Postprandial Triglyceride, Glucose and Insulin Levels 10 Years After Bariatric Surgery in Women With Severe Obesity - A Pilot Study: Part 1 - Laparoscopic Greater Curvature Plication.

The long-term effects of bariatric surgery on postprandial profiles in patients with obesity and type 2 diabetes (T2D) have not yet been investigated. Therefore, this study examined postprandial profiles before laparoscopic greater curvature plication (LGCP), and then at 2 and 10 years after surgery.The studied cohort included 10 women (mean age= 54.4±5 years) with obesity (mean BMI= 42.5±7.8 kg/m?) and T2D who underwent LGCP. All subjects underwent a standardized liquid mixed-meal test. For statistical evaluation, ANOVA with Bonferroni multiple comparison was used. Mean postprandial levels were significantly decreased 2 years after surgery. Responses 10 years after the surgery also remained significantly lower than before surgery. Changes observed during the follow-up were significant: glucose: F=34.5, p<0.001; insulin: F=49.3, p<0.001; triglycerides F=9.2, p<0.001. The long-term favorable effects of bariatric surgery on cardiometabolic health may be partly mediated by reductions in postprandial glucose, insulin, and triglyceride levels.

Postprandial Triglyceride, Glucose and Insulin Levels 10 Years After Bariatric Surgery in Women With Severe Obesity - A Pilot Study: Part 2 - Biliopancreatic Diversion.

Obesity significantly increases the risk of developing metabolic and cardiovascular diseases. The most effective management tool for both obesity and type 2 diabetes (T2D) is bariatric/metabolic surgery. Delayed postprandial plasma triglyceride clearance contributes to the development of atherosclerosis in patients with T2D. Biliopancreatic diversion (BPD) was shown to be the most effective procedure in long-term T2D remission. However, the effect of BPD on postprandial metabolic profile has not been studied so far. In this pilot study, we therefore examined the changes in postprandial glucose, insulin, and triglyceride in women with severe obesity and T2D before surgery and then two and ten years after BPD. The studied cohort included 7 women (mean age at baseline=49.3±8.2 years) with severe obesity (mean BMI= 45.7±2.9 kg/m?) and T2D. A standardized liquid mixed-meal test was carried out in all subjects and the mean postprandial levels of plasma glucose, insulin, and triglyceride were analyzed by standard laboratory procedures. For statistical evaluation, ANOVA with Bonferroni multiple comparisons was used. Ten years after BPD not only a significant reduction of an average BMI (F=32.9, p<0.001) but also significant declines in mean postprandial plasma levels of glucose (F=155.3, p<0.001), insulin (F=69.8, p<0.001), and triglyceride (F=139.9, p<0.001) were demonstrated. The observed changes in postprandial metabolic profile may contribute to improved cardiometabolic health after bariatric surgery.

Unusual complications after bariatric surgery gastric plication.

Laparoscopic gastric plication (LGCP) is a relatively new bariatric-metabolic operation. The greater gastric curvature is invaginated into the gastric lumen, resulting in a shape similar to that obtained after sleeve gastrectomy. In our paper, we report two interesting cases of patients with gastric plication who presented specific findings - food bezoar and gastric diverticulum. Case reports of bezoars after bariatric surgery are reported most commonly after gastric banding and gastric bypass surgery. Diverticulum of the gastric wall is a complication specific to LGCP when a part of the invaginated gastric wall is slipped between two sutures. A prompt endoscopic intervention is recommended to relieve the obstruction and, in case of diverticulum, to diagnose and manage it surgically.

Psychometric properties of the PROMIS short form measures in a U.S. cohort of 961 patients with chronic hepatitis C prescribed direct acting antiviral therapy.

