Evaluation of medication-related problems in liver transplant recipients with and without an outpatient medication consultation by a clinical pharmacist: a cohort study.

BACKGROUND: Transplant recipients undergo significant changes in their medication regimen during follow-up and are at an increased risk for medication-related problems (MRPs). AIM: This study aimed to compare the prevalence and types of MRPs and interventions in liver transplant recipients with and without an outpatient medication consultation by a clinical pharmacist as well as the satisfaction with information about medicines and medication adherence. METHOD: We performed a single-center, observational cohort study. A retro- and prospective cohort were used and subdivided in a group that did and did not receive a medication consultation. The prevalence and types of MRPs and interventions were identified and categorized. The satisfaction parameters were evaluated using validated questionnaires. RESULTS: Included were 291 patients. In total, 368 MRPs were identified in 197 patients in the non-medication consultation cohort (median 1; range 1-3 per patient) and 248 MRPs in 94 patients in the medication consultation cohort (median 2; range 1-4 per patient). In the medication consultation cohort, significantly fewer MRPs as unnecessary drugs (17.3% versus 58.7%, p < 0.001), suboptimal therapy (2.4% versus 9.5%, p < 0.001), untreated indication (2.8% versus 6.8%, p = 0.040) and underdosed drugs (0.4% versus 6.3%, p < 0.001) were identified. In the non-medication consultation cohort significantly more patients used unnecessary drugs (72.1% versus 39.4%, p < 0.001) compared to the medication consultation cohort. Patients in both cohorts are satisfied with the information about medicines and reported a high medication adherence. CONCLUSION: Patients in the medication consultation cohort had significantly fewer MRPs and used significantly less unnecessary drugs. Including a clinical pharmacist to the post-transplant care has an added value.

Conservative treatment versus elective repair of umbilical hernia in patients with liver cirrhosis and ascites: results of a randomized controlled trial (CRUCIAL trial).

PURPOSE: To establish optimal management of patients with an umbilical hernia complicated by liver cirrhosis and ascites. METHODS: Patients with an umbilical hernia and liver cirrhosis and ascites were randomly assigned to receive either elective repair or conservative treatment. The primary endpoint was overall morbidity related to the umbilical hernia or its treatment after 24 months of follow-up. Secondary endpoints included the severity of these hernia-related complications, quality of life, and cumulative hernia recurrence rate. RESULTS: Thirty-four patients were included in the study. Sixteen patients were randomly assigned to elective repair and 18 to conservative treatment. After 24 months, 8 patients (50%) assigned to elective repair compared to 14 patients (77.8%) assigned to conservative treatment had a complication related to the umbilical hernia or its repair. A recurrent hernia was reported in 16.7% of patients who underwent repair. For the secondary endpoint, quality of life through the physical (PCS) and mental component score (MCS) showed no significant differences between groups at 12 months of follow-up (mean difference PCS 11.95, 95% CI - 0.87 to 24.77; MCS 10.04, 95% CI - 2.78 to 22.86). CONCLUSION: This trial could not show a relevant difference in overall morbidity after 24 months of follow-up in favor of elective umbilical hernia repair, because of the limited number of patients included. However, elective repair of umbilical hernia in patients with liver cirrhosis and ascites appears feasible, nudging its implementation into daily practice further, particularly for patients experiencing complaints. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01421550, on 23 August 2011.

In-hospital cardiovascular events after liver transplantation: predictors and long-term outcome.

INTRODUCTION: Liver transplantation has emerged as a successful therapy for end-stage liver disease. However, cardiovascular mortality is the leading cause of fatality in the postoperative period. The aim of this study was to reveal the prevalence and identify risk factors of early cardiovascular events (CVEs). METHODS: We performed a retrospective study of all consecutive patients who underwent a primary liver transplantation from 1986 to 2017 (n = 916). We investigated the occurrence of in-hospital CVEs, their predictors, and short- and long-term outcome. RESULTS: The prevalence of CVEs was 11%. The adjusted analysis showed that higher age (OR 1.06, 95% CI 1.03-1.09), higher MELD score (OR 1.04, 95% CI 1.01-1.07 CI) and sinus tachycardia at time of screening (OR 3.12, 95% CI 1.45-6.72) were positive predictors for a CVE. Preoperative propranolol use showed a trend towards a higher risk of CVE (OR 1.66, 95% CI 1.00-2.77, p = 0.051). In a sub-analysis of patients where echocardiography data were available (n = 597), a larger left atrial diameter and a higher E/E' ratio were related to early CVEs. Ten-year survival in 30-day survivors was favourable (68.6%; 56.0% vs. 69.8% in the CVE+ vs. the CVE-group, respectively, p = 0.056). DISCUSSION: In conclusion, besides known risk factors (age and MELD score), sinus tachycardia (related to the presence of acute liver failure and cirrhosis) was an independent predictor for CVE after liver transplantation.

