Mitigating Quantum Decoherence in Force Sensors by Internal Squeezing.

The most efficient approach to laser interferometric force sensing to date uses monochromatic carrier light with its signal sideband spectrum in a squeezed vacuum state. Quantum decoherence, i.e., mixing with an ordinary vacuum state due to optical losses, is the main sensitivity limit. In this Letter, we present both theoretical and experimental evidence that quantum decoherence in high-precision laser interferometric force sensors enhanced with optical cavities and squeezed light injection can be mitigated by a quantum squeeze operation inside the sensor's cavity. Our experiment shows an enhanced measurement sensitivity that is independent of the optical readout loss in a wide range. Our results pave the way for quantum improvements in scenarios where high decoherence previously precluded the use of squeezed light. Our results hold significant potential for advancing the field of quantum sensors and enabling new experimental approaches in high-precision measurement technology.

Squeezed-Light Interferometry on a Cryogenically Cooled Micromechanical Membrane.

Squeezed states of light reduce the signal-normalized photon counting noise of measurements without increasing the light power and enable fundamental research on quantum entanglement in hybrid systems of light and matter. Squeezed states of light have high potential to complement cryogenically cooled sensors, whose thermal noise is suppressed below the quantum noise of light by operation at low temperature. They allow us to reduce the optical heat load on cooled devices by lowering the light power without losing measurement precision. Here, we demonstrate the squeezed-light position sensing of a cryo-cooled micromechanical membrane. The sensing precision is improved by up to 4.8 dB below photon counting noise, limited by optical loss, at a membrane temperature of about 20 K. We prove that realizing a high interference contrast in a cryogenic Michelson interferometer is feasible. Our setup is the first conceptual demonstration towards the envisioned European gravitational-wave detector, the "Einstein telescope," which is planned to use squeezed states of light together with cryo-cooled mirror test masses.

Cardiac Imaging After Ischemic Stroke or Transient Ischemic Attack.

PURPOSE OF REVIEW: Cardiac imaging after ischemic stroke or transient ischemic attack (TIA) is used to identify potential sources of cardioembolism, to classify stroke etiology leading to changes in secondary stroke prevention, and to detect frequent comorbidities. This article summarizes the latest research on this topic and provides an approach to clinical practice to use cardiac imaging after stroke. RECENT FINDINGS: Echocardiography remains the primary imaging method for cardiac work-up after stroke. Recent echocardiography studies further demonstrated promising results regarding the prediction of non-permanent atrial fibrillation after ischemic stroke. Cardiac magnetic resonance imaging and computed tomography have been tested for their diagnostic value, in particular in patients with cryptogenic stroke, and can be considered as second line methods, providing complementary information in selected stroke patients. Cardiac imaging after ischemic stroke or TIA reveals a potential causal condition in a subset of patients. Whether systematic application of cardiac imaging improves outcome after stroke remains to be established.

Using online tools at the Bovine Genome Database to manually annotate genes in the new reference genome.

With the availability of a new highly contiguous Bos taurus reference genome assembly (ARS-UCD1.2), it is the opportune time to upgrade the bovine gene set by seeking input from researchers. Furthermore, advances in graphical genome annotation tools now make it possible for researchers to leverage sequence data generated with the latest technologies to collaboratively curate genes. For many years the Bovine Genome Database (BGD) has provided tools such as the Apollo genome annotation editor to support manual bovine gene curation. The goal of this paper is to explain the reasoning behind the decisions made in the manual gene curation process while providing examples using the existing BGD tools. We will describe the sources of gene annotation evidence provided at the BGD, including RNA-seq and Iso-Seq data. We will also explain how to interpret various data visualizations when curating gene models, and will demonstrate the value of manual gene annotation. The process described here can be applied to manual gene curation for other species with similar tools. With a better understanding of manual gene annotation, researchers will be encouraged to edit gene models and contribute to the enhancement of livestock gene sets.

Symposium review: Advances in sequencing technology herald a new frontier in cattle genomics and genome-enabled selection.