BACKGROUND: To better understand symptoms experienced by patients infected with chronic hepatitis C virus (HCV), valid and reliable patient-reported outcome (PRO) measures are needed. AIM: To assess the reliability and validity of 10 patient-reported outcomes measurement information system (PROMIS) measures and the Headache Impact Test-6 (HIT-6) in a large national sample of patients with HCV. METHODS: Pre-treatment data from 961 patients with HCV starting direct acting antiviral therapy at 11 U.S. liver centers were analyzed. Internal reliability was evaluated using Cronbach's alpha coefficient; frequency distributions were examined for floor and ceiling effects; structural validity was investigated via item-response-theory models; convergent validity was evaluated using correlations with theoretically-similar items from the HCV-PRO and memorial symptom assessment scale (MSAS); and known-groups validity was investigated by observing PRO differences by liver disease status and number of comorbidities. RESULTS: The HIT-6 and the majority of the PROMIS measures yielded excellent reliability (alphas ≥ 0.87). Ceiling effects were infrequent ( < 4%), while 30%-59% of patients reported no symptoms (floor effects). The data supported structural validity of the HIT-6 and most PROMIS measures. The PROMIS measures showed moderate to strong correlations with theoretically-similar items from the HCV-PRO and MSAS (0.39-0.77). Trends were observed between worse PRO scores and advanced cirrhosis and greater number of comorbidities, lending support for known-groups validity. CONCLUSIONS: The psychometric properties of the HIT-6 and PROMIS measures performed satisfactorily in this large cohort of patients with HCV starting direct acting antiviral therapy. Opportunities exist for further refinement of these PROs. Evaluation of performance over time and in under-represented subgroups is needed.

Diagnostic use of endoscopic full-thickness wall resection (eFTR)-a novel minimally invasive technique for colonic tissue sampling in patients with severe gastrointestinal motility disorders.

BACKGROUND: Complex gastrointestinal (GI) motility disorders such as chronic intestinal pseudo-obstruction (CIPO) or Hirschsprung's disease (HD) are challenging to diagnose and treat appropriately. Thorough assessment of patient history, radiographic exams, endoscopy, and motility measurements aid in diagnostic workup, yet underlying histology is the cornerstone to enable a more distinct diagnosis of neuromuscular GI disorders. Traditionally, surgical procedures have been performed to obtain specimen suitable for accurate histologic analysis. METHODS: We performed endoscopic full-thickness resection (eFTR) using a full-thickness-resection device (FTRD) under moderate propofol sedation in four patients with suspected severe neuromuscular gut disorders including CIPO. KEY RESULTS: The mean age of the four patients was 43 y (range 19-56 y). Technical and histological success providing large colonic full-thickness tissue samples of excellent quality was achieved in all four patients (success rate 100%). The mean procedure time was 12 min (range 5-20 min). The mean diameter of the resected specimen was 21 mm (range 20-22 mm). No adverse events connected to the procedure itself occurred. Histology ranged from aganglionosis such as Hirschsprung's disease (HD) to hypoganglionosis and eosinophilic leiomyositis combined with lymphocytic ganglionitis in a third patient. Histology was unspecific in one patient. CONCLUSION AND INFERENCES: EFTR allows safe and minimal invasive harvesting of ample full-thickness tissue samples for accurate histological analysis in patients with suspicion of neuromuscular gut disorders.

Developing a novel risk prediction model for severe malarial anemia.

As a pilot study to investigate whether personalized medicine approaches could have value for the reduction of malaria-related mortality in young children, we evaluated questionnaire and biomarker data collected from the Mother Offspring Malaria Study Project birth cohort (Muheza, Tanzania, 2002-2006) at the time of delivery as potential prognostic markers for pediatric severe malarial anemia. Severe malarial anemia, defined here as a Plasmodium falciparum infection accompanied by hemoglobin levels below 50 g/L, is a key manifestation of life-threatening malaria in high transmission regions. For this study sample, a prediction model incorporating cord blood levels of interleukin-1ß provided the strongest discrimination of severe malarial anemia risk with a C-index of 0.77 (95% CI 0.70-0.84), whereas a pragmatic model based on sex, gravidity, transmission season at delivery, and bed net possession yielded a more modest C-index of 0.63 (95% CI 0.54-0.71). Although additional studies, ideally incorporating larger sample sizes and higher event per predictor ratios, are needed to externally validate these prediction models, the findings provide proof of concept that risk score-based screening programs could be developed to avert severe malaria cases in early childhood.

Five-Year Outcomes: Laparoscopic Greater Curvature Plication for Treatment of Morbid Obesity.

