphy have proven useful in these patients. In conclusion, ambient methods can diagnose functional biliary syndromes. However, there are still a number of issues where further knowledge is needed. Probably the next step forward will be in the area of sensory testing and impedance planimetric methods.
PMCID: PMC4087799  PMID: 16718807
Functional biliary pain; Scintigraphy; Manometry; Pain; Sphincter of Oddi; Gallbladder
17.  Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid 
AIM: Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization.
METHODS: Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine.
RESULTS: The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change.
CONCLUSION: Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs.
PMCID: PMC4434664  PMID: 16038036
Esophagus; Mechanical; Sensitization; Motility; Reflux; Pain

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