Cardiovascular multidisciplinary heart teams (MDHTs) have evolved significantly over the past decade. These teams play a central role in the treatment of a wide array of cardiovascular diseases ...affecting interventional cardiology, cardiac surgery, interventional imaging, advanced heart failure, adult congenital heart disease, cardio-oncology, and cardio-obstetrics. To meet the specific needs of both patients and heart programs, the composition and function of cardiovascular MDHTs have had to adapt and evolve. Although lessons have been learned from multidisciplinary cancer care, best practices for the operation of cardiovascular MDHTs have yet to be defined, and the evidence base supporting their effectiveness is limited. This expert panel review discusses the history and evolution of cardiovascular MDHTs, their composition and role in treating patients across a broad spectrum of disciplines, basic tenets for successful operation, and the future challenges facing them.
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•The MDHT team plays a central role in the treatment of a broad array of complex diseases across multiple cardiovascular medicine subspecialties.•There is no widely accepted standard on the composition and function of cardiovascular MDHTs and the processes for rendering treatment decisions.•Key principles exist for the effective operationalization of the MDHT.•MDHTs must adapt to the specific needs of the patient and changing landscape of cardiovascular therapies.•Further research is required to determine best practices for cardiovascular MDHTs and their impact on team efficiency and satisfaction and patient outcomes.
Site-specific genome editing provides a promising approach for achieving long-term, stable therapeutic gene expression. Genome editing has been successfully applied in a variety of preclinical ...models, generally focused on targeting the diseased locus itself; however, limited targeting efficiency or insufficient expression from the endogenous promoter may impede the translation of these approaches, particularly if the desired editing event does not confer a selective growth advantage. Here we report a general strategy for liver-directed protein replacement therapies that addresses these issues: zinc finger nuclease (ZFN) –mediated site-specific integration of therapeutic transgenes within the albumin gene. By using adeno-associated viral (AAV) vector delivery in vivo, we achieved long-term expression of human factors VIII and IX (hFVIII and hFIX) in mouse models of hemophilia A and B at therapeutic levels. By using the same targeting reagents in wild-type mice, lysosomal enzymes were expressed that are deficient in Fabry and Gaucher diseases and in Hurler and Hunter syndromes. The establishment of a universal nuclease-based platform for secreted protein production would represent a critical advance in the development of safe, permanent, and functional cures for diverse genetic and nongenetic diseases.
•AAV- and ZFN-mediated targeting of the albumin locus corrects disease phenotype in mouse models of hemophilia A and B.•Robust expression from the albumin locus provides a versatile platform for liver-directed protein replacement therapy.
Nonhomologous end-joining (NHEJ) is the primary DNA repair pathway thought to underlie chromosomal translocations and other genomic rearrangements in somatic cells. The canonical NHEJ pathway, ...including DNA ligase IV (Lig4), suppresses genomic instability and chromosomal translocations, leading to the notion that a poorly defined, alternative NHEJ (alt-NHEJ) pathway generates these rearrangements. Here, we investigate the DNA ligase requirement of chromosomal translocation formation in mouse cells. Mammals have two other DNA ligases, Lig1 and Lig3, in addition to Lig4. As deletion of Lig3 results in cellular lethality due to its requirement in mitochondria, we used recently developed cell lines deficient in nuclear Lig3 but rescued for mitochondrial DNA ligase activity. Further, zinc finger endonucleases were used to generate DNA breaks at endogenous loci to induce translocations. Unlike with Lig4 deficiency, which causes an increase in translocation frequency, translocations are reduced in frequency in the absence of Lig3. Residual translocations in Lig3-deficient cells do not show a bias toward use of pre-existing microhomology at the breakpoint junctions, unlike either wild-type or Lig4-deficient cells, consistent with the notion that alt-NHEJ is impaired with Lig3 loss. By contrast, Lig1 depletion in otherwise wild-type cells does not reduce translocations or affect microhomology use. However, translocations are further reduced in Lig3-deficient cells upon Lig1 knockdown, suggesting the existence of two alt-NHEJ pathways, one that is biased toward microhomology use and requires Lig3 and a back-up pathway which does not depend on microhomology and utilizes Lig1.
