Search

With the increasing rate of infections caused by multidrug‐resistant organisms (MDRO), selecting appropriate empiric antibiotics has become challenging. We aimed to develop and externally validate a model for predicting the risk of MDRO infections in patients with cirrhosis. Methods: We included patients with cirrhosis and bacterial infections from two prospective studies: a transcontinental study was used for model development and internal validation (n = 1302), and a study from Argentina and Uruguay was used for external validation (n = 472). All predictors were measured at the time of infection. Both culture‐positive and culture‐negative infections were included. The model was developed using logistic regression with backward stepwise predictor selection. We externally validated the optimism‐adjusted model using calibration and discrimination statistics and evaluated its clinical utility. Results: The prevalence of MDRO infections was 19% and 22% in the development and external validation datasets, respectively. The model's predictors were sex, prior antibiotic use, type and site of infection, MELD‐Na, use of vasopressors, acute‐on‐chronic liver failure, and interaction terms. Upon external validation, the calibration slope was 77 (95% CI.48–1.05), and the area under the ROC curve was.68 (95% CI.61–.73). The application of the model significantly changed the post‐test probability of having an MDRO infection, identifying patients with nosocomial infection at very low risk (8%) and patients with community‐acquired infections at significant risk (36%). Conclusion: This model achieved adequate performance and could be used to improve the selection of empiric antibiotics, aligning with other antibiotic stewardship program strategies. [ABSTRACT FROM AUTHOR]

Transjugular intrahepatic portosystemic shunt (TIPS) has become essential in the treatment or prevention of portal hypertension‐related complications. In the early 1990s, the primary indication was refractory bleeding. It is now proposed for the treatment of ascites for the prevention of bleeding and in patients with vascular diseases of the liver. Thus, there are a growing number of patients being treated with TIPS all over the world. The broadening of indications, the involvement of multiple stakeholders, the need for an accurate selection, the positioning in relation to transplantation and the lack of standardization in pre‐therapeutic assessment, in the procedure itself and in the follow‐up have led the board of the French Association for the Study of the Liver to establish recommendations. [ABSTRACT FROM AUTHOR]

Introduction: The presence of median arcuate ligament (MAL) during orthotopic liver transplantation (OLT) may cause a significant reduction in the arterial hepatic flow. The aim of the present study is to investigate the impact of MAL on biliary complications in patients who underwent OLT. Methods: We performed a retrospective case‐control study among patients who underwent OLT in Geneva University Hospital between 2007 and 2017, depending on the presence or absence of MAL. The matching was performed according to age, gender, lab‐MELD score at the time of OLT and type of donor (living or dead). The presence of MAL was assessed by an expert liver radiologist on the preoperative CT angiographic evaluation. Results: The incidence of MAL was 6.1% (19 patients). Baseline characteristics were comparable between the two groups. No significant difference in biliary complications was found between patients with and without MAL (37% and 24%, respectively). No patient presented hepatic artery thrombosis. After logistic regression, in patients with MAL, the MAL release and gastroduodenal artery preservation compared to no treatment, showed an odds ratio for post‐OLT biliary complications of 1.5 and 1.25, respectively. There was no difference in overall graft survival and in hazard for biliary complications between patients with and without MAL. Conclusion: In the present study, we did not find any difference in the prevalence of biliary and arterial complications between patients with and without MAL. The choice of MAL treatment did not influence in a significant way the overall outcome and development of complications. However, if, at the end of arterial reconstruction, the arterial flow is not adequately established, MAL needs to be treated with the least invasive technique. [ABSTRACT FROM AUTHOR]