BACKGROUND: Laparoscopic greater curvature plication (LGCP) is a newer metabolic/bariatric surgical procedure that requires no resection, bypass, or implantable device. We report outcomes in a cohort of LGCP patients at 5-year follow-up. METHODS: Body mass index (BMI, kg/m2) evolution, excess weight loss (%EWL), excess BMI loss (%EBMIL), and total weight loss (%TWL) were recorded. Repeated measures analysis of variance (ANOVA) was used to assess BMI change over 5 years. Two-step cluster analysis was used to profile LGCP patients according to significant characteristics relative to successful 5-year weight loss. RESULTS: Of patients entering the study between 2010 and 2011 with complete weight data through 5-year follow-up (86.9%, 212/244), mean age was 45.8 ± 10.9 years; mean baseline BMI, 41.4 ± 5.5 (81.6% women); 58 patients (27.4%) had type 2 diabetes. Mean operative time was 69.0 min; mean hospitalization, 38 h (24-72). ANOVA indicated a significant BMI reduction out to 2 years (p < 0.001), a plateau at 3 and 4 years, and a moderate but significant BMI increase at 5 years (p < 0.01). EBMIL at 1, 2, 3, 4, and 5 years was as follows: 50.7 ± 9.1%, 61.5 ± 8.1%, 60.2 ± 7.0%, 58.5 ± 7.0%, and 56.8 ± 6.3%. At 5 years, 79.2% (168/212) of patients were successful; 20.8% (44/212) experienced a suboptimal weight outcome; mean weight regain, 9.2%. Cluster analysis identified four distinct LGCP patient profiles. Diabetes improvement rate was 65.5%. There were 12 reoperations (4.9%): 4 emergency (1.6%) and 8 (3.3%) elective. There was no mortality. CONCLUSIONS: At 5-year follow-up, LGCP proved to be safe and effective, with 56.8% EBMIL and a low rate of complications.

Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.

BACKGROUND: Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. AIM: To assess efficacy of all-oral HCV therapy in advanced liver disease. METHODS: Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. RESULTS: Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. CONCLUSIONS: All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.

Prevalence and risk factors for functional bowel disorders in South China: a population based study using the Rome III criteria.

BACKGROUND: Functional bowel disorders (FBDs) such as irritable bowel syndrome (IBS) impact on quality of life and health care resources. It is uncertain whether patients with functional digestive symptoms have similar characteristics in different populations. This population-based study assessed the prevalence and identified risk factors for these disorders in South-East China. METHODS: Five communities were selected at random and invitations distributed to a representative sample (block randomization). Questionnaires were completely supervised by investigators. Demographic and medical data with FBD symptoms (Rome III criteria), psychological condition, life event stress, and quality of life were collected. KEY RESULTS: Functional bowel disorder prevalence was 41.6% in 1999/2115 (94.5%) completed questionnaires: 9.9% functional constipation (FC), 6.8% bloating (FB), 6.5% diarrhea (FD), 5.9% IBS (IBS-D 47.1%, IBS-M 23.9%, IBS-C 12.8%, IBS-U 16.2%), and 12.6% unspecified. Similar numbers of men and women had FBDs or IBS (overall; 51.3% male vs 48.7% female, P=.796); however, there was female predominance in FC (62.1%, P<.001) and FB (58.5%, P=.038). FBDs were associated with greater anxiety, depression, life event stress, and a lower quality of life compared with those without symptoms (all, P<.0001). Logistic regression identified medical co-morbidity, anxiety/depression, and life event stress as independent risk factors for these disorders. CONCLUSIONS & INFERENCES: Functional bowel disorders are as common in South China as in western populations. A similar number of men and women report FBDs and IBS. Only FC and FB are more prevalent in females. Independent risk factors associated with FBDs included physical and psychosocial stressors.

[10 years of sleeve gastrectomy in the Czech Republic in terms of the surgical procedure]. / 10 let sleeve gastrectomy - tubulizace zaludku v Ceské republice z hlediska operacního výkonu.

