scholarly journals Rationale and Design of the Lead EvaluAtion for Defibrillation and Reliability (LEADR) Study: Safety and Efficacy of a Novel ICD Lead Design

2021 ◽  
Author(s):  
George Crossley ◽  
Prashanthan Sanders ◽  
Paolo De Filippo ◽  
Khaldoun Tarakji ◽  
Bert Hansky ◽  
...  
Keyword(s):  
Clinical Study ◽  
Adaptive Design ◽  
De Novo ◽  
Small Diameter ◽  
Virtual Patient ◽  
Implantable Cardioverter Defibrillators ◽  
Safety And Efficacy ◽  
Icd Leads

Background: Implantable cardioverter defibrillators (ICD) are indicated for primary and secondary prevention of sudden cardiac arrest. Despite enhancements in design and technologies, the ICD lead is the most vulnerable component of the ICD system and failure of ICD leads remains a significant clinical problem. A novel, small diameter, lumenless, catheter delivered, defibrillator lead was developed with the aim to improve long term reliability. Methods and Results: The Lead Evaluation for Defibrillation and Reliability (LEADR) study is a multi-center, single-arm, Bayesian, adaptive design, pre-market interventional pivotal clinical study. Up to 60 study sites from around the world will participate in the study. Patients indicated for a de novo ICD will undergo defibrillation testing at implantation and clinical assessments at baseline, implant, pre-hospital discharge, 3 months, 6 months, and every 6 months thereafter until official study closure. Patients will participate for a minimum of 18 months to approximately 3 years. Fracture-free survival will be evaluated using a Bayesian statistical method that incorporates both virtual patient data (combination of bench testing to failure with in-vivo use condition data) with clinical patients. The clinical subject sample size will be determined using decision rules for number of subject enrollments and follow-up time based upon the observed number of fractures at certain time points in the study. The adaptive study design will therefore result in a minimum of 500 and a maximum of 900 patients enrolled. Conclusion: The LEADR Clinical Study was designed to efficiently provide evidence for short- and long-term safety and efficacy of a novel lead design using Bayesian methods including a novel virtual patient approach.

scholarly journals Vectored Immunotherapeutics for Infectious Diseases: Can rAAVs Be The Game Changers for Fighting Transmissible Pathogens?

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Zhan ◽  
Manish Muhuri ◽  
Phillip W. L. Tai ◽  
Guangping Gao
Keyword(s):  
Infectious Diseases ◽  
Neutralizing Antibodies ◽  
Viral Vectors ◽  
De Novo ◽  
Genomic Variation ◽  
Transduction Efficiency ◽  
Foreign Proteins ◽  
Repeated Dosing

Conventional vaccinations and immunotherapies have encountered major roadblocks in preventing infectious diseases like HIV, influenza, and malaria. These challenges are due to the high genomic variation and immunomodulatory mechanisms inherent to these diseases. Passive transfer of broadly neutralizing antibodies may offer partial protection, but these treatments require repeated dosing. Some recombinant viral vectors, such as those based on lentiviruses and adeno-associated viruses (AAVs), can confer long-term transgene expression in the host after a single dose. Particularly, recombinant (r)AAVs have emerged as favorable vectors, given their high in vivo transduction efficiency, proven clinical efficacy, and low immunogenicity profiles. Hence, rAAVs are being explored to deliver recombinant antibodies to confer immunity against infections or to diminish the severity of disease. When used as a vaccination vector for the delivery of antigens, rAAVs enable de novo synthesis of foreign proteins with the conformation and topology that resemble those of natural pathogens. However, technical hurdles like pre-existing immunity to the rAAV capsid and production of anti-drug antibodies can reduce the efficacy of rAAV-vectored immunotherapies. This review summarizes rAAV-based prophylactic and therapeutic strategies developed against infectious diseases that are currently being tested in pre-clinical and clinical studies. Technical challenges and potential solutions will also be discussed.

scholarly journals In Vivo Distribution of Poly(ethylene glycol) Functionalized Iron Oxide Nanoclusters: An Ultrastructural Study