Targeted therapies have revolutionized cancer treatment. It is well established that alterations of chromatin configuration and modifications affect tumorigenesis of some, possibly most, bone and soft-tissue sarcomas. As epigenetic regulators play a major role in the development of bone and soft-tissue sarcomas, epigenetic drugs provide a novel potential avenue for rational targeted therapies for these aggressive cancers. The present review summarizes the application of epigenetic drugs for clinical utilization in bone and soft-tissue sarcomas and provides an overview of clinical trials currently evaluating epigenetic therapies in this space. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver stiffness measured with 2‐dimensional shear wave elastography by Supersonic Imagine (2DSWE‐SSI) is well‐established for fibrosis diagnostics, but non‐conclusive for portal hypertension. Methods: We performed an individual patient data meta‐analysis of 2DSWE‐SSI to identify clinically significant portal hypertension (CSPH), severe portal hypertension and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta‐analytical integration of diagnostic accuracies with optimized rule‐out (sensitivity‐90%) and rule‐in (specificity‐90%) cut‐offs. Results: Five studies from seven centres shared data on 519 patients. After exclusion, we included 328 patients. Eighty‐nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE‐SSI < 14 kPa ruled out CSPH with a summary AUROC (sROC), sensitivity and specificity of 0.88, 91% and 37%, and correctly classified 85% of patients, with minimal between‐study heterogeneity. The false negative rate was 60%, of which decompensated patients accounted for 78%. 2DSWE‐SSI ≥ 32 kPa ruled in CSPH with sROC, sensitivity, specificity and correct classifications of 0.83, 47%, 89% and 55%. In a subgroup analysis, the 14 kPa cut‐off showed consistent sensitivity and higher specificity for patients with compensated cirrhosis, without ascites, viral aetiology or BMI < 25 kg/m2. 2DSWE‐SSI ruled out severe portal hypertension and large varices with fewer correctly classified and lower sROC, and with minimal benefit for ruling in. Conclusion: Liver stiffness using 2‐dimensional shear wave elastography below 14 kPa may be used to rule out clinically significant portal hypertension in cirrhosis patients, but this would need validation in populations of compensated liver disease. 2DSWE‐SSI cannot predict varices needing treatment. [ABSTRACT FROM AUTHOR]

Key points: Chronic obstructive pulmonary disease (COPD) is largely caused by smoking, and patient limb muscle exhibits a fast fibre shift and atrophy. We show that this fast fibre shift is associated with type grouping, suggesting recurring cycles of denervation–reinnervation underlie the type shift. Compared to patients with normal fat‐free mass index (FFMI), patients with low FFMI exhibited an exacerbated fibre type shift, marked accumulation of very small persistently denervated muscle fibres, and a blunted denervation‐responsive transcript profile, suggesting failed denervation precipitates muscle atrophy in patients with low FFMI. Sixteen weeks of passive tobacco smoke exposure in mice caused neuromuscular junction degeneration, consistent with a key role for smoke exposure in initiating denervation in COPD. Abstract: A neurological basis for the fast fibre shift and atrophy seen in limb muscle of patients with chronic obstructive pulmonary disease (COPD) has not been considered previously. The objective of our study was: (1) to determine if denervation contributes to fast fibre shift and muscle atrophy in COPD; and (2) to assess using a preclinical smoking mouse model whether chronic tobacco smoke (TS) exposure could initiate denervation by causing neuromuscular junction (NMJ) degeneration. Vastus lateralis muscle biopsies were obtained from severe COPD patients [n = 10 with low fat‐free mass index (FFMI), 65 years; n = 15 normal FFMI, 65 years) and healthy age‐ and activity‐matched non‐smoker control subjects (CON; n = 11, 67 years), to evaluate morphological and transcriptional markers of denervation. To evaluate the potential for chronic TS exposure to initiate these changes, we examined NMJ morphology in male adult mice following 16 weeks of passive TS exposure. We observed a high proportion of grouped fast fibres and a denervation transcript profile in COPD patients, suggesting that motor unit remodelling drives the fast fibre type shift in COPD patient limb muscle. A further exacerbation of fast fibre grouping in patients with low FFMI, coupled with blunted reinnervation signals, accumulation of very small non‐specific esterase hyperactive fibres and neural cell adhesion molecule‐positive type I and type II fibres, suggests denervation‐induced exhaustion of reinnervation contributes to muscle atrophy in COPD. Evidence from a smoking mouse model showed significant NMJ degeneration, suggesting that recurring denervation in COPD is probably caused by decades of chronic TS exposure. [ABSTRACT FROM AUTHOR]

