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Transdermal delivery of glyceryl trinitrate: clinical applications in acute stroke.
No full text: Glyceryl trinitrate (GTN), a nitric oxide donor, is a candidate treatment for the management of acute stroke with hemodynamic and potential reperfusion and neuroprotective effects.: Here we discuss the evidence to date from clinical trials and present and future possibilities for the clinical application of transdermal GTN in acute stroke. When administered as a transdermal patch during the acute and subacute phases after stroke, GTN was safe, lowered blood pressure, maintained cerebral blood flow, and did not induce cerebral steal or alter functional outcome. However, when given within the hyperacute phase (<6 h of stroke onset), GTN reduced death and dependency, death, disability, cognitive impairment, and mood disturbance, and improved quality of life. However, in a large prehospital trial with treatment within 4 h, GTN did not influence clinical outcomes.: Transdermal GTN is an easy to administer BP-lowering therapy, which is safe when given after 2 h of stroke onset, may improve outcome when initiated within 2-6 h, but should be avoided (outside of a clinical trial) in the ultra-acute period within 2 h of stroke onset. Further research needs to investigate the mechanisms of benefit or harm in ultra/hyperacute stroke patients
Chest wall resection and reconstruction for recurrent breast cancer – A multidisciplinary approach
No full textCorrigendum to "Lipoprotein apheresis efficacy, challenges and outcomes: A descriptive analysis from the UK Lipoprotein Apheresis Registry, 1989-2017" [Atherosclerosis 290 (November 2019) 44-51].
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Anticoagulant strategies for the patient with chronic kidney disease.
No full textChronic kidney disease (CKD) is a global health problem affecting up to 14% of the adult population in developed countries. On the basis of current guidelines, patients with CKD will often fulfil criteria for both short-term and long-term anticoagulation. Paradoxically, patients with CKD are not only at a higher risk of thrombosis, they are also at increased risk of bleeding. Furthermore, the pharmacokinetics and pharmacodynamics of many anticoagulant therapies are significantly affected by renal dysfunction. In addition, patients with advanced CKD are often systematically excluded from major clinical trials. As such, the decision on whether to anticoagulate or not, and if so with what agent, poses significant challenges. A solid understanding of the condition in question and the available treatments is required to make an informed judgement call. An in-depth appreciation of the advantages and disadvantages of the currently available anticoagulants is a key element in the decision-making process
Comments on "Anastomotic Techniques and Associated Morbidity in Total Minimally Invasive Transthoracic Esophagectomy: Results from the EsoBenchmark Database".
No full textMechanical Circulatory Support in Cardiogenic Shock: A Patient- Versus Device-Directed Approach.
No full textNew Developments in Transcriptomic Analysis of Synovial Tissue.
No full textTranscriptomic technologies are constantly changing and improving, resulting in an ever increasing understanding of gene expression in health and disease. These technologies have been used to investigate the pathological changes occurring in the joints of rheumatoid arthritis patients, leading to discoveries of disease mechanisms, and novel potential therapeutic targets. Microarrays were initially used on both whole tissue and cell subsets to investigate research questions, with bulk RNA sequencing allowing for further elaboration of these findings. A key example is the classification of pathotypes in rheumatoid arthritis using RNA sequencing that had previously been discovered using microarray and histology. Single-cell sequencing has now delivered a step change in understanding of the diversity and function of subpopulations of cells, in particular synovial fibroblasts. Future technologies, such as high resolution spatial transcriptomics, will enable step changes integrating single cell transcriptomic and geographic data to provide an integrated understanding of synovial pathology
Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A.
No full textBACKGROUND
Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ.
METHODS
We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years.
RESULTS
Three years after infusion, two participants (one who had received 6×10 vector genomes [vg] per kilogram of body weight and one who had received 2×10 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed.
CONCLUSIONS
Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 vg per kilogram or 6×10 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.)
