Five-year outcome in 18 010 patients from the German Aortic Valve Registry

OBJECTIVES: To determine the 5-year outcome in patients treated by isolated transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (sAVR)—a prospective observational cohort study. METHODS: A total of 18 010 patients were included (n = 8942 TAVI and n = 9068 sAVR) in the German Aortic Valve Registry (GARY) who were treated in 2011 and 2012 at 92 sites in central Germany. Eligible patients with TAVI and sAVR were matched using propensity scores in a nearest-neighbour approach. Patients with repeat procedures or unequivocal indication for one treatment option (e.g. frailty) were excluded (n = 4785 for TAVI and n = 2 for sAVR). This led to 13 223 patients (4157 TAVI and 9066 sAVR) as an unmatched subcohort. The main outcome measure was the 5-year all-cause mortality. RESULTS: TAVI patients were significantly older (80.9 ± 6.1 vs 68.5 ± 11.1 years, P < 0.001), had a higher Society of Thoracic Surgeons (STS) score (6.3 ± 4.9 vs 2.6 ± 3.0, P < 0.001) and a higher 5-year all-cause mortality (49.8% vs 16.5%, P < 0.0001). There was no major difference in in-hospital stroke, in-hospital myocardial infarction, or temporary and chronic dialysis. In the propensity score-matched group (n = 3640), there were 763 deaths (41.9%) among 1820 TAVI patients compared with 552 (30.3%) among 1820 treated with sAVR during the 5-year follow-up (hazard ratio 1.51, 95% confidence interval 1.35–1.68; P < 0.0001). New pacemaker implantation was performed in 448 patients (24.6%) after TAVI and in 201 (11.0%) after sAVR (P < 0.0001). CONCLUSIONS: The 5-year follow-up data show that TAVI patients were significantly older and had a higher STS score than sAVR patients. After propensity score matching, TAVI with early-generation prosthesis was associated with significantly higher 5-year all-cause mortality than sAVR

Targeted gene delivery in tumor xenografts by the combination of ultrasound-targeted microbubble destruction and polyethylenimine to inhibit survivin gene expression and induce apoptosis

<p>Abstract</p> <p>Background</p> <p>Noninvasive and tissue-specific technologies of gene transfection would be valuable in clinical gene therapy. This present study was designed to determine whether it could enhance gene transfection <it>in vivo </it>by the combination of ultrasound-targeted microbubble destruction (UTMD) with polyethylenimine (PEI) in tumor xenografts, and illuminate the effects of gene silencing and apoptosis induction with short hairpin RNA (shRNA) interference therapy targeting human survivin by this novel technique.</p> <p>Methods</p> <p>Two different expression vectors (pCMV-LUC and pSIREN) were incubated with PEI to prepare cationic complexes (PEI/DNA) and confirmed by the gel retardation assay. Human cervical carcinoma (Hela) tumors were planted subcutaneously in both flanks of nude mice. Tumor-bearing mice were administered by tail vein with PBS, plasmid, plasmid and SonoVue microbubble, PEI/DNA and SonoVue microbubble. One tumor was exposed to ultrasound irradiation, while the other served as control. The feasibility of targeted delivery and tissue specificity facilitated by UTMD and PEI were investigated. Moreover, immunohistochemistry analyses about gene silencing and apoptosis induction were detected.</p> <p>Results</p> <p>Electrophoresis experiment revealed that PEI could condense DNA efficiently. The application of UTMD significantly increases the tissue transfection. Both expression vectors showed that gene expressions were present in all sections of tumors that received ultrasound exposure but not in control tumors. More importantly, the increases in transgene expression were related to UTMD with the presence of PEI significantly. Silencing of the survivin gene could induce apoptosis effectively by downregulating survivin and bcl-2 expression, also cause up-regulation of bax and caspase-3 expression.</p> <p>Conclusions</p> <p>This noninvasive, novel combination of UTMD with PEI could enhance targeted gene delivery and gene expression in tumor xenografts at intravenous administration effectively without causing any apparently adverse effect, and might be a promising candidate for gene therapy. Silencing of survivin gene expression with shRNA could be facilitated by this non-viral technique, and lead to significant cell apoptosis.</p

Transcatheter aortic valve implantation in failed bioprosthetic surgical valves.

IMPORTANCE: Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE: To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS: Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (&gt;21 and &lt;25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES: Survival, stroke, and New York Heart Association functional class. RESULTS: Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE: In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis

Head to head comparisons of two modalities of perfusion adenosine stress echocardiography with simultaneous SPECT