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2184
Author(s):  
Maria Suciu ◽  
Claudiu Mirescu ◽  
Izabell Crăciunescu ◽  
Sergiu Gabriel Macavei ◽  
Cristian Leoștean ◽  
...  
Keyword(s):  
Iron Oxide ◽  
De Novo ◽  
Superparamagnetic Iron Oxide ◽  
In Vivo Distribution ◽  
Transmission Electron ◽  
Blood And Urine Samples ◽  
Poly Ethylene ◽  
Exposure Evaluation

The in vivo distribution of 50 nm clusters of polyethylene glycol-conjugated superparamagnetic iron oxide nanoparticles (SPIONs-PEG) was conducted in this study. SPIONs-PEG were synthesized de novo, and their structure and paramagnetic behaviors were analyzed by specific methods (TEM, DLS, XRD, VSM). Wistar rats were treated with 10 mg Fe/kg body weight SPIONs-PEG and their organs and blood were examined at two intervals for short-term (15, 30, 60, 180 min) and long-term (6, 12, 24 h) exposure evaluation. Most exposed organs were investigated through light and transmission electron microscopy, and blood and urine samples were examined through fluorescence spectrophotometry. SPIONs-PEG clusters entered the bloodstream after intraperitoneal and intravenous administrations and ended up in the urine, with the highest clearance at 12 h. The skin and spleen were within normal histological parameters, while the liver, kidney, brain, and lungs showed signs of transient local anoxia or other transient pathological affections. This study shows that once internalized, the synthesized SPIONs-PEG disperse well through the bloodstream with minor to nil induced tissue damage, are biocompatible, have good clearance, and are suited for biomedical applications.

scholarly journals Paradoxical interaction between cancer and long-term postsepsis disorder: impairment of de novo carcinogenesis versus favoring the growth of established tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000129
Author(s):  
Caio Abner Leite ◽  
Jose Mauricio Mota ◽  
Kalil Alves de Lima ◽  
Carlos Wagner Wanderley ◽  
Leticia Almeida Nascimento ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Regulatory Cells ◽  
De Novo ◽  
Tumor Development ◽  
Dependent Manner ◽  
Colorectal Cancer Cells ◽  
Tumor Load ◽  
Early Carcinogenesis

BackgroundPrevious data have reported that the growth of established tumors may be facilitated by postsepsis disorder through changes in the microenvironment and immune dysfunction. However, the influence of postsepsis disorder in initial carcinogenesis remains elusive.MethodsIn the present work, the effect of postsepsis on inflammation-induced early carcinogenesis was evaluated in an experimental model of colitis-associated colorectal cancer (CAC). We also analyzed the frequency and role of intestinal T regulatory cells (Treg) in CAC carcinogenesis.ResultsThe colitis grade and the tumor development rate were evaluated postmortem or in vivo through serial colonoscopies. Sepsis-surviving mice (SSM) presented with a lower colonic DNA damage, polyp incidence, reduced tumor load, and milder colitis than their sham-operated counterparts. Ablating Treg led to restoration of the ability to develop colitis and tumor polyps in the SSM, in a similar fashion to that in the sham-operated mice. On the other hand, the growth of subcutaneously inoculated MC38luc colorectal cancer cells or previously established chemical CAC tumors was increased in SSM.ConclusionOur results provide evidence that postsepsis disorder has a dual effect in cancer development, inhibiting inflammation-induced early carcinogenesis in a Treg-dependent manner, while increasing the growth of previously established tumors.

scholarly journals Active Surveillance of the Implantable Cardioverter-Defibrillator Registry for Defibrillator Lead Failures

2020 ◽  
Vol 13 (4) ◽  
Author(s):  
Frederic S. Resnic ◽  
Arjun Majithia ◽  
Sanket S. Dhruva ◽  
Henry Ssemaganda ◽  
Susan Robbins ◽  
...  
Keyword(s):  
Active Surveillance ◽  
Failure Rate ◽  
High Energy ◽  
Implantable Cardioverter Defibrillators ◽  
Lead Failure ◽  
Data Registry ◽  
Icd Leads ◽  
First Time ◽  
Cardioverter Defibrillators