['Will I receive a liver transplant in time?'; chance of survival of patients on the liver transplant waiting list]. / 'Komt mijn nieuwe lever wel op tijd?'.

OBJECTIVE: To calculate the chance of receiving a liver transplant for patients on the liver transplant waiting list in the Netherlands. DESIGN: Retrospective cohort research. METHOD: Data of all patients in the Netherlands on the waiting list for liver transplantation, from the introduction of the model of end-stage liver disease score on 16th December 2006 through to 31st December 2013 were collected. Survival analysis was computed with competing risk analyses. RESULTS: A total of 851 patients were listed, of whom 236 patients with hepatocellular carcinoma, 147 patients with primary sclerosing cholangitis, 142 patients with post-alcoholic liver disease, 93 patients with metabolic liver disease, 78 with viral hepatitis and 155 patients listed for other indications. The median waiting time till transplantation was 196 days. The chance to be transplanted at two years from listing was 65% and the risk of death was 17%. Patients with metabolic liver disease had the highest chance of undergoing liver transplantation. Patients with viral hepatitis were at highest risk of death while on the list, as well as having the lowest chance of undergoing liver transplantation. CONCLUSION: Our study shows a 65% chance of getting transplanted in time after a median waiting time of 6 months in the Netherlands. Sadly, 1 in 6 patients die before liver transplantation can be performed, with the highest risk of death occurring in patients with viral hepatitis.

Chronic norovirus infection among solid organ recipients in a tertiary care hospital, the Netherlands, 2006-2014.

OBJECTIVES: Immunocompromised patients can suffer prolonged norovirus symptoms and virus shedding for many years. Little is known about the prevalence of chronic norovirus infection among solid organ transplant (SOT) recipients. In this study, 2182 SOT recipients were retrospectively tested for chronic norovirus infection. METHODS: The first and last norovirus positive faecal samples of SOT recipients were sequenced to distinguish between persisting infection and re-infection. Patient charts were reviewed to obtain data on health status and treatments. RESULTS: In all, 101 of 2182 (4.6%) recipients were norovirus infected and 23 (22.8%) of these developed chronic norovirus infection. Chronic norovirus infection was found among allogeneic heart, kidney and lung transplant recipients. The median shedding period at the end of the study period was 218 days (range 32-1164 days). CONCLUSIONS: This study shows that chronic norovirus infection is not a rare phenomenon among SOT recipients in a tertiary-care hospital. Further research is needed to study the risk of norovirus transmission to other immunocompromised patients in the hospital and to the general population.

Systematic Review and Meta-Analysis of the Impact of Computed Tomography-Assessed Skeletal Muscle Mass on Outcome in Patients Awaiting or Undergoing Liver Transplantation.

Liver transplant outcome has improved considerably as a direct result of optimized surgical and anesthesiological techniques and organ allocation programs. Because there remains a shortage of human organs, strict selection of transplant candidates remains of paramount importance. Recently, computed tomography (CT)-assessed low skeletal muscle mass (i.e. sarcopenia) was identified as a novel prognostic parameter to predict outcome in liver transplant candidates. A systematic review and meta-analysis on the impact of CT-assessed skeletal muscle mass on outcome in liver transplant candidates were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Nineteen studies, including 3803 patients in partly overlapping cohorts, fulfilled the inclusion criteria. The prevalence of sarcopenia ranged from 22.2% to 70%. An independent association between low muscle mass and posttransplantation and waiting list mortality was described in 4 of the 6 and 6 of the 11 studies, respectively. The pooled hazard ratios of sarcopenia were 1.84 (95% confidence interval 1.11-3.05, p = 0.02) and 1.72 (95% confidence interval 0.99-3.00, p = 0.05) for posttransplantation and waiting list mortality, respectively, independent of Model for End-stage Liver Disease score. Less-consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients. In conclusion, sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment.

Disparity of basal and therapeutically activated interferon signalling in constraining hepatitis E virus infection.