The cattle reference genome assembly has underpinned major innovations in beef and dairy genetics through genome-enabled selection, including removal of deleterious recessive variants and selection for favorable alleles affecting quantitative production traits. The initial reference assemblies, up to and including UMD3.1 and Btau4.1, were based on a combination of clone-by-clone sequencing of bacterial artificial chromosome clones generated from blood DNA of a Hereford bull and whole-genome shotgun sequencing of blood DNA from his inbred daughter/granddaughter named L1 Dominette 01449 (Dominette). The approach introduced assembly gaps, misassemblies, and errors, and it limited the ability to assemble regions that undergo rearrangement in blood cells, such as immune gene clusters. Nonetheless, the reference supported the creation of genotyping tools and provided a basis for many studies of gene expression. Recently, long-read sequencing technologies have emerged that facilitated a re-assembly of the reference genome, using lung tissue from Dominette to resolve many of the problems and providing a bridge to place historical studies in common context. The new reference, ARS-UCD1.2, successfully assembled germline immune gene clusters and improved overall continuity (i.e., reduction of gaps and inversions) by over 250-fold. This reference properly places nearly all of the legacy genetic markers used for over a decade in the industry. In this review, we discuss the improvements made to the cattle reference; remaining issues present in the assembly; tools developed to support genome-based studies in beef and dairy cattle; and the emergence of newer genome assembly methods that are producing even higher-quality assemblies for other breeds of cattle at a fraction of the cost. The new frontier for cattle genomics research will likely include a transition from the individual Hereford reference genome, to a "pan-genome" reference, representing all the DNA segments existing in commonly used cattle breeds, bringing the cattle reference into line with the current direction of human genome research.

A homozygous ADAMTS2 nonsense mutation in a Doberman Pinscher dog with Ehlers Danlos syndrome and extreme skin fragility.

An eight-week old Doberman Pinscher was diagnosed with Ehlers Danlos syndrome based on the dog's hyper-mobile carpal, tarsal and stifle joints and abnormal skin. The skin was loose and hyper-elastic with several wounds and large atrophic scars. The dog was euthanized after a severe degloving injury from minimal trauma. A whole-genome sequence, generated with DNA from the dog's blood, contained a rare, homozygous C-to-T transition at position 2408978 on chromosome 11. This transition is predicted to alter the ADAMTS2 transcript (ADAMTS2:c.769C>T) and encode a nonsense mutation (p.Arg257Ter). Biallelic ADAMTS2 mutations have caused a type of Ehlers Danlos syndrome known as dermatosparaxis in other species.

Cardiac imaging after ischemic stroke : Echocardiography, CT, or MRI?

About 20-25% of all ischemic strokes are of cardioembolic etiology, with atrial fibrillation and heart failure as the most common underlying pathologies. Diagnostic work-up by noninvasive cardiac imaging is essential since it may lead to changes in therapy, e.g., in-but not exclusively-secondary stroke prevention. Echocardiography remains the cornerstone of cardiac imaging after ischemic stroke, with the combination of transthoracic and transesophageal echocardiography as gold standard thanks to their high sensitivity for many common pathologies. Transesophageal echocardiography should be considered as the initial diagnostic tool when a cardioembolic source of stroke is suspected. However, to date, there is no proven benefit of transesophageal echocardiography-related therapy changes on the main outcomes after ischemic stroke. Based on the currently available data, cardiac computed tomography and magnetic resonance imaging should be regarded as complementary methods to echocardiography, providing additional information in specific situations; however, they cannot be recommended as first-line modalities.

Silicon-Based Optical Mirror Coatings for Ultrahigh Precision Metrology and Sensing.

Thermal noise of highly reflective mirror coatings is a major limit to the sensitivity of many precision laser experiments with strict requirements such as low optical absorption. Here, we investigate amorphous silicon and silicon nitride as an alternative to the currently used combination of coating materials, silica, and tantala. We demonstrate an improvement by a factor of ≈55 with respect to the lowest so far reported optical absorption of amorphous silicon at near-infrared wavelengths. This reduction was achieved via a combination of heat treatment, final operation at low temperature, and a wavelength of 2 µm instead of the more commonly used 1550 nm. Our silicon-based coating offers a factor of 12 thermal noise reduction compared to the performance possible with silica and tantala at 20 K. In gravitational-wave detectors, a noise reduction by a factor of 12 corresponds to an increase in the average detection rate by three orders of magnitude (≈12^{3}).