INTRODUCTION: Sleeve gastrectomy (SG) as a single bariatric/metabolic procedure has been performed since 2003 in the world, and since 2006 in the Czech Republic. We report 10 years experience with SG in the Czech Republic from 2006 to 2015. METHOD: Prospectively collected data from 14 surgical departments was evaluated retrospectively using descriptive statistics for every year from 2006 to 2015 and subsequently evaluated and compared for the entire period. The number of the patients, mean age, mean weight and BMI at the time of surgery, the number of patients with T2DM after SG, mean follow-up, mean %BMIL (% Body Mass Index Loss), distance of the starting point of the resection line from the pylorus, the size of the calibration bougie, the rate of complications, and the number and type of conversion procedures were evaluated. RESULTS: 4134 sleeve gastrectomies were done in the Czech Republic from 2006 to 2015 with the mean follow-up of 32.9 months (range 2145 months) from the procedure. The mean weight at the time of surgery fluctuated between 114.2 kg and 128.9 kg; mean BMI fluctuated between 42.3 and 46.7. Mean %BMIL was 63.2% for the entire evaluated period. The distance of the starting point of the resection line from the pylorus changed from the mean 6.1 cm (range 67 cm) to mean 4.2 cm (range 36 cm) and the size of the calibration bougie changed from the mean 39.2 F (range 3642 F) to mean 37.1 F (range 3542 F). As regards early postoperative complications, bleeding from the resection line occurred in 1.4% and a leak from the staple line occurred in 1.1%. The gastroesophageal reflux disease and hiatal hernia occurred in 17.3% as the most frequent late complications. Conversion to another bariatric procedure was approached in 3.8% in the event of an unsatisfactory effect of the SG. CONCLUSION: Bariatric or metabolic surgery, respectively, is a safe and effective surgical method for the treatment of severe obesity and T2DM in morbidly obese patients. Currently, SG is the most widely used bariatric/metabolic procedure in the Czech Republic as well as in most other countries and the long-time results are similar in comparison with other authors.Key words: bariatric surgery - sleeve gastrectomy - resection line - complications.

Fatty acid composition of adipose tissue triglycerides in obese diabetic women after bariatric surgery: a 2-year follow up.

Bariatric surgery is the most effective method in the treatment of obesity and type 2 diabetes (T2DM). The aim of this study was to evaluate the effects of different types of bariatric procedures on remission of T2DM and on the fatty acid composition in subcutaneous adipose tissue. Patients included obese diabetic women who underwent bariatric surgery: biliopancreatic diversion (BPD), n=8, laparoscopic gastric banding (LAGB), n=9 or laparoscopic greater curvature plication (LGCP), n=12. Anthropometric characteristics and fatty acid composition of adipose tissue (FA AT) were analyzed before surgery, then 6 months and 2 years after surgery. FA AT was analyzed by gas chromatography. Diabetes remission was estimated. BPD was most efficient in inducing a remission of diabetes (p=0.004). Significantly higher increases in lauric (12:0), myristoleic (14:1n-5) and palmitoleic (16:1n-7) acids and delta-9 desaturase were found two years after BPD, suggesting higher lipogenesis in adipose tissue. Docosatetraenoic acid (22:4n-6) increased significantly after BPD, while docosapentaenoic acid (22:5n-3) decreased 6 months after BPD and increased after 2 years. No changes were found after LAGB and LGCP after 2 years. Bariatric surgery led to significant changes in the fatty acid composition of subcutaneous adipose tissue in severely obese diabetic women after six months and two years, and was partly influenced by the type of surgery used.

Plasma levels of growth-related oncogene (CXCL1-3) associated with fibrosis and platelet counts in HCV-infected patients.

BACKGROUND: Fibrosis progression in hepatitis C virus (HCV)-infected patients varies greatly between individuals. Chemokines recruit immune cells to the infected liver and may thus play a role in the fibrosis process. AIM: To investigate plasma levels of a diverse chemokine panel in relation to liver fibrosis. METHODS: African-American and Caucasian HCV genotype 1 infected patients were treated with peginterferon (pegIFN) and ribavirin (RBV) for 48 weeks (VIRAHEP-C cohort). Plasma levels of 13 cytokines were studied at baseline (n = 386). Subsequently, GROα levels were assessed in a sub cohort (n = 99) at baseline, and at 4 and 12 weeks after start of pegIFN/RBV treatment. RESULTS: Increased severity of fibrosis (Ishak fibrosis score 0-2 vs. 3-6) was associated with increased plasma IP-10 (CXCL10) and IL-8 (CXCL8) levels, and decreased plasma levels of the chemokine growth-related oncogene (GRO, CXCL1-3). Plasma GRO levels were also positively correlated with platelet counts, and were higher in African-American as compared to Caucasian patients. In response to pegIFN/RBV treatment, GROα levels increased in Caucasian but not African-American patients from week 4 onwards. CONCLUSIONS: The association with severity of fibrosis and platelet count positions plasma GRO as a potential biomarker for liver fibrosis in HCV-infected patients. The secretion of GRO by platelets may explain the correlation between GRO plasma level and platelet count. The ethnic difference in GRO levels both pre-treatment and in response to pegIFN/RBV might be driven by a genetic polymorphism in GROα associated with higher plasma levels and more common in the African-American population.