Hepatitis E virus (HEV) represents one of the foremost causes of acute hepatitis globally. Although there is no proven medication for hepatitis E, pegylated interferon-α (IFN-α) has been used as off-label drug for treating HEV. However, the efficacy and molecular mechanisms of how IFN signalling interacts with HEV remain undefined. As IFN-α has been approved for treating chronic hepatitis C (HCV) for decades and the role of interferon signalling has been well studied in HCV infection, this study aimed to comprehensively investigate virus-host interactions in HEV infection with focusing on the IFN signalling, in comparison with HCV infection. A comprehensive screen of human cytokines and chemokines revealed that IFN-α was the sole humoral factor inhibiting HEV replication. IFN-α treatment exerted a rapid and potent antiviral activity against HCV, whereas it had moderate and delayed anti-HEV effects in vitro and in patients. Surprisingly, blocking the basal IFN pathway by inhibiting JAK1 to phosphorylate STAT1 has resulted in drastic facilitation of HEV, but not HCV infection. Gene silencing of the key components of JAK-STAT cascade of the IFN signalling, including JAK1, STAT1 and interferon regulatory factor 9 (IRF9), stimulated HEV infection. In conclusion, compared to HCV, HEV is less sensitive to IFN treatment. In contrast, the basal IFN cascade could effectively restrict HEV infection. This bears significant implications in management of HEV patients and future therapeutic development.

Prednisolone does not affect direct-acting antivirals against hepatitis C, but inhibits interferon-alpha production by plasmacytoid dendritic cells.

BACKGROUND: Chronic hepatitis C virus (HCV) infection compromises long-term outcomes of liver transplantation. Although glucocorticosteroid-based immunosuppression is commonly used, discussion is ongoing on the effect of prednisolone (Pred) on HCV recurrence and response to antiviral therapy post transplantation. Recently, new drugs (direct-acting antivirals) have been approved for the treatment of HCV, however, it remains unknown whether their antiviral activity is affected by Pred. The aim of this study was to investigate the effects of Pred on the antiviral activity of asunaprevir (Asu), daclatasvir (Dac), ribavirin (RBV), and interferon-alpha (IFN-α), and on plasmacytoid dendritic cells (PDCs), the main IFN-α-producing immune cells. METHODS: The effects of Pred and antiviral compounds were tested in both a subgenomic and infectious HCV replication model. Furthermore, effects were tested on human PDCs stimulated with a Toll-like receptor-7 ligand. RESULT: Pred did not directly affect HCV replication and did not inhibit the antiviral action of Asu, Dac, RBV, or IFN-α. Stimulated PDCs potently suppressed HCV replication. This suppression was reversed by treating PDCs with Pred. Pred significantly decreased IFN-α production by PDCs without affecting cell viability. When Asu and Dac were combined with PDCs, a significant cooperative antiviral effect was observed. CONCLUSION: This study shows that Pred acts on the antiviral function of PDCs. Pred does not affect the antiviral action of Asu, Dac, RBV, or IFN-α. This implies that there is no contraindication to combine antiviral therapies with Pred in the post-transplantation management of HCV recurrence.

CMV Primary Infection Is Associated With Donor-Specific T Cell Hyporesponsiveness and Fewer Late Acute Rejections After Liver Transplantation.

Viral infections, including cytomegalovirus (CMV), abrogate transplantation tolerance in animal models. Whether this also occurs in humans remains elusive. We investigated how CMV affects T cells and rejection episodes after liver transplantation (LT). Phenotype and alloreactivity of peripheral and allograft-infiltrating T cells from LT patients with different CMV status were analyzed by flow cytometry. The association of CMV status with early and late acute rejection was retrospectively analyzed in a cohort of 639 LT patients. CMV-positivity was associated with expansion of peripheral effector memory T cell subsets after LT. Patients with CMV primary infection showed donor-specific CD8(+) T cell hyporesponsiveness. While terminally differentiated effector memory cells comprised the majority of peripheral donor-specific CD8(+) T cells in CMV primary infection patients, they were rarely present in liver allografts. Retrospective analysis showed that R(-) D(+) serostatus was an independent protective factor for late acute rejection by multivariate Cox regression analysis (hazard ratio [HR] = 0.18, 95% CI = 0.04-0.86, p = 0.015). Additionally, CMV primary infection patients showed the highest Vδ1/Vδ2 γδ T cell ratio, which has been shown to be associated with operational tolerance after LT. In conclusion, our data suggest that CMV primary infection may promote tolerance to liver allografts, and CMV status should be considered when tapering or withdrawing immunosuppression.

Rotavirus in organ transplantation: drug-virus-host interactions.