Anticoagulation strategies in patients with atrial fibrillation after PCI or with ACS : The end of triple therapy?

Clinicians struggle daily with the optimal regimen for patients with an indication for antiplatelet therapy after stenting and in patients needing oral anticoagulation treatment for atrial fibrillation (AF). This is not only difficult in patients with acute coronary syndrome (ACS) but also in the large number of patients with AF undergoing elective percutaneous coronary intervention (PCI). The challenge is to strike a balance between the increasing risk of bleeding events and ischemic or thrombotic events. Until recently, guidelines were based on expert consensus and a few small, many of them retrospective, trials. A so-called triple therapy with a vitamin K antagonist (VKA) and dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was recommended for patients with AF undergoing PCI in stable coronary artery disease or for those with ACS. However, severe bleeding complications remain a major issue during triple therapy, particularly in the growing aging population. In the past year, randomized controlled trials (RCT) with direct-acting oral anticoagulants (DOACs) have modified the standard use of care, now favoring dual therapy with DOACs. This review elucidates the current influential RCTs on the new antiplatelet and anticoagulation strategies for patients with AF undergoing PCI or with ACS, and discusses whether triple therapy is still required.

Beating the Standard Sensitivity-Bandwidth Limit of Cavity-Enhanced Interferometers with Internal Squeezed-Light Generation.

The shot-noise limited peak sensitivity of cavity-enhanced interferometric measurement devices, such as gravitational-wave detectors, can be improved by increasing the cavity finesse, even when comparing fixed intracavity light powers. For a fixed light power inside the detector, this comes at the price of a proportional reduction in the detection bandwidth. High sensitivity over a large span of signal frequencies, however, is essential for astronomical observations. It is possible to overcome this standard sensitivity-bandwidth limit using nonclassical correlations in the light field. Here, we investigate the internal squeezing approach, where the parametric amplification process creates a nonclassical correlation directly inside the interferometer cavity. We theoretically analyze the limits of the approach and measure 36% increase in the sensitivity-bandwidth product compared to the classical case. To our knowledge, this is the first experimental demonstration of an improvement in the sensitivity-bandwidth product using internal squeezing, opening the way for a new class of optomechanical force sensing devices.

Homocysteine concentration in coronary artery disease: Influence of three common single nucleotide polymorphisms.

BACKGROUND AND AIMS: Whether single nucleotide polymorphisms (SNPs) of homocysteine metabolism enzymes influence the rate of cardiovascular (CV) events in coronary artery disease (CAD) patients remains controversial. METHODS AND RESULTS: In this analysis, 1126 subjects from the AtheroGene study with CAD and 332 control subjects without known CAD were included. The following SNPs were investigated: methylentetrahydrofolate reductase (MTHFR-C667T), methionin synthetase (MS-D919G), and cystathionin beta synthetase (CBS-I278T). The endpoint was the combination of cardiovascular death, stroke, and non-fatal myocardial infarction (N = 286). The median follow-up time was 6.4 years. Kaplan-Meier curve analysis showed an increasing event rate with rising homocysteine levels (p < 0.001) in CAD patients. Further, in Cox-Regression analysis homocysteine was a predictor of the endpoint with a hazard ratio (HR) of 6.5 (95% CI: 2.9-14.6, p < 0.001) in the adjusted model including cardiovascular risk factors. Of the three SNPs, homozygous MTHFR SNP increased homocysteine levels significantly in patients with CAD and individuals without CAD (both p < 0.001). The SNPs in MS and CBS were not related to relevant changes in homocysteine levels in CAD patients or controls. The different SNPs of MTHFR, MS, and CBS were not related to an increased event rate. CONCLUSION: Homocysteine level is a strong predictor of CV events. Subjects with and without CAD and SNPs in the enzyme MTHFR had increased homocysteine levels. This was not observed for MS and CBS SNPs. Although MTHFR SNPs alter homocysteine levels in patients and controls, these polymorphisms had no impact on prognosis in CAD patients.

