Relief of branch pulmonary artery stenosis reduces pulmonary valve insufficiency in a swine model

ObjectiveWe sought to determine the impact of relieving branch pulmonary artery stenosis on pulmonary valve insufficiency and right ventricular function. Long-standing pulmonary insufficiency causes progressive right ventricular dilatation, leading to decreased right ventricular function. Adults with pulmonary insufficiency are at risk of decreased exercise tolerance, arrhythmias, and sudden cardiac death. Branch pulmonary artery stenosis frequently occurs in these patients, and the presence of branch stenosis may exacerbate valve insufficiency.MethodsNeonatal piglets (n = 7) underwent surgery to create pulmonary insufficiency and left pulmonary artery stenosis. At 3 months of age, the animals underwent baseline cardiac magnetic resonance imaging followed by stenting of the left pulmonary artery. A repeat magnetic resonance imaging scan was performed 1 week after intervention. Magnetic resonance imaging evaluation included (1) velocity mapping to assess the forward and reverse flow at the main, left and right pulmonary arteries, and aorta; and (2) volumetric assessment of the right ventricle.ResultsLeft pulmonary artery flow increased from 14.5% to 36.3% of total net flow after stenting (P < .01). Pulmonary regurgitation decreased from 38.7% to 27.4% (P < .02). Right ventricular ejection fraction improved from a median of 53.5% to 58.2% after stenting (P < .01). Cardiac index improved from a median of 2.7 to 3.5 L/min/m2 (P = .01).ConclusionRelief of branch pulmonary artery stenosis reduces insufficiency and improves right ventricular systolic function in this animal model. This supports the practice of aggressive intervention in patients with branch pulmonary artery stenosis and pulmonary insufficiency

Clinical Perspectives in Integrating Whole Genome Sequencing into the Investigation of Healthcare and Public Health Outbreaks - Hype or Help?

Bioinformatics and Computational Biology analyses were supported by the University of St Andrews Bioinformatics Unit which is funded by a Wellcome Trust ISSF award [grant 097831/Z/11/Z]. The SHAIPI consortium is funded by the Chief Scientist Office through the Scottish Infection Research Network (SIRN10).Outbreaks pose a significant patient safety risk as well as being costly and time consuming to investigate. The implementation of targeted infection prevention and control (IPC) measures relies on infection prevention and control teams (IPCTs) having access to rapid results that accurately detect resistance, and typing results that give clinically useful information on the relatedness of isolates. At present, determining whether transmission has occurred can be a major challenge. Conventional typing results do not always have sufficient granularity or robustness to unequivocally define strains, and sufficient epidemiological data to establish links between patients and the environment is not always available. Whole genome sequencing (WGS) has emerged as the ultimate genotyping tool, but has not yet fully crossed the divide between research method and routine clinical diagnostic microbiology technique. A clinical WGS service was officially established in 2014 as part of the Scottish Healthcare Associated Infection Prevention Institute (SHAIPI) to confirm or refute outbreaks in hospital settings from across Scotland. In this personal view we describe our experiences that we believe provide new insights into the practical application of the use of WGS to investigate healthcare and public health outbreaks. We also propose solutions to overcome barriers to implementation of this technology in a clinical environment.Publisher PDFPeer reviewe

Drp2 and Periaxin Form Cajal Bands with Dystroglycan But Have Distinct Roles in Schwann Cell Growth