Summary: Background: Two algorithms based on sequential measurements of liver and spleen stiffness using two‐dimensional shearwave elastography (2D‐SWE) have been recently proposed to estimate clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mm Hg) in patients with cirrhosis, with excellent diagnostic accuracy. Aim: To validate externally these algorithms in a large cohort of patients with cirrhosis. Methods: One hundred and ninety‐one patients with stable cirrhosis (Child‐Pugh class A 39%, B 29% and C 31%) who underwent liver and spleen stiffness measurements using 2D‐SWE at the time of HVPG measurement were included. Diagnostic accuracy of the 2 algorithms was assessed by calculating sensitivity, specificity, positive and negative predictive values. Results: The first algorithm, using liver stiffness <16.0 kilopascals (kPa) and then spleen stiffness <26.6 kPa, was used to rule‐out HVPG ≥10 mm Hg. In our population, its sensitivity and negative predictive value were 95% and 63% respectively. The second algorithm, using liver stiffness >38.0 kPa, or liver stiffness ≤38.0 kPa but spleen stiffness >27.9 kPa, was used to rule‐in HVPG ≥10 mm Hg. In our population, its specificity and positive predictive value were 52% and 83% respectively. Restricting the analyses to the 74 patients without any history of decompensation of cirrhosis or to the 65 patients with highly reliable liver stiffness measurement did not improve the results. Conclusion: In our population, diagnostic accuracies of non‐invasive algorithms based on sequential measurements of liver and spleen stiffness using 2D‐SWE were acceptable, but not good enough to replace HVPG measurement or to base clinical decisions. [ABSTRACT FROM AUTHOR]

Disorders of glucose metabolism, namely glucose intolerance and diabetes, are frequent in patients with chronic liver diseases. In patients with cirrhosis, diabetes can be either a classical type 2 diabetes mellitus or the so-called hepatogenous diabetes, i.e. a consequence of liver insufficiency and portal hypertension. This review article provides an overview of the possible pathophysiological mechanisms explaining diabetes in patients with cirrhosis. Cirrhosis is associated with portosystemic shunts as well as reduced hepatic mass, which can both impair insulin clearance by the liver, contributing to peripheral insulin resistance through insulin receptors down-regulation. Moreover, cirrhosis is associated with increased levels of advanced-glycation-end products and hypoxia-inducible-factors, which may play a role in the development of diabetes. This review also focuses on the clinical implications of diabetes in patients with cirrhosis. First, diabetes is an independent factor for poor prognosis in patients with cirrhosis. Specifically, diabetes is associated with the occurrence of major complications of cirrhosis, including ascites and renal dysfunction, hepatic encephalopathy and bacterial infections. Diabetes is also associated with an increased risk of hepatocellular carcinoma in patients with chronic liver diseases. Last, the management of patients with concurrent diabetes and liver disease is also addressed. Recent findings suggest a beneficial impact of metformin in patients with chronic liver diseases. Insulin is often required in patients with advanced cirrhosis. However, the favourable impact of controlling diabetes in patients with cirrhosis has not been demonstrated yet. [ABSTRACT FROM AUTHOR]

Background Beta-blockers may have to be interrupted in patients with cirrhosis. The concept of a rebound after interruption of beta-blockers is based on an animal study and on isolated case reports of variceal bleeding. Aim To determine if a rebound occurs in patients with cirrhosis following abrupt interruption of beta-blockers. Methods We prospectively included all consecutive patients with cirrhosis undergoing right heart and hepatic vein catheterisation. Four groups were defined: 'no beta-blockers' including patients not receiving beta-blockers; '≤1 day', '2-3 days' and '≥4 days' classified according to the time patients had interrupted beta-blockers before catheterisation. Results were expressed as median (interquartile range). Results A total of 150 patients were included. Among the 25 patients in the groups '2-3 days' and '≥4 days', median duration of beta-blockers interruption was 4 (3-6) days. No gastrointestinal bleeding occurred during that period, nor during the following month. Hepatic venous pressure gradient was not different among patients in usually treated with beta-blockers. After adjustment, beta-blockers interruption was not associated with hepatic venous pressure gradient. Cardiac index was higher in the '≥4 days' group [4.6 L/min/m2 (3.5-5.1)] than in the '≤1 day' group [3.4 (2.6-4.0); P = 0.001] or in the '2-3 days' group [3.1 (2.7-3.7); P = 0.007], but not different from the 'no beta-blockers' group. Conclusions Abrupt interruption of beta-blockers is associated neither with an apparent increase in the risk of variceal bleeding nor with a haemodynamic rebound. Thus, interruption of beta-blockers in patients with cirrhosis may not require particular dosing or surveillance. [ABSTRACT FROM AUTHOR]

