Update on Mitral Repair in Dilated Cardiomyopathy

Heart failure is one of the leading causes of hospitalization worldwide. Mitral regurgitation (MR) is a known complication of end-stage cardiomyopathy and is associated with a poor prognosis due to progressive mitral annular dilation. A vicious cycle of continuing volume overload, ventricular dilation, progression of annular dilation, increased LV wall tension, and worsening of MR and CHF occur. Commonly, these patients were managed medically with diuretics and afterload reduction, and frequently with mitral valve replacement, both of which have poor long term survival in patients with CHF and MR. Over a 10-year period we prospectively studied over 200 patients with cardiomyopathy and severe MR who underwent mitral valve repair utilizing an undersizing overcorrecting annuloplasty ring. The mortality was low with one intraoperative death and eight 30-day mortalities. There were 26 late deaths; 2 of these patients had progression of heart failure and underwent transplantation. The 1-, 2-, and 5-year actuarial survivals have been 82%, 71%, and 52%, respectively. The NYHA class has improved for all patients from a preoperative mean of 3.2 ± 0.2 to 1.8 ± 0.4 postoperatively. All patients demonstrated improvement in ejection fraction, cardiac output, and end diastolic volumes with a reduction in sphericity index and regurgitant volume at 2 years post operation. All of the observed changes contribute to reverse remodeling and restoration of the normal left ventricular geometry. Mitral valve repair is a safe and effective operative intervention that corrects MR and offers a new strategy for patients with MR and end-stage cardiomyopathy. (J Card Surg 2004;19:396-400)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72871/1/j.0886-0440.2004.04079.x.pd

800-5 Improving Accuracy of Ultrafast Computed Tomography in the Detection of Angiographically Significant Coronary Artery Disease

In differentiating coronary calcium from artifact by ultrafast computed tomography (UFCT), many different thresholds have been proposed. UFCT has demonstrated a high sensitivity and only modest specificity to detect coronary calcifications when compared to angiography. The Agatston method is most widely used today, utilizing a minimum CT number of 130 Hounsfield units (HU). In an attempt to improve specificity without markedly reducing sensitivity, we evaluated 272 coronary vessels from 68 patients with angiography and UFCT coronary scanning. All patients underwent coronary angiography for clinical indications, and had UFCT scanning done within three months of the angiogram. A blinded reader evaluated all the UFCT scans. We then varied the minimum CT number to assess whether 130 HU was truly the best threshold. Sensitivity, specificity and accuracy for different thresholds are listed.Threshold130 HU150 HU170 HU200 HUSensitivity95%92%89%87%Specificity65%72%75%78%Accuracy72%77%78%79%The results above indicate that 130 HU is too low a threshold to maximize accuracy of this test when compared with angiography. Sensitivity is reduced as the threshold is improved, however this result is not significant (p=0.61). The improved specificity from 130 to 150 represents a significant improvement (p<0.0001), although a larger study must be performed before widespread use of this new threshold is employed

A Recurrent Silent Mutation Implicates fecA in Ethanol Tolerance by Escherichia coli.

BACKGROUND: An issue associated with efficient bioethanol production is the fact that the desired product is toxic to the biocatalyst. Among other effects, ethanol has previously been found to influence the membrane of E. coli in a dose-dependent manner and induce changes in the lipid composition of the plasma membrane. We describe here the characterization of a collection of ethanol-tolerant strains derived from the ethanologenic Escherichia coli strain FBR5. RESULTS: Membrane permeability assays indicate that many of the strains in the collection have alterations in membrane permeability and/or responsiveness of the membrane to environmental changes such as temperature shifts or ethanol exposure. However, analysis of the strains by gas chromatography and mass spectrometry revealed no qualitative changes in the acyl chain composition of membrane lipids in response to ethanol or temperature. To determine whether these strains contain any mutations that might contribute to ethanol tolerance or changes in membrane permeability, we sequenced the entire genome of each strain. Unexpectedly, none of the strains displayed mutations in genes known to control membrane lipid synthesis, and a few strains carried no mutations at all. Interestingly, we found that four independently-isolated strains acquired an identical C → A (V244 V) silent mutation in the ferric citrate transporter gene fecA. Further, we demonstrated that either a deletion of fecA or over-expression of fecA can confer increased ethanol survival, suggesting that any misregulation of fecA expression affects the cellular response to ethanol. CONCLUSIONS: The fact that no mutations were observed in several ethanol-tolerant strains suggested that epigenetic mechanisms play a role in E. coli ethanol tolerance and membrane permeability. Our data also represent the first direct phenotypic evidence that the fecA gene plays a role in ethanol tolerance. We propose that the recurring silent mutation may exert an effect on phenotype by altering RNA-mediated regulation of fecA expression

