Telecom-Wavelength Quantum Repeater Node Based on a Trapped-Ion Processor.

A quantum repeater node is presented based on trapped ions that act as single-photon emitters, quantum memories, and an elementary quantum processor. The node's ability to establish entanglement across two 25-km-long optical fibers independently, then to swap that entanglement efficiently to extend it over both fibers, is demonstrated. The resultant entanglement is established between telecom-wavelength photons at either end of the 50 km channel. Finally, the system improvements to allow for repeater-node chains to establish stored entanglement over 800 km at hertz rates are calculated, revealing a near-term path to distributed networks of entangled sensors, atomic clocks, and quantum processors.

Entanglement of Trapped-Ion Qubits Separated by 230 Meters.

We report on an elementary quantum network of two atomic ions separated by 230 m. The ions are trapped in different buildings and connected with 520(2) m of optical fiber. At each network node, the electronic state of an ion is entangled with the polarization state of a single cavity photon; subsequent to interference of the photons at a beam splitter, photon detection heralds entanglement between the two ions. Fidelities of up to (88.0+2.2-4.7)% are achieved with respect to a maximally entangled Bell state, with a success probability of 4×10^{-5}. We analyze the routes to improve these metrics, paving the way for long-distance networks of entangled quantum processors.

The value of bronchoalveolar lavage for discrimination between healthy and diseased individuals.

BACKGROUND: Bronchoalveolar lavage (BAL) is standard diagnostic procedure. Procedural recommendations have been made by pneumological societies including normal values for interpretation of BAL cytology. These normal values derive from small studies in healthy volunteers and have never been analysed for their sensitivity and specificity. OBJECTIVES: This study aims to analyse sensitivity and specificity of these normal values by assessing lavage cell composition in healthy and diseased individuals. METHODS: More than 6000 BAL were retrospectively analysed for their cellular distribution including BALs of 250 healthy individuals. All BALs were obtained under similar conditions. RESULTS: Bronchoalveolar lavage cytology of healthy individuals mirrors data from previous studies with smoking being the most important manipulator of BAL cytology. Analyses of proposed normal values demonstrate specificity between 80% and 95%, whereas sensitivity ranges between 35% and 65%. Using different mathematical models, a value summing up the differences to ATS-proposed normal values of the cytological pattern was found to best discriminate between healthy and diseased individuals with a sensitivity of nearly 60% with a predefined specificity of 95%. CONCLUSION: In summary, our analysis confirmed prior results for healthy volunteers and enlarged these findings by analysing sensitivity and specificity of lavage results in an independent validation cohort of diseased individuals. Thereby, the study may influence the acceptance of BAL in the diagnostic workup of individuals with pulmonary diseases. Additionally, the study proposes a novel value that facilitates lavage interpretation and may therefore be useful in further studies.

[E-Cigarettes - Operating Principle, Ingredients, and Associated Acute Lung Injury]. / E-Zigaretten ­ Funktionsweise, Inhaltsstoffe und die Vaping-assoziierte akute Lungenschädigung.

Beginning in April of 2019, the US saw > 2,000 cases of hospitalized, often young, patients with severe acute lung injury, of which over 40 died, and the only existing connection between patients was their use of electronic cigarettes (e-cigarettes). The acronym EVALI ("e-cigarette, or vaping, product use associated lung injury") has since been established for the condition. This review article is intended to provide an overview of recent, mainly US literature on EVALI, including the case definition, epidemiology, clinical presentation, typical disease progression, as well as potential triggers. Ancillary to this, the review further provides a general overview of the basic function of e-cigarettes, the ingredients of the liquids used in these (e-liquids), as well as a brief description of the associated potential inhalation risks.

[German Guideline for Idiopathic Pulmonary Fibrosis]. / S2K-Leitlinie zur Diagnostik der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since publication of the international IPF guideline in the year 2011 and Update 2018 several studies and technical advances occurred, which made a new assessment of the diagnostic process mandatory. In view of the antifibrotic drugs which have been approved for the treatment of IPF patients, the goal of this guideline is to foster early, confident and effective diagnosis of IPF. The guideline focusses on the typical clinical setting of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardised questionnaires, serologic testing and cellular analysis of bronchoalveolar lavage. High resolution computed tomography remains crucial in the diagnostic work-up. If it is necessary to obtain specimen for histology transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom bronchoscopic diagnosis did not provide the information needed. Despite considerable progress, IPF remains a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis.