Cajal bands are cytoplasmic channels flanked by appositions where the abaxonal surface of Schwann cell myelin apposes and adheres to the overlying plasma membrane. These appositions contain a dystroglycan complex that includes periaxin and dystrophin-related protein 2 (Drp2). Loss of periaxin disrupts appositions and Cajal bands in Schwann cells and causes a severe demyelinating neuropathy in mouse and man. Here we have investigated the role of mouse Drp2 in apposition assembly and Cajal band function and compared it to periaxin. We show that Periaxin and Drp2 are not only both required to form appositions, but they must also interact. Periaxin-Drp2 interaction is also required for Drp2 phosphorylation but phosphorylation is not required for the assembly of appositions. Drp2 loss causes corresponding increases in Dystrophin family members, utrophin and dystrophin Dp116 though dystroglycan remains unchanged. We also show that all dystroglycan complexes in Schwann cells utilise the uncleaved form of β-dystroglycan. Drp2-null Schwann cells have disrupted appositions and Cajal bands, and they undergoe focal hypermyelination and concomitant demyelination. Nevertheless, they do not have the short internodal lengths and associated reduced nerve conduction velocity seen in the absence of periaxin, showing that periaxin regulates Schwann cell elongation independent of its role in the dystroglycan complex. We conclude that the primary role of the dystroglycan complex in appositions is to stabilize and limit the radial growth of myelin

Percutaneous Transvenous Melody Valve-in-Ring Procedure for Mitral Valve Replacement

ObjectivesThe purpose of this study was to demonstrate the feasibility of percutaneous transvenous mitral valve-in-ring (VIR) implantation using the Melody valve in an ovine model.BackgroundThe recurrence of mitral regurgitation following surgical mitral valve (MV) repair in both adult and pediatric patients remains a significant clinical problem. Mitral annuloplasty rings are commonly used in MV repair procedures and may serve as secure landing zones for percutaneous valves.MethodsFive sheep underwent surgical MV annuloplasty (24 mm, n = 2; 26 mm, n = 2; 28 mm, n = 1). Animals underwent cardiac catheterization with VIR implantation via a transfemoral venous, transatrial septal approach 1 week following surgery. Hemodynamic, angiographic, and echocardiographic data were recorded before and after VIR.ResultsVIR was technically successful and required <1 h of procedure time in all animals. Fluoroscopy demonstrated securely positioned Melody valves within the annuloplasty ring in all animals. Angiography revealed no significant MV regurgitation in 4 and moderate central MV regurgitation in the animal with the 28-mm annuloplasty. All animals demonstrated vigorous left ventricular function, no outflow tract obstruction, and no aortic valve insufficiency.ConclusionsThis study demonstrated the feasibility of a purely percutaneous approach to MV replacement in patients with preexisting annuloplasty rings. This novel approach may be of particular benefit to patients with failed repair of ischemic mitral regurgitation and in pediatric patients with complex structural heart disease

Variable Step Random Walks and Self-Similar Distributions

We study a scenario under which variable step random walks give anomalous statistics. We begin by analyzing the Martingale Central Limit Theorem to find a sufficient condition for the limit distribution to be non-Gaussian. We note that the theorem implies that the scaling index $\zeta$ is 1/2. For corresponding continuous time processes, it is shown that the probability density function $W(x;t)$ satisfies the Fokker-Planck equation. Possible forms for the diffusion coefficient are given, and related to $W(x,t)$. Finally, we show how a time-series can be used to distinguish between these variable diffusion processes and L\'evy dynamics.Comment: 13pages, 2 figure

Multimodal image analysis and subvalvular dynamics in ischemic mitral regurgitation

Background: The exact geometric pathogenesis of leaflet tethering in ischemic mitral regurgitation (IMR) and the relative contribution of each component of the mitral valve complex (MVC) remain largely unknown. In this study, we sought to further elucidate mitral valve (MV) leaflet remodeling and papillary muscle dynamics in an ovine model of IMR with magnetic resonance imaging (MRI) and 3-dimensional echocardiography (3DE). Methods: Multimodal imaging combining 3DE and MRI was used to analyze the MVC at baseline, 30 minutes post–myocardial infarction (MI), and 12 weeks post-MI in ovine IMR models. Advanced 3D imaging software was used to trace the MVC from each modality, and the tracings were verified against resected specimens. Results: 3DE MV remodeling was regionally heterogenous and observed primarily in the anterior leaflet, with significant increases in surface area, especially in A2 and A3. The posterior leaflet was significantly shortened in P2 and P3. Mean posteromedial papillary muscle (PMPM) volume was decreased from 1.9 ± 0.2 cm3 at baseline to 0.9 ± 0.3 cm3 at 12 weeks post-MI (P <.05). At 12 weeks post-MI, the PMPM was predominately displaced horizontally and outward along the intercommissural axis with minor apical displacement. The subvalvular contribution to tethering is a combination of unilateral movement, outward displacement, and degeneration of the PMPM. These findings have led to a proposed new framework for characterizing PMPM dynamics in IMR. Conclusions: This study provides new insights into the complex interrelated and regionally heterogenous valvular and subvalvular mechanisms involved in the geometric pathogenesis of IMR tethering