SARS-CoV-2 Viral Load in Saliva Rises Gradually and to Moderate Levels in Some Humans

Transmission of SARS-CoV-2 in community settings often occurs before symptom onset, therefore testing strategies that can reliably detect people in the early phase of infection are urgently needed. Early detection of SARS-CoV-2 infection is especially critical to protect vulnerable populations who require frequent interactions with caretakers. Rapid COVID-19 tests have been proposed as an attractive strategy for surveillance, however a limitation of most rapid tests is their low sensitivity. Low-sensitivity tests are comparable to high sensitivity tests in detecting early infections when two assumptions are met: (1) viral load rises quickly (within hours) after infection and (2) viral load reaches and sustains high levels (>10⁵ - 10⁶ RNA copies/mL). However, there are no human data testing these assumptions. In this study, we document a case of presymptomatic household transmission from a healthy college student to his brother and father. Participants prospectively provided twice-daily saliva samples. Samples were analyzed by RT-qPCR and RT-ddPCR and we measured the complete viral load profiles throughout the course of infection of the brother and father. This study provides evidence that in at least some human cases of SARS-CoV-2, viral load rises slowly (over days, not hours) and not to such high levels to be detectable reliably by any low-sensitivity test. Additional viral load profiles from different samples types across a broad demographic must be obtained to describe the early phase of infection and determine which testing strategies will be most effective for identifying SARS-CoV-2 infection before transmission can occur

The standard posture of the hand

Perceived limb position is known to rely on sensory signals and motor commands. Another potential source of input is a standard representation of body posture, which may bias perceived limb position towards more stereotyped positions. Recent results show that tactile stimuli are processed more efficiently when delivered to a thumb in a relatively low position or an index finger in a relatively high position. This observation suggests that we may have a standard posture of the body that promotes a more efficient interaction with the environment. In this study, we mapped the standard posture of the entire hand by characterizing the spatial associations of all five digits. Moreover, we show that the effect is not an artefact of intermanual integration. Results showed that the thumb is associated with low positions, while the other fingers are associated with upper locations

Characterizing DNA Star-Tile-Based Nanostructures Using a Coarse-Grained Model

We use oxDNA, a coarse-grained model of DNA at the nucleotide level, to simulate large nanoprisms that are composed of multi-arm star tiles, in which the size of bulge loops that have been incorporated into the tile design is used to control the flexibility of the tiles. The oxDNA model predicts equilibrium structures for several different nanoprism designs that are in excellent agreement with the experimental structures as measured by cryoTEM. In particular we reproduce the chiral twisting of the top and bottom faces of the nanoprisms, as the bulge sizes in these structures are varied due to the greater flexibility of larger bulges. We are also able to follow how the properties of the star tiles evolve as the prisms are assembled. Individual star tiles are very flexible, but their structures become increasingly well-defined and rigid as they are incorporated into larger assemblies. oxDNA also finds that the experimentally observed prisms are more stable than their inverted counterparts, but interestingly this preference for the arms of the tiles to bend in a given direction only emerges after they are part of larger assemblies. These results show the potential for oxDNA to provide detailed structural insight as well as to predict the properties of DNA nanostructures and hence to aid rational design in DNA nanotechnology

Drop in the hard pulsed fraction and a candidate cyclotron line in IGR J16320-4751 seen by NuSTAR

We report on a timing and spectral analysis of a 50-ks NuSTAR observation of IGR J16320-4751 (= AX J1631.9-4752); a high-mass X-ray binary hosting a slowly-rotating neutron star. In this observation from 2015, the spin period was 1,308.8+/-0.4 s giving a period derivative dP/dt ~ 2E-8 s s-1 when compared with the period measured in 2004. In addition, the pulsed fraction decreased as a function of energy, as opposed to the constant trend that was seen previously. This suggests a change in the accretion geometry of the system during the intervening 11 years. The phase-averaged spectra were fit with the typical model for accreting pulsars: a power law with an exponential cutoff. This left positive residuals at 6.4 keV attributable to the known iron K-alpha line, as well as negative residuals around 14 keV from a candidate cyclotron line detected at a significance of 5-sigma. We found no significant differences in the spectral parameters across the spin period, other than the expected changes in flux and component normalizations. A flare lasting around 5 ks was captured during the first half of the observation where the X-ray emission hardened and the local column density decreased. Finally, the binary orbital period was refined to 8.9912+/-0.0078 d thanks to Swift/BAT monitoring data from 2005-2022.Comment: 17 pages, 11 figures, Referee-revised version accepted for publication in the Astrophysical Journa

Influence of antigen density and TLR ligands on preclinical efficacy of a VLP-based vaccine against peanut allergy.