Direct detection of Coccidioides from Arizona soils using CocciENV, a highly sensitive and specific real-time PCR assay.

Coccidioides immitis and Coccidioides posadasii are soil fungi endemic to desert regions of the southwestern United States, and the causative agents of valley fever, or coccidioidomycosis. Studies have shown that the distribution of Coccidioides in soils is sporadic and cannot be explained by soil characteristics alone, suggesting that biotic and other abiotic factors should be examined. However, tools to reliably and robustly screen the large number of soils needed to investigate these potential associations have not been available. Thus, we developed a real-time polymerase chain reaction (PCR) assay for testing environmental samples by modifying CocciDx, an assay validated for testing clinical specimens to facilitate coccidioidomycosis diagnosis. For this study, we collected soil samples from previously established locations of C. posadasii in Arizona and new locations in fall 2013 and spring 2014, and screened the extracted DNA with the new assay known as CocciEnv. To verify the presence of Coccidioides in soil using an alternate method, we employed next generation amplicon sequencing targeting the ITS2 region. Results show our modified assay, CocciEnv, is a rapid and robust method for detecting Coccidioides DNA in complex environmental samples. The ability to test a large number of soils for the presence of Coccidioides is a much-needed tool in the understanding of the ecology of the organism and epidemiology of the disease and will greatly improve our understanding of this human pathogen.

Coinfections identified from metagenomic analysis of cervical lymph nodes from tularemia patients.

BACKGROUND: Underlying coinfections may complicate infectious disease states but commonly go unnoticed because an a priori clinical suspicion is usually required so they can be detected via targeted diagnostic tools. Shotgun metagenomics is a broad diagnostic tool that can be useful for identifying multiple microbes simultaneously especially if coupled with lymph node aspirates, a clinical matrix known to house disparate pathogens. The objective of this study was to analyze the utility of this unconventional diagnostic approach (shotgun metagenomics) using clinical samples from human tularemia cases as a test model. Tularemia, caused by the bacterium Francisella tularensis, is an emerging infectious disease in Turkey. This disease commonly manifests as swelling of the lymph nodes nearest to the entry of infection. Because swollen cervical nodes are observed from many different types of human infections we used these clinical sample types to analyze the utility of shotgun metagenomics. METHODS: We conducted an unbiased molecular survey using shotgun metagenomics sequencing of DNA extracts from fine-needle aspirates of neck lymph nodes from eight tularemia patients who displayed protracted symptoms. The resulting metagenomics data were searched for microbial sequences (bacterial and viral). RESULTS: F. tularensis sequences were detected in all samples. In addition, we detected DNA of other known pathogens in three patients. Both Hepatitis B virus (HBV) and Human Parvovirus B-19 were detected in one individual and Human Parvovirus B-19 alone was detected in two other individuals. Subsequent PCR coupled with Sanger sequencing verified the metagenomics results. The HBV status was independently confirmed via serological diagnostics, despite evading notice during the initial assessment. CONCLUSION: Our data highlight that shotgun metagenomics of fine-needle lymph node aspirates is a promising clinical diagnostic strategy to identify coinfections. Given the feasibility of the diagnostic approach demonstrated here, further steps to promote integration of this type of diagnostic capability into mainstream clinical practice are warranted.

Polarisation-preserving photon frequency conversion from a trapped-ion-compatible wavelength to the telecom C-band.

We demonstrate polarisation-preserving frequency conversion of single-photon-level light at 854 nm, resonant with a trapped-ion transition and qubit, to the 1550-nm telecom C band. A total photon in / fiber-coupled photon out efficiency of ∼ 30% is achieved, for a free-running photon noise rate of ∼ 60 Hz. This performance would enable telecom conversion of 854 nm polarisation qubits, produced in existing trapped-ion systems, with a signal-to-noise ratio greater than 1. In combination with near-future trapped-ion systems, our converter would enable the observation of entanglement between an ion and a photon that has travelled more than 100 km in optical fiber: three orders of magnitude further than the state-of-the-art.

[Sarcoidosis]. / Sarkoidose.