Next-generation sequencing of the basal cell carcinoma miRNome and a description of novel microRNA candidates under neoadjuvant vismodegib therapy: an integrative molecular and surgical case study.

BACKGROUND: MicroRNAs (miRNAs) have been identified as key players in posttranscriptional gene regulation and have a significant impact on basal cell carcinoma (BCC) development. The Sonic hedgehog pathway inhibitor vismodegib has been approved for oral therapy of metastatic or advanced BCC. Here, a high-throughput miRNA sequencing analysis was carried out to identify differentially expressed miRNAs and possible novel miRNA candidates in vismodegib-treated BCC tissue. Additionally, we described our surgical experience with neoadjuvant oral vismodegib therapy. PATIENTS AND METHODS: A punch biopsy (4 mm) from a patient with an extensive cranial BCC under oral vismodegib therapy and a corresponding nonlesional epithelial skin biopsy were harvested. Total RNA was isolated, after which a sequencing cDNA library was prepared, and cluster generation was carried out, which was followed by an ultra-high-throughput miRNA sequencing analysis to indicate the read number of miRNA expression based on miRBase 21. In addition to the identification of differentially expressed miRNAs from RNA sequencing data, additional novel miRNA candidates were determined with a tool for identifying new miRNA sequences (miRDeep2). RESULTS: We identified 33 up-regulated miRNAs (fold change ≥2) and 39 potentially new miRNA candidates (miRDeep scores 0-43.6). A manual sequence analysis of the miRNA candidates on the genomic locus of chromosome 1 with provisional IDs of chr1_1913 and chr1_421 was further carried out and rated as promising (chr1_1913) and borderline (chr1_421). Histopathology revealed skip lesions in clinically healthy appearing skin at the tumor margins, which were the cause of seven re-excisions by micrographic controlled surgery to achieve tumor-free margins. CONCLUSION: miRNA sequencing revealed novel miRNA candidates that need to be further confirmed in functional Dicer knockout studies. Clinically, on the basis of our surgical experience described here, neoadjuvant vismodegib therapy in BCC appears to impede histopathologic evaluations with effects on surgical therapy. Thus, larger studies are necessary, but are not preferable at this time if other options are available.

Origins of cattle on Chirikof Island, Alaska, elucidated from genome-wide SNP genotypes.

Feral livestock may harbor genetic variation of commercial, scientific, historical or esthetic value. The origins and uniqueness of feral cattle on Chirikof Island, Alaska, are uncertain. The island is now part of the Alaska Maritime Wildlife Refuge and Federal wildlife managers want grazing to cease, presumably leading to demise of the cattle. Here we characterize the cattle of Chirikof Island relative to extant breeds and discern their origins. Our analyses support the inference that Yakut cattle from Russia arrived first on Chirikof Island, then ~120 years ago the first European taurine cattle were introduced to the island, and finally a large wave of Hereford cattle were introduced on average 40 years ago. In addition, this mixture of European and East-Asian cattle is unique compared with other North American breeds and we find evidence that natural selection in the relatively harsh environment of Chirikof Island has further impacted their genetic architecture. These results provide an objective basis for decisions regarding conservation of the Chirikof Island cattle.

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5.

We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs.

Clinical course and complications following diagnostic bronchoalveolar lavage in critically ill mechanically ventilated patients.