The endocannabinoid (eCB) system is widely expressed in various parts of the central nervous system, including the retina. The localization of the key eCB receptors, particularly CB1R and CB2R, has been recently reported in rodent and primate retinas with striking interspecies differences. Little is known about the distribution of the enzymes involved in the synthesis and degradation of these eCBs. We therefore examined the expression and localization of the main components of the eCB system in the retina of mice, tree shrews, and monkeys. We found that CB1R and FAAH distributions are well-preserved among these species. However, expression of NAPE-PLD is circumscribed to the photoreceptor layer only in monkeys. In contrast, CB2R expression is variable across these species; in mice, CB2R is found in retinal neurons but not in glial cells; in tree shrews, CB2R is expressed in Müller cell processes of the outer retina and in retinal neurons of the inner retina; in monkeys, CB2R is restricted to Müller cells. Finally, the expression patterns of MAGL and DAGLα are differently expressed across species. Overall, these results provide evidence that the eCB system is differently expressed in the retina of these mammals and suggest a distinctive role of eCBs in visual processing. [ABSTRACT FROM AUTHOR]

Background & Aims The most serious complication of acute mesenteric vein thrombosis ( MVT) is acute intestinal ischaemia requiring intestinal resection or causing death. Risk factors for this complication are unknown. To identify risk factors for severe intestinal ischaemia leading to intestinal resection in patients with acute MVT. Methods We retrospectively analysed consecutive patients seen between 2002 and 2012 with acute MVT in 2 specialized units. Patients with cirrhosis were excluded. We compared patients who required intestinal resection to patients who did not. Results Among 57 patients, a local risk factor was identified in 14 (24%) patients, oral contraceptive use in 16 (29%), and at least one or more other systemic prothrombotic condition in 25 (44%). Five (9%) patients had diabetes mellitus ( DM), 33 (58%) had overweight or obesity, 9 (18%) had hypertriglyceridemia and 10 (19%) had arterial hypertension. Eleven patients (19%) underwent intestinal resection. DM was significantly associated with intestinal resection ( P = 0.02) while local factors or prothrombotic conditions were not. Computed tomography ( CT) scans performed at diagnosis found that occlusion of second order radicles of the superior mesenteric vein was more frequently observed in patients who underwent intestinal resection ( P = 0.009). Conclusions In acute MVT, patients with underlying DM have an increased risk of requiring intestinal resection. Neither local factors nor systemic prothrombotic conditions are associated with intestinal resection. When CT scan shows the preservation of second order radicles of the superior mesenteric vein, the risk of severe resection is low. [ABSTRACT FROM AUTHOR]

Background Guidelines recommend antibiotic prophylaxis ( AP) in well-selected groups of cirrhotic patients, but the impact of these recommendations has not been assessed in France. Aim To evaluate AP prescription tendencies for gastrointestinal bleeding, and primary and secondary prophylaxis of spontaneous bacterial peritonitis ( SBP). Methods Practitioners ( n = 1,159) working in general hospitals ( GH) or in university hospitals ( UH) received a self-administered questionnaire. Results Three hundred and eighty-nine (33.6%; GH 35% and UH 30.4%) practitioners responded. AP was prescribed by 97.7%, 72.3% and 94.8% of practitioners, without significant differences between UH and GH, respectively, for gastrointestinal bleeding (quinolones 48.2%, third-generation cephalosporins 27.7% and amoxicillin-clavulanic acid 22.2%), primary (quinolones 97.2%) and secondary prophylaxis of SBP (quinolones 99%). For gastrointestinal bleeding, ofloxacin (47.6%) and norfloxacin (37.4%) were the main quinolones prescribed, and ceftriaxone (77%) was the main third-generation cephalosporin prescribed. The principal reasons for prescribing AP were a decrease in bacterial infection (88.9% for gastrointestinal bleeding, 91.3% for primary and 94.3% for secondary prophylaxis of SBP), a recommendation by a consensus conference (83%, 38% and 74.4% respectively) and an improvement in survival (72.8%, 41.3% and 57.7% respectively). Only 31.7% of practitioners (39.6% for UH vs. 28.6% for GH; P = 0.038) believed that AP may reduce the risk of bleeding recurrence. Reported side effects (28%) of AP mainly concerned the risk of quinolone resistance (62% of cases). Conclusion Antibiotic prophylaxis is well-recognized by French practitioners, but its routine use depends on the expertise of practitioners. Quinolones remain the main antibiotic class prescribed irrespective of the type of prophylaxis. [ABSTRACT FROM AUTHOR]

See Article on Page 454 [ABSTRACT FROM AUTHOR]