Background: Several defibrillator leads have been recalled due to early lead failure leading to significant patient harm. Confirming the safety of contemporary defibrillator leads is essential to optimizing treatment for patients receiving implantable cardioverter-defibrillators (ICDs). We therefore sought to assess the comparative long-term safety of the 4 most commonly implanted ICD leads within the National Cardiovascular Data Registry ICD Registry. Methods and Results: A propensity-matched survival analysis of the ICD Registry was performed evaluating 4 contemporary ICD leads in patients receiving an ICD system for the first time. All patients in the ICD Registry aged ≥18 years who underwent an implant of an ICD between April 1, 2011 and March 31, 2016 were included. Monitoring of safety began with ICD implant and continued up to 5 years. A meaningful difference in ICD failure rate was defined as twice (or more) the lead failure rate observed in the propensity-matched comparator patients. Among the 374 132 patients who received a new ICD implant, no safety alerts were triggered for the primary safety end point of lead failure for any of the high energy leads studied. Estimated rates of freedom from lead failure at 5 years ranged from 97.7% to 98.9% for the 4 high-energy leads of interest. Conclusions: Though limited by incomplete long-term outcomes ascertainment, active surveillance of the ICD Registry suggests that there were no meaningful differences in the rate of ICD high-energy lead survival for the 4 most commonly used high-energy ICD leads.

scholarly journals BIODEGRADABLE VASCULAR GRAFT REINFORCED WITH A BIODEGRADABLE SHEATH

2019 ◽  
Vol 8 (2) ◽  
pp. 87-97
Author(s):  
L. V. Antonova ◽  
E. O. Krivkina ◽  
M. A. Rezvova ◽  
V. V. Sevost'yanova ◽  
A. V. Mironov ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Growth Factor ◽  
Carotid Artery ◽  
Vascular Grafts ◽  
Small Diameter ◽  
Fold Increase ◽  
Layer By Layer ◽  
Layer Coating

Background. Tissue-engineered vascular grafts can be reinforced by a biostable or biodegradable polymer sheath. A combination of electrospinning, routinely used for fabrication of biodegradable tubular grafts, and the layer-by-layer coating allows forming a polymeric sheath ensuring long-term integrity and high biocompatibility of the vascular grafts after the implantation. Aim To evaluate mechanical properties and in vivo performance of biodegradable small-diameter vascular grafts with a reinforcing sheath.Methods. Tubular grafts (4 mm diameter) were fabricated from poly(3-hydroxybutyrate-co3-hydroxyvalerate) and poly(ε-caprolactone) by emulsion electrospinning with the incorporation of vascular endothelial growth factor (VEGF) into the inner third of the graft and basic fibroblast growth factor (bFGF) along with stromal cell-derived factor-1α (SDF-1α) into the outer two thirds of the graft wall. Poly(ε-caprolactone) sheath was formed by the layer-by-layer coating. Upon graft fabrication, scanning electron microscopy was performed to assess the grafts’ surface, tensile testing allowed evaluating mechanical properties. The samples were implanted into the ovine carotid artery (n = 5 animals) for 12 months with the subsequent histological examination.Results. Sintering temperature of 160°C during the extrusion allowed effective and delicate merging of poly(ε-caprolactone) coating with the outer surface of the poly(3hydroxybutyrate-co-3-hydroxyvalerate)/poly(ε-caprolactone) tubular graft. The thickness of poly(ε-caprolactone) fiber was 380–400 μm, the increment of the reinforcing filament was 1 mm. The reinforcing sheath led to a 3-fold increase in durability and elastic modulus of the vascular grafts. At the 12-months follow-up, the grafts reported retained integrity. No signs of inflammation or calcification were found.Conclusion. The poly(3-hydroxybutyrate-co-3-hydroxyvalerate) and poly(ε-caprolactone) vascular grafts with hierarchically incorporated growth factors and the reinforced poly(ε-caprolactone) spiral sheath demonstrated improved mechanical properties while retaining integrity and high biocompatibility after the long-term implantation into the ovine carotid artery.

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