BACKGROUND: Flexible, fibreoptic bronchoscopy (FFB) and bronchoalveolar lavage (BAL) have been used for diagnostic purposes in critically ill ventilated patients. The additional diagnostic value compared to tracheal aspirations in ventilator-associated pneumonia (VAP) has been questioned. Nevertheless, BAL can provide extra information for the differential diagnosis of respiratory disease and good antibiotic stewardship. These benefits should outweigh potential hazards caused by the invasiveness of this diagnostic technique. The focus of the present study was on the clinical course and complications of patients following BAL procedures up to 24 h. METHODS: Hundred sixty-four FFB guided BAL procedures for suspected pneumonia were analysed in an observational study. The clinical course of patients was monitored by respiratory and haemodynamic data before BAL, 1 and 24 h after BAL. Complications were defined and registered. Factors associated with complications were analysed by logistic regression. CLINICAL COURSE: a decrease in average pO2/FiO2 ratio 1 h after BAL from 29 kPa (218 mmHg) to 25 kPa (189 mmHg) (p < 0.05) was observed which fully recovered within 24 h. Respiratory complications: the incidence of procedure related hypo-oxygenation (SaO2 ≤ 88 %) and/or bronchospasm was 9 %; a decrease of >25 % PaO2/FiO2 ratio 1 h after BAL was found in 29 % of patients; no bleeding or pneumothorax were registered. Haemodynamic complications: there were no cases of hypertension and cardiac rhythm disturbances; haemodynamic instability within the first 24 h after BAL was recorded in 22 %; this was correlated with a cardiovascular diagnosis at admission (OR 2.9; 95 % CI 1.2 - 6.7) and the presence of cardiovascular co-morbidity (OR 3.5; 95 % CI 1.5 - 8.3). The incidence of bacteraemia was 7 %. There was no case of procedure related death. DISCUSSION: Frequently occurring haemodynamic and respiratory instability but no cases of cardiac rhythm disturbances, bleeding, pneumothorax or procedure related death were attributable to diagnostic FFB and BAL. The procedures should be conducted under careful supervision by experienced physicians. Only a randomized controlled trial that compares diagnostic FFB and BAL with a non-invasive strategy could ultimately establish the safety profile and clinical utility of these procedures in critically ill ventilated patients.

[Prevalence and risk factors of atrial fibrillation in Germany : data from the Gutenberg Health Study]. / Prävalenz und Risikofaktoren von Vorhofflimmern in Deutschland : Daten aus der Gutenberg Health Study.

Atrial fibrillation (AF) is a disease with increasing clinical and public health importance. We describe the prevalence of AF, the current distribution of AF risk factors and their importance in a general population. The distribution of AF risk factors and the medicinal treatment were determined among 10,000 individuals in the population-based Gutenberg Health Study (median age 56 years and 49% women). Individuals with AF (n=309, 3.1%) had a higher median age (67 years) and significantly more risk factors. A large percentage of individuals with AF were taking antithrombotic medication (84% with a CHAD2DS2-VASc score of ≥3). Multiple logistic regression analysis showed that male gender (odds ratio, OR 2.07, 95% CI: 1.59-2.71), age (OR 1.09, 95% CI: 1.07-1.11), body mass index (OR 1.04, 95% CI: 1.02-1.07), prevalent cardiovascular disease (OR 3.06, 95% CI: 2.26-4.11) and heart failure (OR 3.11, 95% CI: 1.92-4.97) were the strongest predictors of AF. The full model explained 18% (Nagelkerke's determination coefficient R(2)) of the variation in AF prevalence. The addition of echocardiographic variables in a subgroup analysis with 5.000 participants increased the explained variation to 23%. AF is a common disease in the general population. Important risk factors for AF, apart from age and male gender, were cardiovascular disease, in particular heart failure, hypertension and increased body mass index. Awareness for AF in the population and medical community needs to be improved.

Genome scan for meat quality traits in Nelore beef cattle.