On the validity of the (13) C-acetate breath test for comparing gastric emptying of different liquid test meals: a validation study using magnetic resonance imaging.

BACKGROUND: (13) C-acetate breath testing (BT) is applied to assess and compare gastric emptying of liquid meals. Gastric half-emptying times (t50 ) from BT show offsets compared to t50 values from γ-scintigraphy and ultrasonography. Linear transformations have been proposed to correct these offsets. This investigation critically validates the BT for the assessment of liquid gastric emptying by using simultaneously recorded meal and total gastric content volume emptying data from magnetic resonance imaging (MRI). METHODS: Data were collected during a recently published double-blind, randomized, cross-over MRI gastric emptying study of three (13) C-labeled enteral formulas differing in protein sources (PMID: 24699556). Breath testing-derived t50 was computed with the analysis methods commonly applied in gastric emptying research, i.e., the exponential-beta function and the Wagner-Nelson (WN) method, respectively. KEY RESULTS: Breath testing t50 values from exponential-beta function and WN method showed a positive and negative offset to MRI data, respectively. Linear regression detected low concordance between MRI and both BT methods revealing meal specific and emptying rate-dependent offsets. The WN method showed worse agreement and correlation with MRI emptying data. Breath testing rather reflected meal volume than total gastric content volume emptying. CONCLUSIONS & INFERENCES: This validation study indicates that the (13) C-acetate breath test may not be applied to compare gastric emptying of arbitrary liquid meals without prior validation by imaging methods. t50 values from BT are biased by (i) the properties of the meal and (ii) the selected method used for (13) CO2 exhalation analysis. No linear transformation common for all meals was applicable to correct the offsets between BT and MRI.

Self-reported lactose intolerance in clinic patients with functional gastrointestinal symptoms: prevalence, risk factors, and impact on food choices.

BACKGROUND: Many patients complain of abdominal symptoms with dairy products; however, clinical and psychosocial factors associated with self-reported lactose intolerance (SLI) have not been assessed in large studies. In particular, data are lacking from lactase deficient populations. This prospective cohort study assessed the prevalence of, and risk factors for, SLI in Chinese patients attending a gastroenterology clinic. METHODS: Consecutive patients completed questionnaires to assess digestive health (Rome III), psychological state (HADS), life event stress (LES), food intake, and quality-of-life (SF-8). A representative sample completed genetic studies and hydrogen breath testing (HBT) at the clinically relevant dose of 20 g lactose. KEY RESULTS: SLI was present in 411/910 (45%) clinic patients with functional abdominal symptoms. The genotype in all subjects was C/C-13910. A small number of novel SNPs in lactase promoter region were identified, including C/T-13908 which appeared to confer lactase persistence. Over half of the patients (54%) completed the 20 g lactose HBT with 58% (285/492) reporting typical symptoms. Positive and negative predictive values of SLI for abdominal symptoms during HBT were 60% and 44%, respectively. Psychological state and stress were not associated with SLI in clinic patients. SLI impacted on physical quality-of-life and was associated with reduced ingestion of dairy products, legumes, and dried fruit (p ≤ 0.05). CONCLUSIONS & INFERENCES: In a lactase deficient population, approximately half of patients attending clinic with functional gastrointestinal symptoms reported intolerance to dairy products; however, SLI did not predict findings on 20 g lactose HBT. Independent of psychosocial factors, SLI impacted on quality-of-life and impacted on food choices with restrictions not limited to dairy products.

Increased lymphocyte apoptosis in mouse models of colitis upon ABT-737 treatment is dependent upon BIM expression.

