Stationary entangled radiation from micromechanical motion.

Mechanical systems facilitate the development of a hybrid quantum technology comprising electrical, optical, atomic and acoustic degrees of freedom1, and entanglement is essential to realize quantum-enabled devices. Continuous-variable entangled fields-known as Einstein-Podolsky-Rosen (EPR) states-are spatially separated two-mode squeezed states that can be used for quantum teleportation and quantum communication2. In the optical domain, EPR states are typically generated using nondegenerate optical amplifiers3, and at microwave frequencies Josephson circuits can serve as a nonlinear medium4-6. An outstanding goal is to deterministically generate and distribute entangled states with a mechanical oscillator, which requires a carefully arranged balance between excitation, cooling and dissipation in an ultralow noise environment. Here we observe stationary emission of path-entangled microwave radiation from a parametrically driven 30-micrometre-long silicon nanostring oscillator, squeezing the joint field operators of two thermal modes by 3.40 decibels below the vacuum level. The motion of this micromechanical system correlates up to 50 photons per second per hertz, giving rise to a quantum discord that is robust with respect to microwave noise7. Such generalized quantum correlations of separable states are important for quantum-enhanced detection8 and provide direct evidence of the non-classical nature of the mechanical oscillator without directly measuring its state9. This noninvasive measurement scheme allows to infer information about otherwise inaccessible objects, with potential implications for sensing, open-system dynamics and fundamental tests of quantum gravity. In the future, similar on-chip devices could be used to entangle subsystems on very different energy scales, such as microwave and optical photons.

Whole-genome landscape of pancreatic neuroendocrine tumours.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Corrigendum: Whole-genome landscape of pancreatic neuroendocrine tumours.

This corrects the article DOI: 10.1038/nature21063.

Whole genomes redefine the mutational landscape of pancreatic cancer.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Experimental realization of non-Abelian non-adiabatic geometric gates.

The geometric aspects of quantum mechanics are emphasized most prominently by the concept of geometric phases, which are acquired whenever a quantum system evolves along a path in Hilbert space, that is, the space of quantum states of the system. The geometric phase is determined only by the shape of this path and is, in its simplest form, a real number. However, if the system has degenerate energy levels, then matrix-valued geometric state transformations, known as non-Abelian holonomies--the effect of which depends on the order of two consecutive paths--can be obtained. They are important, for example, for the creation of synthetic gauge fields in cold atomic gases or the description of non-Abelian anyon statistics. Moreover, there are proposals to exploit non-Abelian holonomic gates for the purposes of noise-resilient quantum computation. In contrast to Abelian geometric operations, non-Abelian ones have been observed only in nuclear quadrupole resonance experiments with a large number of spins, and without full characterization of the geometric process and its non-commutative nature. Here we realize non-Abelian non-adiabatic holonomic quantum operations on a single, superconducting, artificial three-level atom by applying a well-controlled, two-tone microwave drive. Using quantum process tomography, we determine fidelities of the resulting non-commuting gates that exceed 95 per cent. We show that two different quantum gates, originating from two distinct paths in Hilbert space, yield non-equivalent transformations when applied in different orders. This provides evidence for the non-Abelian character of the implemented holonomic quantum operations. In combination with a non-trivial two-quantum-bit gate, our method suggests a way to universal holonomic quantum computing.

Hypermutation In Pancreatic Cancer.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Strong Spin Dependence of Correlation Effects in Ni Due to Stoner Excitations.

Using high-resolution angle-resolved photoemission, we observe a strong spin-dependent renormalization and lifetime broadening of the quasiparticle excitations in the electronic band structure of Ni(111) in an energy window of ∼0.3 eV below the Fermi level. We derive a quantitative result for the spin-dependent lifetime broadening by comparing the scattering rates of majority and minority d states, and further show that spin-dependent electron correlations are instead negligible for sp states. From our analysis we experimentally determine the effective on-site Coulomb interaction U caused by Stoner-like interband transitions between majority and minority d states. The present results demonstrate the remarkable impact of spin-dependent electron correlation effects originating from single-particle excitations in a prototypical 3d transition metal, paving the way for further refinement of current many-body theoretical approaches.

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Nutrition screening in public hospital emergency rooms: Malnutrition Universal Screening Tool and Nutritional Risk Screening-2002 can be applied.

OBJECTIVE: To evaluate the agreement between two nutritional screening tools (Malnutrition Universal Screening Tool [MUST] and Nutritional Risk Screening-2002 [NRS-2002]) and Subjective Global Assessment (SGA) to identify nutritional risk in patients admitted to public emergency rooms. STUDY DESIGN: Cross-sectional study. METHODS: Patients aged ≥18 years who were admitted to an emergency room of a tertiary public hospital were evaluated. A nutritional risk assessment was performed in the first 48 h following hospital admission, through MUST, NRS-2002, and SGA. The Cohen's kappa coefficient was calculated. RESULTS: The study included 577 patients, with an average age of 53.9 ± 15.8 years; 56% of whom were women. Prevalence of nutritional risk was 35.3% and 28.5% according to MUST and NRS-2002, respectively, and malnutrition prevalence was equal to 32.9% according to SGA. The Cohen's kappa coefficient between SGA and MUST was 0.67 and between SGA and NRS-2002 was 0.62. CONCLUSION: MUST and NRS-2002 showed good agreement with SGA in identification of nutritional risk, suggesting that both tools have similar applicability for nutritional screening in adults or older patients admitted to public emergency rooms.

Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma.

Multiple Myeloma (MM) is a haematological malignancy characterised by the clonal expansion of plasma cells (PCs) within the bone marrow. Despite advances in therapy, MM remains a largely incurable disease with a median survival of 6 years. In almost all cases, the development of MM is preceded by the benign PC condition Monoclonal Gammopathy of Undetermined Significance (MGUS). Recent studies show that the transformation of MGUS to MM is associated with complex genetic changes. Understanding how these changes contribute to evolution will present targets for clinical intervention. We discuss three models of MM evolution; the linear, the expansionist and the intraclonal heterogeneity models. Of particular interest is the intraclonal heterogeneity model. Here, distinct populations of MM PCs carry differing combinations of genetic mutations. Acquisition of additional mutations can contribute to subclonal lineages where "driver" mutations may influence selective pressure and dominance, and "passenger" mutations are neutral in their effects. Furthermore, studies show that clinical intervention introduces additional selective pressure on tumour cells and can influence subclone survival, leading to therapy resistance. This review discusses how Next Generation Sequencing approaches are revealing critical insights into the genetics of MM development, disease progression and treatment. MM disease progression will illuminate possible mechanisms underlying the tumour.

[Internal Hernia Following Laparoscopic Roux-Y Gastric Bypass - a Challenge not only for the General Surgeon]. / Innere Hernien nach laparoskopischem Roux-Y-Magenbypass ­ eine Herausforderung nicht nur für den Allgemeinchirurgen.

The frequency of bariatric operations has increased in Germany. Primary operations are usually performed at specialised centres. However, late complications may develop months or even years after the operation, and every general and visceral surgeon may be confronted with them, regardless of the size and specialisation of their clinics. The laparoscopic Roux-Y gastric bypass is the most frequently performed bariatric operation worldwide. During this procedure, the alimentary loop is lifted up in front of the colon to form a pouch, which creates a mesenteric space, also called the Petersen space, dorsal to the alimentary loop and below the transverse colon. Both here and around the mesenteric space of the Roux anastomosis, an internal hernia may develop, i.e. the small intestine can twist on its own axis. Abdominal discomfort due to intestinal obstruction is unspecific, but very pronounced. Clinically, patients either present with an acute abdomen or with intermittent unspecific abdominal pain with nausea, and rarely also with vomiting. Clinical examinations and lab chemistry tests usually do not reveal any indicative findings. In cases of doubt, therefore, contrast-enhanced computed tomography of the abdomen is the diagnostic imaging procedure of choice. A diagnostic laparoscopy should be performed in every patient with a clinical suspicion of an internal hernia, even if the CT scan is unremarkable. This should be done by a surgeon who is well-versed in laparoscopy and experienced in bariatric surgery, since classification of the intestinal loops is very difficult without knowledge of the hernial orifices. First, an inframesocolic view is obtained with the transverse colon being lifted. From here, the open Petersen space offers a direct view of the ligament of Treitz from the right side. If small intestine is found to the right of the ligament, there is a Petersen hernia. After the inframesocolic view, the gastroenterostomy should be located and the alimentary loop should be followed in distal direction towards the jejunojejunostomy, where the second possible space may be found. Once both spaces have been located and a hernia has been reduced as appropriate, the spaces should be closed with non-absorbable suture.

Computational approaches to identify functional genetic variants in cancer genomes.

The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor but only a minority of these drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype.

Unusual Dirac Fermions on the Surface of a Noncentrosymmetric α-BiPd Superconductor.

Combining multiple emergent correlated properties such as superconductivity and magnetism within the topological matrix can have exceptional consequences in garnering new and exotic physics. Here, we study the topological surface states from a noncentrosymmetric α-BiPd superconductor by employing angle-resolved photoemission spectroscopy and first-principles calculations. We observe that the Dirac surface states of this system have several interesting and unusual properties, compared to other topological surface states. The surface state is strongly anisotropic and the in-plane Fermi velocity varies rigorously on rotating the crystal about the y axis. Moreover, it acquires an unusual band gap as a function of k_{y}, possibly due to hybridization with bulk bands, detected upon varying the excitation energy. The coexistence of all the functional properties in addition to the unusual surface state characteristics make this an interesting material.

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.

High-energy anomaly in the angle-resolved photoemission spectra of Nd(2-x)Ce(x)CuO4: evidence for a matrix element effect.