Meat quality traits are economically important because they affect consumers' acceptance, which, in turn, influences the demand for beef. However, selection to improve meat quality is limited by the small numbers of animals on which meat tenderness can be evaluated due to the cost of performing shear force analysis and the resultant damage to the carcass. Genome wide-association studies for Warner-Bratzler shear force measured at different times of meat aging, backfat thickness, ribeye muscle area, scanning parameters [lightness, redness (a*), and yellowness] to ascertain color characteristics of meat and fat, water-holding capacity, cooking loss (CL), and muscle pH were conducted using genotype data from the Illumina BovineHD BeadChip array to identify quantitative trait loci (QTL) in all phenotyped Nelore cattle. Phenotype count for these animals ranged from 430 to 536 across traits. Meat quality traits in Nelore are controlled by numerous QTL of small effect, except for a small number of large-effect QTL identified for a*fat, CL, and pH. Genomic regions harboring these QTL and the pathways in which the genes from these regions act appear to differ from those identified in taurine cattle for meat quality traits. These results will guide future QTL mapping studies and the development of models for the prediction of genetic merit to implement genomic selection for meat quality in Nelore cattle.

Mimivirus is not a frequent cause of ventilator-associated pneumonia in critically ill patients.

Acanthamoeba polyphaga mimivirus (APMV) belongs to the amoebae-associated microorganisms. Antibodies to APMV have been found in patients with pneumonia suggesting a potential role as a respiratory pathogen. In addition, positive serology for APMV was associated with an increased duration of mechanical ventilation and intensive care unit stay in patients with ventilator-associated pneumonia. The aim of the present study was to assess the presence of APMV in bronchoalveolar lavage fluid samples of critically ill patients suspected of ventilator-associated pneumonia. The study was conducted in the intensive care unit of the Maastricht University Medical Centre. All consecutive bronchoalveolar lavage fluid samples obtained between January 2005 and October 2009 from patients suspected of ventilator-associated pneumonia were eligible for inclusion. All samples were analyzed by real-time PCR targeting the APMV. A total of 260 bronchoalveolar lavage fluid samples from 214 patients (139 male, 75 female) were included. Bacterial ventilator-associated pneumonia was confirmed microbiologically in 105 out of 260 (40%) suspected episodes of ventilator-associated pneumonia (86 patients). The presence of APMV DNA could not be demonstrated in the bacterial ventilator-associated pneumonia positive or in the bacterial ventilator-associated pneumonia negative bronchoalveolar lavage fluid samples. Although suspected, APMV appeared not to be present in critically ill patients suspected of ventilator-associated pneumonia, and APMV does not seem to be a frequent cause of ventilator-associated pneumonia.

Squeezed quadrature fluctuations in a gravitational wave detector using squeezed light.

Squeezed states of light are an important tool for optical measurements below the shot noise limit and for optical realizations of quantum information systems. Recently, squeezed vacuum states were deployed to enhance the shot noise limited performance of gravitational wave detectors. In most practical implementations of squeezing enhancement, relative fluctuations between the squeezed quadrature angle and the measured quadrature (sometimes called squeezing angle jitter or phase noise) are one limit to the noise reduction that can be achieved. We present calculations of several effects that lead to quadrature fluctuations, and use these estimates to account for the observed quadrature fluctuations in a LIGO gravitational wave detector. We discuss the implications of this work for quantum enhanced advanced detectors and even more sensitive third generation detectors.

First long-term application of squeezed states of light in a gravitational-wave observatory.

We report on the first long-term application of squeezed vacuum states of light to improve the shot-noise-limited sensitivity of a gravitational-wave observatory. In particular, squeezed vacuum was applied to the German-British detector GEO 600 during a period of three months from June to August 2011, when GEO 600 was performing an observational run together with the French-Italian Virgo detector. In a second period, the squeezing application continued for about 11 months from November 2011 to October 2012. During this time, squeezed vacuum was applied for 90.2% (205.2 days total) of the time that science-quality data were acquired with GEO 600. A sensitivity increase from squeezed vacuum application was observed broadband above 400 Hz. The time average of gain in sensitivity was 26% (2.0 dB), determined in the frequency band from 3.7 to 4.0 kHz. This corresponds to a factor of 2 increase in the observed volume of the Universe for sources in the kHz region (e.g., supernovae, magnetars). We introduce three new techniques to enable the long-term application of squeezed light, and show that the glitch rate of the detector did not increase from squeezing application. Squeezed vacuum states of light have arrived as a permanent application, capable of increasing the astrophysical reach of gravitational-wave detectors.