<p>Abstract</p> <p>Background</p> <p>Real-time perfusion (RTP) contrast echocardiography can be used during adenosine stress echocardiography (ASE) to evaluate myocardial ischemia. We compared two different types of RTP power modulation techniques, angiomode (AM) and high-resolution grayscale (HR), with ^99mTc-tetrofosmin single-photon emission computed tomography (SPECT) for the detection of myocardial ischemia.</p> <p>Methods</p> <p>Patients with known or suspected coronary artery disease (CAD), admitted to SPECT, were prospectively invited to participate. Patients underwent RTP imaging (SONOS 5500) using AM and HR during Sonovue^®infusion, before and throughout the adenosine stress, also used for SPECT. Analysis of myocardial perfusion and wall motion by RTP-ASE were done for AM and HR at different time points, blinded to one another and to SPECT. Each segment was attributed to one of the three main coronary vessel areas of interest.</p> <p>Results</p> <p>In 50 patients, 150 coronary areas were analyzed by SPECT and RTP-ASE AM and HR. SPECT showed evidence of ischemia in 13 out of 50 patients. There was no significant difference between AM and HR in detecting ischemia (p = 0.08). The agreement for AM and HR, compared to SPECT, was 93% and 96%, with Kappa values of 0.67 and 0.75, respectively (p < 0.001).</p> <p>Conclusion</p> <p>There was no significant difference between AM and HR in correctly detecting myocardial ischemia as judged by SPECT. This suggests that different types of RTP modalities give comparable data during RTP-ASE in patients with known or suspected CAD.</p

Quantitative detection of myocardial ischaemia by stress echocardiography; a comparison with SPECT

<p>Abstract</p> <p>Aims</p> <p>Real-time perfusion (RTP) adenosine stress echocardiography (ASE) can be used to visually evaluate myocardial ischaemia. The RTP power modulation technique angio-mode (AM), provides images for off-line perfusion quantification using Qontrast^®software, generating values of peak signal intensity (A), myocardial blood flow velocity (β) and myocardial blood flow (Axβ). By comparing rest and stress values, their respective reserve values (A-r, β-r, Axβ-r) are generated. We evaluated myocardial ischaemia by RTP-ASE Qontrast^®quantification, compared to visual perfusion evaluation with ^99mTc-tetrofosmin single-photon emission computed tomography (SPECT).</p> <p>Methods and Results</p> <p>Patients admitted to SPECT underwent RTP-ASE (SONOS 5500) using AM during Sonovue^®infusion, before and throughout adenosine stress, also used for SPECT. Visual myocardial perfusion and wall motion analysis, and Qontrast^®quantification, were blindly compared to one another and to SPECT, at different time points off-line.</p> <p>We analyzed 201 coronary territories (left anterior descendent [LAD], left circumflex [LCx] and right coronary [RCA] artery territories) in 67 patients. SPECT showed ischaemia in 18 patients and 19 territories. Receiver operator characteristics and kappa values showed significant agreement with SPECT only for β-r and Axβ-r in all segments: area under the curve 0.678 and 0.665; P < 0.001 and < 0.01, respectively. The closest agreements were seen in the LAD territory: kappa 0.442 for both β-r and Axβ-r; P < 0.01. Visual evaluation of ischaemia showed good agreement with SPECT: accuracy 93%; kappa 0.67; P < 0.001; without non-interpretable territories.</p> <p>Conclusion</p> <p>In this agreement study with SPECT, RTP-ASE Qontrast^®quantification of myocardial ischaemia was less accurate and less feasible than visual evaluation and needs further development to be clinically useful.</p

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease

We thank Dr. Haohua Qian and Yichao Li (Visual function core, NEI, NIH) for technical assistance with OCT; Phyllis Silver (NEI, NIH) for EAU scoring of the eyes; Rashid Mahdi. M.J.M. for technical assistance with western blot analyses and Rafael Villasmil (NEI FLOW Cytometry Core facility) for assistance with FACS analysis.Peer reviewedPublisher PD

Bacteria Modulate the CD8+ T Cell Epitope Repertoire of Host Cytosol-Exposed Proteins to Manipulate the Host Immune Response

The main adaptive immune response to bacteria is mediated by B cells and CD4+ T-cells. However, some bacterial proteins reach the cytosol of host cells and are exposed to the host CD8+ T-cells response. Both gram-negative and gram-positive bacteria can translocate proteins to the cytosol through type III and IV secretion and ESX-1 systems, respectively. The translocated proteins are often essential for the bacterium survival. Once injected, these proteins can be degraded and presented on MHC-I molecules to CD8+ T-cells. The CD8+ T-cells, in turn, can induce cell death and destroy the bacteria's habitat. In viruses, escape mutations arise to avoid this detection. The accumulation of escape mutations in bacteria has never been systematically studied. We show for the first time that such mutations are systematically present in most bacteria tested. We combine multiple bioinformatic algorithms to compute CD8+ T-cell epitope libraries of bacteria with secretion systems that translocate proteins to the host cytosol. In all bacteria tested, proteins not translocated to the cytosol show no escape mutations in their CD8+ T-cell epitopes. However, proteins translocated to the cytosol show clear escape mutations and have low epitope densities for most tested HLA alleles. The low epitope densities suggest that bacteria, like viruses, are evolutionarily selected to ensure their survival in the presence of CD8+ T-cells. In contrast with most other translocated proteins examined, Pseudomonas aeruginosa's ExoU, which ultimately induces host cell death, was found to have high epitope density. This finding suggests a novel mechanism for the manipulation of CD8+ T-cells by pathogens. The ExoU effector may have evolved to maintain high epitope density enabling it to efficiently induce CD8+ T-cell mediated cell death. These results were tested using multiple epitope prediction algorithms, and were found to be consistent for most proteins tested

Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development

Acute mountain sickness.

Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days