We use polarization-dependent angle-resolved photoemission spectroscopy (ARPES) to study the high-energy anomaly (HEA) in the dispersion of Nd(2-x)Ce(x)CuO4, x=0.123. We find that at particular photon energies the anomalous, waterfall-like dispersion gives way to a broad, continuous band. This suggests that the HEA is a matrix element effect: it arises due to a suppression of the intensity of the broadened quasiparticle band in a narrow momentum range. We confirm this interpretation experimentally, by showing that the HEA appears when the matrix element is suppressed deliberately by changing the light polarization. Calculations of the matrix element using atomic wave functions and simulation of the ARPES intensity with one-step model calculations provide further evidence for this scenario. The possibility to detect the full quasiparticle dispersion further allows us to extract the high-energy self-energy function near the center and at the edge of the Brillouin zone.

Climbing the Jaynes-Cummings ladder and observing its nonlinearity in a cavity QED system.

The field of cavity quantum electrodynamics (QED), traditionally studied in atomic systems, has gained new momentum by recent reports of quantum optical experiments with solid-state semiconducting and superconducting systems. In cavity QED, the observation of the vacuum Rabi mode splitting is used to investigate the nature of matter-light interaction at a quantum-mechanical level. However, this effect can, at least in principle, be explained classically as the normal mode splitting of two coupled linear oscillators. It has been suggested that an observation of the scaling of the resonant atom-photon coupling strength in the Jaynes-Cummings energy ladder with the square root of photon number n is sufficient to prove that the system is quantum mechanical in nature. Here we report a direct spectroscopic observation of this characteristic quantum nonlinearity. Measuring the photonic degree of freedom of the coupled system, our measurements provide unambiguous spectroscopic evidence for the quantum nature of the resonant atom-field interaction in cavity QED. We explore atom-photon superposition states involving up to two photons, using a spectroscopic pump and probe technique. The experiments have been performed in a circuit QED set-up, in which very strong coupling is realized by the large dipole coupling strength and the long coherence time of a superconducting qubit embedded in a high-quality on-chip microwave cavity. Circuit QED systems also provide a natural quantum interface between flying qubits (photons) and stationary qubits for applications in quantum information processing and communication.

Analysis of endonasal sinus surgery in a private outpatient setting in a tropical environment: A STROBE analysis.

OBJECTIVES: To evaluate results and failure factors in endonasal surgery in a private outpatient setting in a tropical environment. MATERIAL AND METHOD: A single-center observational study included 337 patients consecutively undergoing endonasal surgery in a private hospital on Réunion Island, a French overseas administrative Département in the Indian Ocean between 2019 and 2021. The main objective was to assess the success rate of the outpatient pathway. Secondary objectives comprised analysis of complications and identification and management of factors for failure of outpatient management. The study was conducted according to the STROBE editorial guideline. RESULTS: The 337 surgeries notably comprised 112 septoplasties (37.5%), 104 meatotomies (30.3%), 15 unilateral total ethmoidectomies (4.6%), 48 bilateral total ethmoidectomies with sphenoidotomy (14.3%), and 18 Draf procedures (5.5%). Seventy-five percent of patients (252/337) were operated on as outpatients, with a success rate of 90% (227/252 patients). The rate of severe intraoperative complications was 1.5% (5/337). On multivariate analysis, 3 variables were identified as influencing risk of failure of the outpatient pathway: emergency analgesia in the operating room [odds ratio (OR): 91.61; 95% confidence interval (CI): 22.8-540.3], operating time (OR: 1.05; 95% CI: 1.01-1.09), and recovery room time (OR: 1.02; 95% CI: 1.01-1.03). CONCLUSION: Our study in a tropical environment found eligibility and success rates for outpatient endonasal surgery similar to those in metropolitan France. This makes surgical and anesthesiological training a key factor in the success of outpatient care, while the location of the care structure and the climate seem to have little impact.

Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family.

Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1, a gene associated with breast and ovarian cancer and RNF43, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998-2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43:c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO2019) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Resonant elastic soft x-ray scattering.

Resonant (elastic) soft x-ray scattering (RSXS) offers a unique element, site and valence specific probe to study spatial modulations of charge, spin and orbital degrees of freedom in solids on the nanoscopic length scale. It is not only used to investigate single-crystalline materials. This method also enables one to examine electronic ordering phenomena in thin films and to zoom into electronic properties emerging at buried interfaces in artificial heterostructures. During the last 20 years, this technique, which combines x-ray scattering with x-ray absorption spectroscopy, has developed into a powerful probe to study electronic ordering phenomena in complex materials and furthermore delivers important information on the electronic structure of condensed matter. This review provides an introduction to the technique, covers the progress in experimental equipment, and gives a survey on recent RSXS studies of ordering in correlated electron systems and at interfaces.

Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.

The hereditary spastic paraplegias (HSPs; Strümpell-Lorrain syndrome, MIM number 18260) are a diverse class of disorders characterized by insidiously progressive lower-extremity spastic weakness (reviewed in refs. 1-3). Eight autosomal dominant HSP (ADHSP) loci have been identified, the most frequent of which is that linked to the SPG4 locus on chromosome 2p22 (found in approximately 42%), followed by that linked to the SPG3A locus on chromosome 14q11-q21 (in approximately 9%). Only SPG4 has been identified as a causative gene in ADHSP. Its protein (spastin) is predicted to participate in the assembly or function of nuclear protein complexes. Here we report the identification of mutations in a newly identified GTPase gene, SPG3A, in ADHSP affected individuals.