Although rotavirus is usually recognized as the most common etiology of diarrhea in young children, it can in fact cause severe diseases in organ transplantation recipients irrespective of pediatric or adult patients. This comprehensive literature analysis revealed 200 cases of rotavirus infection with 8 related deaths in the setting of organ transplantation been recorded. Based on published cohort studies, an average incidence of 3% (187 infections out of 6176 organ recipients) was estimated. Rotavirus infection often causes severe gastroenteritis complications and occasionally contributes to acute cellular rejection in these patients. Immunosuppressive agents, universally used after organ transplantation to prevent organ rejection, conceivably play an important role in such a severe pathogenesis. Interestingly, rotavirus can in turn affect the absorption and metabolism of particular immunosuppressive medications via several distinct mechanisms. Even though rotaviral enteritis is self-limiting in general, infected transplantation patients are usually treated with intensive care, rehydration and replacement of nutrition, as well as applying preventive strategies. This article aims to properly assess the clinical impact of rotavirus infection in the setting of organ transplantation and to disseminate the interactions among the virus, host and immunosuppressive medications.

SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma.

Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development.

REFINE: a randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C.

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions.

Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)-α production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (Treg ). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN-α secretion potently (-64%) but TLR-9-induced IFN-α secretion only slightly (-20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN-γ and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4(+) forkhead box protein 3 (FoxP3)(+) regulatory T cells, but did not affect the generation of suppressive CD8(+) CD38(+) lymphocyte activation gene (LAG)-3(+) Treg . In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4(+) T cell proliferation and induce CD4(+) FoxP3(+) regulatory T cell generation.

Umbilical hernia management during liver transplantation.

PURPOSE: Patients with liver cirrhosis scheduled for liver transplantation often present with a concurrent umbilical hernia. Optimal management of these patients is not clear. The objective of this study was to compare the outcomes of patients who underwent umbilical hernia correction during liver transplantation through a separate infra-umbilical incision with those who underwent correction through the same incision used to perform the liver transplantation. METHODS: In the period between 1990 and 2011, all 27 patients with umbilical hernia and liver cirrhosis who underwent hernia correction during liver transplantation were identified in our hospital database. In 17 cases, umbilical hernia repair was performed through a separate infra-umbilical incision (separate incision group) and 10 were corrected from within the abdominal cavity without a separate incision (same incision group). Six patients died during follow-up; no deaths were attributable to intraoperative umbilical hernia repair. All 21 patients who were alive visited the outpatient clinic to detect recurrent umbilical hernia. RESULTS: One recurrent umbilical hernia was diagnosed in the separate incision group (6 %) and four (40 %) in the same incision group (p = 0.047). Two patients in the same incision group required repair of the recurrent umbilical hernia; one of whom underwent emergency surgery for bowel incarceration. The one recurrent hernia in the separate incision group was corrected electively. CONCLUSION: In the event of liver transplantation, umbilical hernia repair through a separate infra-umbilical incision is preferred over correction through the same incision used to perform the transplantation.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Clinical outcome of progressive stenting in patients with anastomotic strictures after orthotopic liver transplantation.

BACKGROUND AND STUDY AIMS: Anastomotic strictures are an important cause of morbidity after orthotopic liver transplantation (OLT). Endoscopic treatment is the primary treatment modality for biliary complications after OLT. The outcome and complications of a progressive stenting protocol are largely unknown. PATIENTS AND METHODS: A longitudinal cohort study of OLTs was conducted. Only patients with late strictures were included. Treatment success was defined as cholangiographic stricture resolution and liver enzymes returning to normal with follow-up of at least 12 months. RESULTS: Between May 2000 and June 2009, 375 OLTs were performed. A duct-to-duct anastomosis was created in 304 cases (81 %). In 63 patients (21 %; 95 % confidence interval [CI] 16.5 % - 25.6 %) an anastomotic stricture developed and progressive stenting was started in 35. During treatment two patients died of a non-treatment-related cause and two patients underwent a second OLT during stent therapy. Therefore 31 patients were available for analysis (male : female 21:10; median age 61 years, range 28 - 75 years). Progressive stenting required a median number of 5 endoscopic retrograde cholangiopancreatography (ERCP) procedures (range 4 - 11). A median maximum of 4 stents (range 2 - 8) were inserted. A total of 21 patients (67.7 %; 95 %CI 50.1 % - 81.4 %) developed a treatment-related complication. In 33 out of a total of 155 ERCPs (21.3 %) a complication occurred: cholangitis (n = 12), transient cholestasis (n = 11), post-ERCP pancreatitis (n = 7), and treatment-related pain (n = 3). The median follow-up time after stent removal was 28 months (range 12 - 92). Treatment was successful in 25 patients (80.6 %; 95 %CI 63.7 % - 90.8 %). CONCLUSION: Progressive stenting for anastomotic strictures after OLT is demanding and burdensome, necessitating a median of 5 ERCP procedures with complications occurring in one out of five procedures. Its success rate however is high (81 %), avoiding surgery in the large majority of patients.

Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells.

Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (Tregs ) in humans in vivo. Blood was collected from IVIg-treated patients with immunodeficiency or autoimmune disease who were treated with low-dose (n = 12) or high-dose (n = 15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+)) Tregs and of conventional CD4(+) FoxP3(-) T-helper cells (Tconv) were measured. The suppressive capacity of Tregs purified from blood collected at the time-points indicated was determined in an ex-vivo assay. High-dose, but not low-dose, IVIg treatment enhanced the activation status of circulating Tregs , as shown by increased FoxP3 and human leucocyte antigen D-related (HLA-DR) expression, while numbers of circulating Tregs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified Tregs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of Tconv was not affected by IVIg. We conclude that high-dose IVIg treatment activates Tregs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders.

Meta-analysis of laparoscopic versus open cholecystectomy for patients with liver cirrhosis and symptomatic cholecystolithiasis.

BACKGROUND: Open cholecystectomy (OC) is often preferred over laparoscopic cholecystectomy (LC) in patients with liver cirrhosis and portal hypertension, but evidence is lacking to support this practice. This meta-analysis aimed to clarify which surgical technique is preferable for symptomatic cholecystolithiasis in patients with liver cirrhosis. METHODS: A meta-analysis was conducted according to the PRISMA guidelines. Articles published between January 1990 and October 2011 were identified from MEDLINE, Embase and the Cochrane Library. Randomized clinical trials (RCTs) comparing outcomes of OC versus LC for cholecystolithiasis in patients with liver cirrhosis were included. The quality of the RCTs was assessed using the Jadad criteria. RESULTS: Following review of 1422 papers by title and abstract, a meta-analysis was conducted of four RCTs comprising 234 surgical patients. They provided evidence of at least level 2b on the Oxford Level of Evidence Scale, but scored poorly according to the Jadad criteria. Some 97·0 per cent of the patients had Child-Turcotte-Pugh (CTP) grade A or B liver cirrhosis. In all, 96·6 per cent underwent elective surgery. No postoperative deaths were reported. LC was associated with fewer postoperative complications (risk ratio 0·52, 95 per cent confidence interval (c.i.) 0·29 to 0·92; P = 0·03), a shorter hospital stay (mean difference -3·05 (95 per cent c.i. -4·09 to -2·01) days; P < 0·001) and quicker resumption of a normal diet (mean difference -27·48 (-30·96 to -23·99) h; P < 0·001). CONCLUSION: Patients with CTP grade A or B liver cirrhosis who undergo LC for symptomatic cholecystolithiasis have fewer overall postoperative complications, a shorter hospital stay and resume a normal diet more quickly than those who undergo OC.

Genetic polymorphisms in innate immunity receptors do not predict the risk of bacterial and fungal infections and acute rejection after liver transplantation.

INTRODUCTION: We studied the influence of a broad range of genetic variants in recipient and donor innate immunity receptors on bacterial and fungal infections and acute rejection after liver transplantation (LT). METHODS: Seventy-six polymorphisms in TLR 1-10, NOD2, LBP, CD14, MD2, SIGIRR, Ficolins 1, -2, and -3, MASP 1, -2, and -3, and the complement receptor C1qR1 were determined in 188 LT recipients and 135 of their donors. Associations with clinically significant infections and acute rejection were analyzed for 50 polymorphisms. Significant associations were validated in an independent cohort of 181 recipients and 167 donors. RESULTS: Three recipient polymorphisms and 3 donor polymorphisms were associated with infections in the identification cohort, but none of these associations were confirmed in the validation cohort. Three donor polymorphisms were associated with acute rejection in the identification cohort, but not in the validation cohort. CONCLUSION: In contrast to their effect in the general population, 50 common genetic variations in innate immunity receptors do not influence susceptibility to bacterial/fungal infections after LT. In addition, no reproducible associations with acute rejection after LT were observed. Likely, transplant-related factors play a superior role as risk factors for bacterial/fungal infections and acute rejection after LT.