Sarcoidosis is a rare granulomatous disease mainly affecting lymph nodes and the lungs but joints, bones, muscles and other organs can also be affected. Sarcoidosis therefore represents an important differential diagnosis to various rheumatic diseases. For the diagnosis and differential diagnostic clarification, bronchoscopy including endobronchial ultrasound-guided fine needle aspiration of mediastinal and hilar lymph nodes represent the main procedures. Because of the high spontaneous remission rate initiating a therapy requires a therapeutic goal defined by sarcoidosis-associated functional organ impairment, especially for acute sarcoidosis. Cortisone represents the most commonly administered medication whereas methotrexate and azathioprine are well-established second-line medications. Antibodies which neutralize tumor necrosis factors (TNF) are a potential third-line therapy.

[New Pathogenetic Concepts and Early Pharmacological Studies in Sarcoidosis]. / Neue pathogenetische Konzepte und frühe pharmakologische Studien bei der Sarkoidose.

The etiology of sarcoidosis is still elusive, yet there has been considerable progress in various areas of basic and clinical research. This review focuses on mechanisms of granuloma formation and on new findings in autoimmunity and genetics of sarcoidosis. A new promising concept arose, where serum amyloid A and/or mycobacterial antigens serve as nidus for granuloma formation. Furthermore, autoimmunity in sarcoidosis was neglected for a long time, yet new studies found autoantigens and abnormalities in antigen presentation in sarcoidosis. Last but not least, large genome-wide association studies discovered several new predisposing genes, leading to new hypotheses on pathomechanisms of sarcoidosis.In the second part, we focus on ongoing or recently completed clinical-pharmacological studies in patients with sarcoidosis: Positive studies were published in well characterized and homogenous subcohorts of sarcoid patients. Several drugs have shown a positive effect on sarcoidosis-associated fatigue, on sarcoidosis of the skin and on pulmonary hypertension in sarcoid patients. It seems that the generation of clinically closely defined subcohorts is necessary to achieve positive outcomes in studies on sarcoidosis.

[Diagnosis and treatment of sarcoidosis. Current standards]. / Diagnostik und Therapie der Sarkoidose. Was ist gesichert?

Sarcoidosis is a granulomatous disease that mainly affects the lungs and intrathoracic lymph nodes; however, virtually any organ can be affected. As an orphan disease, recommendations are mainly based on observational or small randomized studies as well as experts' opinion. Diagnosing sarcoidosis requires proof of non-necrotizing granulomas in patients with a compatible symptomatic pattern and the exclusion of other granulomatous diseases. Granulomas can be detected best in the lungs or intrathoracic lymph nodes. Therefore, bronchoscopy and endobronchial ultrasound with biopsies of lymph nodes are the major tools to diagnose sarcoidosis. Frequently, close follow-up and symptomatic therapy are sufficient to allow for spontaneous resolution. In case of functional organ impairment, cardial or CNS involvement, or other complications, steroid therapy is necessary with a starting dose of 0.5 mg/kg body weight that should be tapered-off over 6-12 months. Steroid-refractory disease can be treated by adding methotrexate or azathioprine, two drugs long known in sarcoidosis treatment. Monoclonal antibodies against TNF and lung transplantation are further therapeutic options.

Association of gamma-glutamyltransferase with severity of disease at diagnosis and prognosis of ovarian cancer.

BACKGROUND: Gamma-glutamyltransferase (GGT) - a membrane-bound enzyme crucially involved in the cell's detoxification pathway and apoptotic balance - is involved in tumour development, progression and chemotherapy resistance. Elevated GGT serum levels are associated with increased cancer risk in women and worse prognosis in gynaecologic cancers. The present study investigated the prognostic role of GGT in ovarian cancer patients. METHODS: In this multicenter study, pre-therapeutic GGT levels were ascertained in 634 consecutive patients with epithelial ovarian cancer (EOC, n=567) and borderline tumour of the ovary (BTO, n=67). Gamma-glutamyltransferase serum levels were associated with clinicopathological parameters and uni- and multivariate survival analyses were performed. Immunohistochemistry of GGT was performed in ovarian cancer tissue and correlated with GGT serum levels. RESULTS: Pre-therapeutic GGT serum levels were higher in patients with EOC (28.56 (38.24) U l(-1)) than in patients with BTO (20.01 (12.78) U l(-1), P=0.01). High GGT serum levels were associated with advanced FIGO stage (P<0.001) and with worse overall survival in univariate (P<0.001) and multivariable analysis (P=0.02, HR 1.2 (1.1-1.5)). We further investigated the association between systemic GGT serum levels and local GGT expression in EOC tumour tissue and observed an association between these two parameters (P=0.03). CONCLUSION: High pre-therapeutic GGT serum levels are associated with advanced tumour stage and serve as an independent prognostic marker for worse overall survival in patients with EOC. Gamma-glutamyltransferase expression in ovarian cancer tissue is reflected in GGT serum levels.