BACKGROUND Virus-like particle (VLP) Peanut is a novel immunotherapeutic vaccine candidate for the treatment of peanut allergy. The active pharmaceutical ingredient represents cucumber mosaic VLPs (CuMVTT -VLPs) that are genetically fused with one of the major peanut allergens, Ara h 2 (CuMVTT -Ara h 2). We previously demonstrated the immunogenicity and the protective capacity of VLP Peanut-based immunization in a murine model for peanut allergy. Moreover, a Phase I clinical trial has been initiated using VLP Peanut material manufactured following a GMP-compliant manufacturing process. Key product characterization studies were undertaken here to understand the role and contribution of critical quality attributes that translate as predictive markers of immunogenicity and protective efficacy for clinical vaccine development. METHOD The role of prokaryotic RNA encapsulated within VLP Peanut on vaccine immunogenicity was assessed by producing a VLP Peanut batch with a reduced RNA content (VLP Peanut low RNA). Immunogenicity and peanut allergen challenge studies were conducted with VLP Peanut low RNA, as well as with VLP Peanut in WT and TLR 7 KO mice. Furthermore, mass spectrometry and SDS-PAGE based methods were used to determine Ara h 2 antigen density on the surface of VLP Peanut particles. This methodology was subsequently applied to investigate the relationship between Ara h 2 antigen density and immunogenicity of VLP Peanut. RESULTS A TLR 7 dependent formation of Ara h 2 specific high-avidity IgG antibodies, as well as a TLR 7 dependent change in the dominant IgG subclass, was observed following VLP Peanut vaccination, while total allergen-specific IgG remained relatively unaffected. Consistently, a missing TLR 7 signal caused only a weak decrease in allergen tolerability after vaccination. In contrast, a reduced RNA content for VLP Peanut resulted in diminished total Ara h 2 specific IgG responses, followed by a significant impairment in peanut allergen tolerability. The discrepant effect on allergen tolerance caused by an absent TLR 7 signal versus a reduced RNA content is explained by the observation that VLP Peanut-derived RNA not only stimulates TLR 7 but also TLR 3. Additionally, a strong correlation was observed between the number of Ara h 2 antigens displayed on the surface of VLP Peanut particles and the vaccine's immunogenicity and protective capacity. CONCLUSIONS Our findings demonstrate that prokaryotic RNA encapsulated within VLP Peanut, including antigen density of Ara h 2 on viral particles, are key contributors to the immunogenicity and protective capacity of the vaccine. Thus, antigenicity and RNA content are two critical quality attributes that need to be determined at the stage of manufacturing, providing robust information regarding the immunogenicity and protective capacity of VLP Peanut in the mouse which has translational relevance to the human setting

Search for gravitational waves from low mass compact binary coalescence in LIGO’s sixth science run and Virgo’s science runs 2 and 3

We report on a search for gravitational waves from coalescing compact binaries using LIGO and Virgo observations between July 7, 2009, and October 20, 2010. We searched for signals from binaries with total mass between 2 and 25M⊙; this includes binary neutron stars, binary black holes, and binaries consisting of a black hole and neutron star. The detectors were sensitive to systems up to 40 Mpc distant for binary neutron stars, and further for higher mass systems. No gravitational-wave signals were detected. We report upper limits on the rate of compact binary coalescence as a function of total mass, including the results from previous LIGO and Virgo observations. The cumulative 90% confidence rate upper limits of the binary coalescence of binary neutron star, neutron star-black hole, and binary black hole systems are 1.3×10−4, 3.1×10−5, and 6.4×10−6  Mpc−3 yr−1, respectively. These upper limits are up to a factor 1.4 lower than previously derived limits. We also report on results from a blind injection challenge

A gravitational wave observatory operating beyond the quantum shot-noise limit: Squeezed light in application

Around the globe several observatories are seeking the first direct detection of gravitational waves (GWs). These waves are predicted by Einstein\u27s general theory of relativity(1) and are generated, for example, by black-hole binary systems(2). Present GW detectors are Michelson-type kilometre-scale laser interferometers measuring the distance changes between mirrors suspended in vacuum. The sensitivity of these detectors at frequencies above several hundred hertz is limited by the vacuum (zero-point) fluctuations of the electromagnetic field. A quantum technology-the injection of squeezed light(3)-offers a solution to this problem. Here we demonstrate the squeezed-light enhancement of GEO 600, which will be the GW observatory operated by the LIGO Scientific Collaboration in its search for GWs for the next 3-4 years. GEO 600 now operates with its best ever sensitivity, which proves the usefulness of quantum entanglement and the qualification of squeezed light as a key technology for future GW astronomy(4)