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The Impact of Direct-acting Antivirals on Overall Mortality and Tumoral Recurrence in Patients With Hepatocellular Carcinoma Listed for Liver Transplantation: An International Multicenter Study.
No full textBACKGROUND
There is a lack of data on the use of direct-acting antivirals (DAA) on the risk of death and tumoral recurrence in patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) listed for liver transplantation (LT). We aimed to assess the impact of antiviral treatment on mortality and HCC recurrence patients with HCC-HCV.
METHODS
This was a retrospective multicenter study of patients with HCC-HCV listed for LT from 2005 to 2015. Patients were divided according to the antiviral treatment received after HCC diagnosis: DAA, interferon (IFN), or no antiviral. Intention-to-treat overall survival and HCC recurrence incidence were compared by the Kaplan-Meier method. Multivariable regression analysis was performed to identify risk factors for outcomes.
RESULTS
A total of 1012 HCV-HCC patients were listed for LT during the study period. The median follow-up was 4.0 (interquartile range = 2.3-6.7) years. Mortality was 5.6 (95% confidence interval [CI], 4.3-7.2), 13.1 (95% CI, 11.0-15.7), and 6.2 (95% CI, 5.4-7.2) deaths per 100 person-year among patients treated with DAA, IFN, and antiviral naïve, respectively (P < 0.001). Of the 875 HCV-HCC transplant recipients, the 5-year recurrence-free survival was 93.4%, 84.8%, 73.9% for the pre-LT DAA, pre-LT IFN, and antiviral naïve groups, respectively (P < 0.001). After multivariable regression, the use of pre-LT DAA was not associated to risk of recurrence (hazard ratio = 0.44 [95% CI, 0.19-1.00]). Post-LT DAA was not related to increased risk of recurrence (hazard ratio = 0.62 [95% CI, 0.33-1.16]).
CONCLUSIONS
In this multicenter intent-to-treat study, DAA therapy was not found to be a risk factor for mortality or HCC recurrence after adjusting for potential confounders
Heat acclimatisation on UK exercise SAIF SAREEA 3.
No full textUK Exercise SAIF SAREEA 3 saw components of first Armoured Infantry Brigade conduct kinetic armoured infantry manoeuvres in Oman in temperatures that at times exceeded 50°C. This paper presents the methods of acclimatisation, recreational physical training in the heat, and reacclimatisation training conducted in theatre during this exercise. In order to reduce the risk of heat illness, individuals underwent either validated heat acclimatisation training in accordance with current policy, or adapted training as dictated by musculoskeletal restrictions or job specification. Direction was issued regarding recreational training. There was a theatre medical consensus agreed for the practice of returning soldiers to the exercise after admission to a medical treatment facility due to the effects of heat and data were collated on all LAND (Army) acclimatisation and heat illness presentations. The rates of climatic effect were much lower than expected in the medical estimate based on Exercise SAIF SAREEA 2 and similar exercises. Only five LAND patients fulfilled the in-theatre case definition of exertional heat illness of a deployed LAND forces population at risk of 2550. Zero patients who were returned to the exercise after symptoms associated with climatic exposure were subsequently readmitted with heat illness
Cell Therapy for Liver Disease: From Promise to Reality.
No full textOver the last decade, there has been a considerable progress in the development of cell therapy products for the treatment of liver diseases. The quest to generate well-defined homogenous cell populations with defined mechanism(s) of action has enabled the progression from use of autologous bone marrow stem cells comprising of heterogeneous cell populations to allogeneic cell types such as monocyte-derived macrophages, regulatory T cells, mesenchymal stromal cells, macrophages, etc. There is growing evidence regarding the multiple molecular mechanisms pivotal to various therapeutic effects and hence, careful selection of cell therapy product for the desired putative effects is crucial. In this review, we have presented an overview of the cell therapies that have been developed thus far, with preclinical and clinical evidence for their use in liver disease. Limitations associated with these therapies have also been discussed. Despite the advances made, there remain multiple challenges to overcome before cell therapies can be considered as viable treatment options, and these include larger scale clinical trials, scalable production of cells according to good manufacturing practice standards, pathways for delivery of cell therapy within hospital environments, and costs associated with the production
Prevalence and predictors of adherence to controller therapy in adult patients with severe/difficult-to-treat asthma: a systematic review and meta-analysis.
No full textNonadherence to prescribed treatment is an important cause for poor asthma control. This systematic review aimed to determine the prevalence and determinants of nonadherence in adult patients with severe asthma. Embase and Pubmed were searched for publications in English studying adult patients and containing the keywords "severe asthma", "adherence", and "compliance". Only studies utilizing objective methods for monitoring adherence and clear definition of the level of asthma severity were included. Predominantly pediatric studies or studies of less severe asthma were excluded. The search returned 488 reports, of which 14 reports (of 2297 patients) were included. The weighted mean age of patients was 44 years and 64% were females. In studies using a cutoff of acquiring 50% or less of the medication, an overall rate of nonadherence was 42.9%. For studies reporting nonadherence of a continuous scale, the weighted mean nonadherence was 42.9% (95% CI 28.2-49.5). Meta-analysis of adherence predictors showed that male sex was associated with adherence with an odds ratio of 2.25 and higher asthma quality of life questionnaire (AQLQ) scores with a mean difference 0.47 points in adherent patients. Other predictors were reported to have significant association with adherence (e.g. older age, more knowledge about asthma, simpler medication schedules) but these were from single studies. Nonadherence to therapy is a common problem in the management of patients with severe asthma. More robust and objective methods are needed to homogenize and improve the accuracy of assessment methods. More studies are needed from developing countries. CRD42018114669
Outcomes of renal transplantation in adult patients with primary focal segmental glomerulosclerosis: a single-centre experience over 5 decades.