[The Socioeconomic Panel (SOEP)]. / Das Sozio-oekonomische Panel (SOEP).

The Socioeconomic panel (SOEP) is currently the largest and longest running multidisciplinary longitudinal study in Germany. The first survey wave was completed in West Germany in 1984 and the study was expanded to include East Germany in June 1990. Every year since 1984 in West Germany and since 1990 in East Germany as well, a survey institute commissioned by the SOEP study has conducted personal oral interviews with more than 20,000 people in over 10,000 households. Although the SOEP does not contain any diagnostic information aside from grip strength for the evaluation of health status, instead using self-reported or proxy-reported indicators, it offers a dataset that is almost unparalleled in its ability to address a diverse range of topics with both objective and subjective indicators. Given the study's prospective longitudinal design, it is also outstandingly suited to controlling and correcting problems of selection that commonly arise in special samples (such as the Berlin Aging Study II). Covering a period of over 25 years, the SOEP also offers a number of possibilities for the analysis of the "natural experiments" that arise through changes in legislation. The SOEP's representative subsamples provide the basis for generalized conclusions about the total population living in private households and its migration samples also make an independent contribution for this population group. The numerous SOEP-based studies being published in the field of health sciences, most of which are currently concentrated around topics of health inequality and health economics, demonstrate the importance of this freely available research database for secondary analysis. Recent improvements in the survey concept will allow the SOEP to be used to an increased degree for analyses in the fields of public health and epidemiology.

[Isometric grip strength and social gerontological research: results and analytic potentials of SHARE and SOEP]. / Isometrische Greifkraft und sozialgerontologische Forschung: Ergebnisse und Analysepotentiale des SHARE und SOEP.

This paper shows that the measurement of hand grip strength provides a non-invasive and reliable objective health indicator for social science research and is easy to collect in general population surveys. Grip strength is not only a useful complement of self-reported indicators of health, but it also exhibits a considerable predictive power with regard to a number of further relevant variables for social gerontological research, such as mortality risks. New data from the 2004 Survey of Health, Ageing and Retirement in Europe (SHARE) and the 2006 wave of the German Socio-Economic Panel Study (SOEP) allow insightful methodological and very first substantive cross-sectional analyses of grip strength in Germany. The focus of the present study is on the analysis of individuals aged 50 or older. The experience of both surveys when measuring grip strength is consistently positive, particularly with regard to the respondents' feedback. Major determinants of isometric grip strength are - beyond the individual's gender - age, body size and weight. A multivariate analysis also provides evidence for a clear positive association between various health indicators and grip strength.

A high resolution four-locus multiplex single nucleotide repeat (SNR) genotyping system in Bacillus anthracis.

The allelic identities of Single Nucleotide Repeat (SNR) markers in Bacillus anthracis are typically ascertained by DNA sequencing through the direct repeat. Here we describe a reproducible method for genotyping closely related isolates by using four SNR loci in a multiplex-PCR capillary electrophoresis system amenable to high-throughput analysis.

Selection for G156A O6-methylguanine DNA methyltransferase gene-transduced hematopoietic progenitors and protection from lethality in mice treated with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea.

