A critical analysis of the tools to evaluate neuropsychiatric lupus.

Neuropsychiatric symptoms occur commonly in patients with systemic lupus erythematosus, but they are not always due to active disease. It is crucial to identify cases that are due to active systemic lupus erythematosus so that appropriate treatment can be instituted. There is no single serological or imaging test that distinguishes active neuropsychiatric systemic lupus erythematosus from neuropsychiatric manifestations caused by other factors such as infection. Most patients with neuropsychiatric systemic lupus erythematosus have generalised features of disease activity. Raised anti-dsDNA and low C3 complement levels are often seen, but are not an invariable guide. The presence of antiphospholipid antibodies is more suggestive of thrombotic than inflammatory causation. A number of other autoantibody tests have been proposed as biomarkers for neuropsychiatric systemic lupus erythematosus, but results in clinical studies have been inconsistent and none has so far entered routine clinical practice. Cerebrospinal fluid features and magnetic resonance imaging appearances are non-specific in neuropsychiatric systemic lupus erythematosus, but are useful in excluding other causes of neuropsychiatric symptoms. Newer magnetic resonance imaging sequences show promise for distinguishing new neuropsychiatric systemic lupus erythematosus activity from previous damage and recent research suggests these may correlate with changes in cognitive function in patients with systemic lupus erythematosus. However, formal cognitive testing is seldom carried out in the acute setting

3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1HIndole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 μM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases

Longterm Outcomes of Patients Undergoing Liver Transplantation for Acute-on-Chronic Liver Failure

AIMS: Recent data have demonstrated greater than 80% one-year survival probability after liver transplantation (LT) for patients with severe acute on chronic liver failure (ACLF). However, long term outcomes and complications are still unknown for this population. Our aim was to compare long-term patient and graft survival among patients transplanted across all grades of ACLF. METHODS: We analyzed the UNOS database, years 2004-2017. Patients with ACLF were identified using the EASL-CLIF criteria. Kaplan-Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. RESULTS: A total of 75,844 patients were transplanted of which 48,854 (64.4%) had no ACLF, 9,337 (12.3%) had ACLF-1, 9,386 (12.4%) had ACLF-2 and 8,267 (10.9%) had ACLF-3. Patients transplanted without ACLF had a greater proportion of hepatocellular carcinoma within (23.8%) and outside (12.7%) Milan criteria. Five-year patient survival after LT was lower in the ACLF-3 patients compared with the other groups (67.7%, p<0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF-1 (31.1%), ACLF-2 (33.3%) and ACLF-3 (36.7%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (38.5%). Graft survival probability at 5 years was above 90% among all patient groups. CONCLUSION: Patients transplanted with ACLF-3 have lower 5-year survival as compared to ACLF 0-2 but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology

Background &amp; Aims: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. Methods: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. Conclusions: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. Lay summary: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model

Common Gene Therapy Viral Vectors Do Not Efficiently Penetrate Sputum from Cystic Fibrosis Patients

Norwalk virus and human papilloma virus, two viruses that infect humans at mucosal surfaces, have been found capable of rapidly penetrating human mucus secretions. Viral vectors for gene therapy of Cystic Fibrosis (CF) must similarly penetrate purulent lung airway mucus (sputum) to deliver DNA to airway epithelial cells. However, surprisingly little is known about the rates at which gene delivery vehicles penetrate sputum, including viral vectors used in clinical trials for CF gene therapy. We find that sputum spontaneously expectorated by CF patients efficiently traps two viral vectors commonly used in CF gene therapy trials, adenovirus (d∼80 nm) and adeno-associated virus (AAV serotype 5; d∼20 nm), leading to average effective diffusivities that are ∼3,000-fold and 12,000-fold slower than their theoretical speeds in water, respectively. Both viral vectors are slowed by adhesion, as engineered muco-inert nanoparticles with diameters as large as 200 nm penetrate the same sputum samples at rates only ∼40-fold reduced compared to in pure water. A limited fraction of AAV exhibit sufficiently fast mobility to penetrate physiologically thick sputum layers, likely because of the lower viscous drag and smaller surface area for adhesion to sputum constituents. Nevertheless, poor penetration of CF sputum is likely a major contributor to the ineffectiveness of viral vector based gene therapy in the lungs of CF patients observed to date

Plasma Proteomic Profiling in HIV-1 Infected Methamphetamine Abusers

We wanted to determine whether methamphetamine use affects a subset of plasma proteins in HIV-infected persons. Plasma samples from two visits were identified for subjects from four groups: HIV+, ongoing, persistent METH use; HIV+, short-term METH abstinent; HIV+, long term METH abstinence; HIV negative, no history of METH use. Among 390 proteins identified, 28 showed significant changes in expression in the HIV+/persistent METH+ group over the two visits, which were not attributable to HIV itself. These proteins were involved in complement, coagulation pathways and oxidative stress. Continuous METH use is an unstable condition, altering levels of a number of plasma proteins