Consideration of within-patient diversity highlights transmission pathways and antimicrobial resistance gene variability in vancomycin-resistant Enterococcus faecium

BackgroundWGS is increasingly being applied to healthcare-associated vancomycin-resistant Enterococcus faecium (VREfm) outbreaks. Within-patient diversity could complicate transmission resolution if single colonies are sequenced from identified cases.ObjectivesDetermine the impact of within-patient diversity on transmission resolution of VREfm.Materials and methodsFourteen colonies were collected from VREfm positive rectal screens, single colonies were collected from clinical samples and Illumina WGS was performed. Two isolates were selected for Oxford Nanopore sequencing and hybrid genome assembly to generate lineage-specific reference genomes. Mapping to closely related references was used to identify genetic variations and closely related genomes. A transmission network was inferred for the entire genome set using Phyloscanner.Results and discussionIn total, 229 isolates from 11 patients were sequenced. Carriage of two or three sequence types was detected in 27% of patients. Presence of antimicrobial resistance genes and plasmids was variable within genomes from the same patient and sequence type. We identified two dominant sequence types (ST80 and ST1424), with two putative transmission clusters of two patients within ST80, and a single cluster of six patients within ST1424. We found transmission resolution was impaired using fewer than 14 colonies.ConclusionsPatients can carry multiple sequence types of VREfm, and even within related lineages the presence of mobile genetic elements and antimicrobial resistance genes can vary. VREfm within-patient diversity could be considered in future to aid accurate resolution of transmission networks

Left atrial geometry in an ovine ischemic mitral regurgitation model:implications for transcatheter mitral valve replacement devices with a left atrial anchoring mechanism

Abstract Background Transcatheter mitral valve replacement (TMVR) is a challenging, but promising minimally invasive treatment option for patients with mitral valve disease. Depending on the anchoring mechanism, complications such as mitral leaflet or chordal disruption, aortic valve disruption or left ventricular outflow tract obstruction may occur. Supra-annular devices only anchor at the left atrial (LA) level with a low risk of these complications. For development of transcatheter valves based on LA anchoring, animal feasibility studies are required. In this study we sought to describe LA systolic and diastolic geometry in an ovine ischemic mitral regurgitation (IMR) model using magnetic resonance imaging (MRI) and echocardiography in order to facilitate future research focusing on TMVR device development for (I)MR with LA anchoring mechanisms. Methods A group of 10 adult male Dorsett sheep underwent a left lateral thoracotomy. Posterolateral myocardial infarction was created by ligation of the left circumflex coronary artery, the obtuse marginal and diagonal branches. MRI and echocardiography were performed at baseline and 8 weeks after myocardial infarction (MI). Results Six animals survived to 8 weeks follow-up. All animals had grade 2 + or higher IMR 8 weeks post-MI. All LA geometric parameters did not change significantly 8 weeks post-MI compared to baseline. Diastolic and systolic interpapillary muscle distance increased significantly 8 weeks post-MI. Conclusions Systolic and diastolic LA geometry do not change significantly in the presence of grade 2 + or higher IMR 8 weeks post-MI. These findings help facilitate future tailored TMVR device development with LA anchoring mechanisms