Exaggerated activation of lymphocytes contributes to the pathogenesis of inflammatory bowel disease (IBD). Medical therapies are linked to the BCL-2 family-mediated apoptosis. Imbalance in BCL-2 family proteins may cause failure in therapeutic responses. We investigated the role of BCL-2 inhibitor ABT-737 for lymphocyte apoptosis in mice under inflammatory conditions. B.6129P2-interleukin (IL)-10(tm1Cgn) /J (IL-10(-/-) ) weighing 25-30 g with ongoing colitis were used. Fifty mg/kg/day ABT-737 was injected intraperitoneally (i.p.). Haematological analyses were performed with an ADVIA 2120 flow cytometer and mass cytometry with a CyTOF 2. Following i.p. administration, ABT-737 was detected in both spontaneous and acute colitis in peripheral blood (PBL) and colon tissue. Treatment led to lymphopenia. CD4(+) CD44(+) CD62L(+) central memory and CD8(+) , CD44(+) CD62L(-) central memory T cells were decreased in PBL upon ABT-737 compared to vehicle-receiving controls. Increased apoptosis upon ABT-737 was determined in blood lymphocytes, splenocytes and Peyer's patches and was accompanied by a decrease in TNF and IL-1B. ABT-737 positively altered the colonic mucosa and ameliorated inflammation, as shown by colonoscopy, histology and colon length. A decreased BIM/BCL-2 ratio or absence of BIM in both Bim(-) (/) (-) and Il10(-) (/) (-) × Bim(-) (/) (-) impeded the protective effect of ABT-737. The BIM/BCL-2 ratio decreased with age and during the course of treatment. Thus, long-term treatment resulted in adapted TNF levels and macroscopic mucosal damage. ABT-737 was efficacious in diminishing lymphocytes and ameliorating colitis in a BIM-dependent manner. Regulation of inappropriate survival of lymphocytes by ABT-737 may provide a therapeutic strategy in IBD.

Virological outcomes and treatment algorithms utilisation in observational study of patients with chronic hepatitis C treated with boceprevir or telaprevir.

BACKGROUND: HCV-TARGET is a longitudinal observational study of chronic hepatitis C virus (HCV) patients treated with direct-acting anti-viral agents (DAAs) in a US consortium of 90 academic and community medical centres. AIM: To assess utilisation of response-guided therapy (RGT) and sustained virological response (SVR) of a large cohort of patients. METHODS: Patients received peginterferon (PEG-IFN), ribavirin and either telaprevir or boceprevir. Demographical, clinical and virological data were collected during treatment and follow-up. RGT and treatment futility stopping rules was assessed at key time points. RESULTS: Of 2084 patients, 38% had cirrhosis and 56% had received prior treatment for HCV. SVR rates were 31% (95% CI: 24-40) and 50% (95% CI: 44-56) in boceprevir patients with and without cirrhosis, respectively. SVR rates were 46% (95% CI: 42-50) and 60% (95% CI: 57-64) in telaprevir patients with and without cirrhosis, respectively. Early clearance of virus, IL28B genotype, platelet counts and diabetes were identified as predictors of SVR among boceprevir patients, while early clearance of virus, IL28B, cirrhosis, HCV subtype, age, haemoglobin, bilirubin and albumin levels were identified as predictors of SVR for telaprevir patients. CONCLUSIONS: In academic and community centres, triple therapy including boceprevir or telaprevir led to SVR rates somewhat lower than those noted in large phase 3 clinical trials. Response rates were consistently higher among patients without cirrhosis compared to those with cirrhosis regardless of DAA used and prior treatment response. Trial registration clinicaltrials.gov NCT01474811.

Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: pooled safety analysis from Phase IIb and III studies.

This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in 'Photosensitivity' were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild-to-moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir-treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient-reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response-guided therapy. Simeprevir is well tolerated in HCV genotype 1-infected patients.

PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis.

Loss-of-function variants within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with increased risk for Crohn's disease (CD). A disturbed regulation of T helper (Th) cell responses causing loss of tolerance against self- or commensal-derived antigens and an altered intestinal microbiota plays a pivotal role in CD pathogenesis. Loss of PTPN2 in the T-cell compartment causes enhanced induction of Th1 and Th17 cells, but impaired induction of regulatory T cells (Tregs) in several mouse colitis models, namely acute and chronic dextran sodium sulfate colitis, and T-cell transfer colitis models. This results in increased susceptibility to intestinal inflammation and intestinal dysbiosis which is comparable with that observed in CD patients. We detected inflammatory infiltrates in liver, kidney, and skin and elevated autoantibody levels indicating systemic loss of tolerance in PTPN2-deficient animals. CD patients featuring a loss-of-function PTPN2 variant exhibit enhanced Th1 and Th17 cell, but reduced Treg markers when compared with PTPN2 wild-type patients in serum and intestinal tissue samples. Our data demonstrate that dysfunction of PTPN2 results in aberrant T-cell differentiation and intestinal dysbiosis similar to those observed in human CD. Our findings indicate a novel and crucial role for PTPN2 in chronic intestinal inflammation.