Contemporary, comprehensive data on epidemiology and outcomes of invasive fungal disease (IFD) including breakthrough IFD among allogeneic hematopoietic stem cell transplantation (HSCT) recipients are scarce. We included 479 allogeneic HSCT recipients with 10 invasive candidiasis (IC) and 31 probable/proven invasive mold disease (IMD) from the Swiss Transplant Cohort Study from 01.2009 to 08.2013. Overall cumulative incidence was 2.3% for IC and 8.5% for probable/proven IMI: 6% for invasive aspergillosis (IA) and 2.5% for non‐AspergillusIMI. Among 41 IFD, 46% IFD were breakthrough, with an overall incidence of 4.6%, more frequently caused by other‐than‐Aspergillus fumigatus molds than primary IFD (47.6% (10/21) vs 13% (3/23), P = 0.04). Twelve‐week mortality among patients with IC was 20% and 58.6% for probable/proven IMD (60% IA and 54.6% non‐Aspergillus). Our results reveal that breakthrough IFD represent a marked burden of probable/proven IFD postallogeneic HSCT and mortality remains above 50% in patients with probable/proven IMD, underscoring the ongoing challenges to prevent and treat IFD in these patients. [ABSTRACT FROM AUTHOR]

Background: Descriptive data on Pneumocystis jirovecii pneumonia (PJP) in solid organ transplant recipients (SOTr) in the era of routine Pneumocystis‐prophylaxis are lacking. Methods: All adult SOTr between 2008 and 2016 were included. PJP was diagnosed based on consensus guidelines. Early‐onset PJP was defined as PJP within the first‐year‐post‐transplant. Results: 41/2842 SOTr (1.4%) developed PJP (incidence rate: 0.01/1000 person‐days) at a mean of 493‐days post‐transplant: 21 (51.2%) early vs 20 (48.8%) late‐onset PJP. 2465 (86.7%) SOTr received Pneumocystis‐prophylaxis for a mean 316 days. PJP incidence was 0.001% and 0.003% (log‐rank < 0.001) in SOTr with and without Pneumocystis‐prophylaxis, respectively. PJP was an early event in 10/12 (83.3%) SOTr who did not receive Pneumocystis‐prophylaxis and developed PJP, compared to those patients who received prophylaxis (11/29, 37.9%; P‐value: 0.008). Among late‐onset PJP patients, most cases (13/20, 65%) were observed during the 2nd year post‐transplant. Age ≥65 years (OR: 2.4, P‐value: 0.03) and CMV infection during the first 6 months post‐SOT (OR: 2.5, P‐value: 0.006) were significant PJP predictors, while Pneumocystis‐prophylaxis was protective for PJP (OR: 0.3, P‐value: 0.006) in the overall population. Most patients (35, 85.4%) were treated with trimethoprim‐sulfamethoxazole for a mean 20.6 days. 1‐year mortality was 14.6%. Conclusions: In the Pneumocystis‐prophylaxis‐era, PJP remains a rare post‐transplant complication. Most cases occurred post‐PJP‐prophylaxis‐discontinuation, particularly during the second‐year‐post‐transplant. Additional research may help identify indications for Pneumocystis‐prophylaxis prolongation. [ABSTRACT FROM AUTHOR]

Background: An outbreak of Pneumocystis pneumonia (PCP) in liver transplant recipients occurred between 2009 and 2011 at the Beaujon University Hospital just after immediate‐release tacrolimus was replaced by extended‐release tacrolimus. We conducted a retrospective study to analyze the transmission mode of Pneumocystis, the role of the change in the immunosuppressive regimen, and the factors associated with PCP. Patients and methods: To analyze transmission, we built a transmission map. Two control groups were built. First, to assess the role of the change from tacIR to tacER, cases were matched to controls transplanted before 2009 (tacIR control group). Tacrolimus trough concentrations were compared between the 2 groups. Then, to assess factors associated with PCP, each PCP case was matched to 2 control patients: the one transplanted just before and the one just after (PCPAsFact control group). No PCP prophylaxis was given to any patient. Results: Fifteen cases of PCP were recorded. A contact between a case and a patient who developed PCP afterward was identified in 4 occasions. The comparison of tacrolimus trough concentrations did not conclude to a difference in the exposure to the drug. Lymphopenia was the only factor independently associated with the occurrence of PCP (odds ratio 0.78, 95% confidence interval 0.61‐0.99, P = .04). Conclusion: Our results suggest that patient‐to‐patient transmission was not the main mode of transmission of PCP. We found no evidence that the switch from tacIR to tacER led to an overexposure to tacrolimus. Our results suggest the possibility of targeted prophylaxis in immunosuppressed liver transplant recipients. [ABSTRACT FROM AUTHOR]