No full text
Comparison of microscopic and endoscopic views in cadaveric ears.
No full textPURPOSE
The advent of endoscopic otosurgery provides reduced tissue destruction with theoretically improved views, yet a quantification of the difference of exposure between microscopic and endoscopic approaches has not yet been performed in human specimens. The objective of this study was to assess the difference in views of cadaveric tympanic membranes when inspected with operating microscopes or endoscopes.
METHODS
A circular graduated disc was inserted into eight cadaveric external ear canals to rest against the tympanic membrane. Three independent observers assessed the maximum possible observable radius of the graduated disc in each ear using a 0° endoscope and a surgical microscope in superior, inferior, posterior, and anterior directions.
RESULTS
The endoscope was able to view a significantly larger mean maximum visible radius than the microscope in posterior, superior, anterior, and inferior directions. This represented a mean gain in observable distance of 19.18%. There was a smaller variation in mean maximum visible radius than the microscope.
CONCLUSION
The wider field of view in an endoscope compared to a microscope implies reduced surgical tissue damage is needed to provide sufficient operative exposure. Enhanced views of the attic were demonstrated by the endoscope, further indicating utility in cholesteatoma observation and surgery
The Delivery of Multipotent Adult Progenitor Cells to Extended Criteria Human Donor Livers Using Normothermic Machine Perfusion.
No full textPre-clinical research with multi-potent adult progenitor cells (MAPC® cells, Multistem, Athersys Inc., Cleveland, Ohio) suggests their potential as an anti-inflammatory and immunomodulatory therapy in organ transplantation. Normothermic machine perfusion of the liver (NMP-L) has been proposed as a way of introducing therapeutic agents into the donor organ. Delivery of cellular therapy to human donor livers using this technique has not yet been described in the literature. The primary objectives of this study were to develop a technique for delivering cellular therapy to human donor livers using NMP-L and demonstrate engraftment. Six discarded human livers were perfused for 6 h at 37°C using the Liver Assist (Organ Assist, Groningen). 50 × 106 CMPTX-labeled MAPC cells were infused directly into the right lobe via the hepatic artery (HA, = 3) or portal vein (PV, = 3) over 20 min at different time points during the perfusion. Perfusion parameters were recorded and central and peripheral biopsies were taken at multiple time-points from both lobes and subjected to standard histological stains and confocal microscopy. Perfusate was analyzed using a 35-plex multiplex assay and proteomic analysis. There was no detrimental effect on perfusion flow parameters on infusion of MAPC cells by either route. Three out of six livers met established criteria for organ viability. Confocal microscopy demonstrated engraftment of MAPC cells across vascular endothelium when perfused via the artery. 35-plex multiplex analysis of perfusate yielded 13 positive targets, 9 of which appeared to be related to the infusion of MAPC cells (including Interleukin's 1b, 4, 5, 6, 8, 10, MCP-1, GM-CSF, SDF-1a). Proteomic analysis revealed 295 unique proteins in the perfusate from time-points following the infusion of cellular therapy, many of which have strong links to MAPC cells and mesenchymal stem cells in the literature. Functional enrichment analysis demonstrated their immunomodulatory potential. We have demonstrated that cells can be delivered directly to the target organ, prior to host immune cell population exposure and without compromising the perfusion. Transendothelial migration occurs following arterial infusion. MAPC cells appear to secrete a host of soluble factors that would have anti-inflammatory and immunomodulatory benefits in a human model of liver transplantation
Venetoclax plus LDAC for patients with untreated AML ineligible for intensive chemotherapy: phase 3 randomized placebo-controlled trial.
No full textBACKGROUND
Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy.
METHODS
Adults ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international Phase 3 randomized, double-blind, placebo-controlled trial. Patients (N=211) were randomized 2:1 to either: venetoclax (N=143) or placebo (N=68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1-10. The primary endpoint was overall survival (OS); secondary endpoints included response rates, transfusion independence, and event-free survival.
RESULTS
Median age was 76 years (range 36-93), 38% had secondary AML, and 20% had prior hypomethylating agent (HMA) treatment. The planned primary analysis showed that the venetoclax arm provided a benefit of 25% reduction in the risk-of-death over the LDAC-alone arm (hazard ratio [HR] 0.75 [95% CI 0.52-1.07], p=0.11), although it was not statistically significant; with median OS of 7.2 months and 4.1 months, respectively. An unplanned analysis with an additional 6 months of follow up demonstrated a median OS of 8.4 months for the venetoclax arm (HR 0.70; 95% CI 0.50-0.98; p=0.04). The CR/CRi rates were 48% and 13% for the Venetoclax plus LDAC arm and LDAC-alone arm, respectively. Key grade ≥3 adverse events (Ven vs. LDAC-alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs. 16%), and thrombocytopenia (45% vs 37%).
CONCLUSION
Venetoclax plus LDAC demonstrates a clinically meaningful improvement in remission rates and OS compared to LDAC alone, in the context of a manageable safety profile. These results confirm venetoclax plus LDAC is an important frontline AML treatment option for patients unfit for intensive chemotherapy