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a ...CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
Coolia
is a widespread and ecologically important genus of benthic marine dinoflagellates found in tropical regions. Historically, there has been taxonomic confusion about the taxonomy and toxicity ...of this group. The goal of this study was to resolve morphological questions concerning
Coolia tropicalis
and determine the taxonomic identity of the Australian
Coolia
isolate which has been reported to produce cooliatoxins. To accomplish this, the morphology of tropical strains from Belize (the type locality of
C. tropicalis
), Malaysia, Indonesia, and Australia were examined and compared to published reports. The morphological analysis showed that
C. tropicalis
differs from the original description in that it has a slightly larger size (35–47 μm long by 30–45 μm wide versus 23–40 μm long by 25–39 μm wide), and the shape of fourth apical plate, and the length of Po plate (7.4–12 μm versus 7 μm). Based on both morphology and phylogenetic analysis using LSU D1‐ D3
rDNA
sequences, the clones of
C. tropicalis
from Malaysia, Indonesia, and Belize were found to form a monophyletic clade within the genus. The strain producing cooliatoxin was found to be
C. tropicalis
, not
Coolia monotis
as originally assumed. To explore the factors influencing the growth of
Coolia
species, the growth rates of
C. tropicalis
and
Coolia malayensis
were determined at different temperatures and salinities. Both species tolerated a wide range of temperatures, but cannot survive at temperatures <20°C or >35°C.
C. monotis
, the dominant species reported in the literature, probably does not produce toxins.
High-speed rotational atherectomy (RA) is a new percutaneous procedure for treatment of coronary stenoses that operates by the unique mechanism of plaque abrasion. This article reports acute ...(in-hospital) outcomes and 1-year follow-up in a large cohort of patients treated with this device by NACI investigators. A total of 525 patients with 670 lesions treated with RA form the substrate of this report. Patients tended to be older (mean age 64.8 years) than those in previously reported series of percutaneous transluminal coronary angioplasty (PTCA), with more extensive disease and more complex lesions. Calcification was present in 54% of lesions, and eccentricity in 41%. Balloon angioplasty postdilation was performed after RA in 88% of cases. Angiographic and procedural success (angiographic success without death, Q-wave myocardial infarction MI or emergency coronary artery bypass graft CABG surgery) rates were 89% and 88%, respectively. Acute in-hospital events included 4 deaths (1%) and 1 emergency CABG surgery (0.4%). MI occurred in 6% of patients, consisting predominantly of non–Q-wave MI (5%). After RA, angiographic complications included coronary dissection (12%), abrupt closure (5%), side branch occlusion (3%), and distal embolization (3%). Most of these were resolved after postdilation except for coronary dissection, which was present in 15% of lesions treated. Mean length of stay was 3 days. At 1-year follow-up, 27% of patients required target lesion revascularization and 30% had experienced death, Q-wave MI, or target lesion revascularization. Preprocedural characteristics that independently predicted 1-year death, Q-wave MI, or target lesion revascularization were male gender, high risk for surgery, target lesions that were proximal to or in bifurcations, eccentric, long, or highly stenosed. RA, even when applied to lesions of traditionally unfavorable morphology, appears to provide reasonable procedural and angiographic success rates. Restenosis and progression of disease contribute to subsequent clinical and procedural events.
The American College of Cardiology Foundation (ACCF), Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, and the American Association for Thoracic Surgery, along ...with key specialty and subspecialty societies, conducted an appropriateness review of common clinical scenarios in which coronary revascularization is frequently considered. The clinical scenarios were developed to mimic common situations encountered in everyday practice and included information on symptom status, extent of medical therapy, risk level as assessed by noninvasive testing, and coronary anatomy. Approximately 180 clinical scenarios were developed by a writing committee and scored by a separate technical panel on a scale of 1 to 9. Scores of 7 to 9 indicate that revascularization was considered appropriate and likely to improve health outcomes or survival. Scores of 1 to 3 indicate revascularization was considered inappropriate and unlikely to improve health outcomes or survival. The mid range (4 to 6) indicates a clinical scenario for which the likelihood that coronary revascularization would improve health outcomes or survival was considered uncertain. For the majority of the clinical scenarios, the panel only considered the appropriateness of revascularization irrespective of whether this was accomplished by percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). In a select subgroup of clinical scenarios in which revascularization is generally considered appropriate, the appropriateness of PCI and CABG individually as the primary mode of revascularization was considered. In general, the use of coronary revascularization for patients with acute coronary syndromes and combinations of significant symptoms and/or ischemia was viewed favorably. In contrast, revascularization of asymptomatic patients or patients with low-risk findings on noninvasive testing and minimal medical therapy were viewed less favorably. It is anticipated that these results will have an impact on physician decision making and patient education regarding expected benefits from revascularization and will help guide future research.
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