A retroviral gene therapy approach was developed to protect early hematopoietic progenitors from 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a stem cell toxin, and O6-benzylguanine (BG), an inhibitor of a key BCNU resistance protein, O6-alkylguanine DNA alkyltransferase (AGT). The retroviral vector MFG was used to transfer the G156A MGMT (deltaMGMT) cDNA, encoding a mutant AGT that is resistant to inhibition by BG, into murine bone marrow-derived hematopoietic progenitors. Following transplantation into lethally irradiated mice, the transduced cells were subjected to in vivo BG and BCNU treatment to examine the ability to enrich for transduced cells expressing deltaAGT. Transplantation of deltaMGMT-transduced cells resulted in deltaAGT expression in 30% of bone marrow nucleated cells 13 weeks after transplantation. After one cycle of BG and BCNU, deltaAGT expression was observed in 60% of bone marrow cells, and the percentage of colony-forming units (culture; CFU-C) containing proviral sequence increased from 67 to 100%. CFU-C obtained from BG and BCNU-treated deltaMGMT animals up to 23 weeks after transplantation were more resistant to combination BG and BCNU than CFU-C from mice transplanted with lacZ-transduced cells and treated with BG and BCNU or from mice transplanted with deltaMGMT-transduced cells and left untreated. The degree of drug resistance in deltaMGMT-transduced hematopoietic progenitors to BG and BCNU was much greater than we observed previously with wild-type MGMT gene transfer and treatment with BCNU alone. Furthermore, whereas 21 of 22 mice transplanted with deltaMGMT-transduced cells survived in vivo BG and BCNU administration, only 3 of 13 mice transplanted with lacZ-transduced progenitors survived similar drug treatment. Thus, deltaMGMT-transduced murine bone marrow cells selectively survive in vivo BG and BCNU exposure, resulting in prolonged enrichment for the transduced cells and protection from mortality induced by this drug combination.

Selective radiosensitization of drug-resistant MutS homologue-2 (MSH2) mismatch repair-deficient cells by halogenated thymidine (dThd) analogues: Msh2 mediates dThd analogue DNA levels and the differential cytotoxicity and cell cycle effects of the dThd analogues and 6-thioguanine.

Mismatch repair (MMR) deficiency, which underlies hereditary nonpolyposis colorectal cancer, has recently been linked to a number of sporadic human cancers as well. Deficiency in this repair process renders cells resistant to many clinically active chemotherapy agents. As a result, it is of relevance to find an agent that selectively targets MMR-deficient cells. We have recently shown that the halogenated thymidine (dThd) analogues iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) selectively target MutL homologue-1 (MLH1)-deficient human cancer cells for radiosensitization. The levels of IdUrd and BrdUrd in cellular DNA directly correlate with the ability of these analogues to increase the sensitivity of cells and tissues to ionizing radiation, and data from our laboratory have demonstrated that MLH1-mediated MMR status impacts dThd analogue DNA levels, and consequently, analogue-induced radiosensitization. Here, we have extended these studies and show that, both in human and murine cells, MutS homologue-2 (MSH2) is also involved in processing dThd analogues in DNA. Using both E1A-transformed Msh2+/+ and Msh2-/- murine embryonic stem (ES)-derived cells (throughout this report we use Msh2+/+ and Msh2-/- to refer to murine ES-derived cell lines that are wild type or mutant, respectively, for the murine Msh2 gene) and human endometrial cancer cells differing in MSH2 status, we see the classic cytotoxic response to 6-thioguanine (6-TG) in Msh2+/+ and human HEC59/2-4 (MSH2+) MMR-proficient cells, whereas Msh2-/- cells and human HEC59 (MSH2-/-) cells are tolerant (2-log difference) to this agent. In contrast, there is very little cytotoxicity in Msh2+/+ ES-derived and HEC59/2-4 cells to IdUrd, whereas Msh2-/- and HEC59 cells are more sensitive to IdUrd. High-performance liquid chromatography analysis of IdUrd and BrdUrd levels in DNA suggests that this differential cytotoxicity may be due to lower analogue levels in MSH2+ murine and human tumor cells. The DNA levels of IdUrd and BrdUrd continue to decrease over time in Msh2+/+ cells following incubation in drug-free medium, whereas they remain high in Msh2-/- cells. This trend was also found in MSH2-deficient human endometrial cancer cells (HEC59) when compared with HEC59/2-4 (hMsh2-corrected) cells. As a result of higher analogue levels in DNA, Msh2-/- cells are selectively targeted for radiosensitization by IdUrd. Fluorescence-activated cell-sorting analysis of Msh2+/+ and Msh2-/- cells shows that selective toxicity of the halogenated nucleotide analogues is not correlated with a G2-M cell cycle arrest and apoptosis, as is found for selective killing of Msh2+/+ cells by 6-TG. Together, these data demonstrate MSH2 involvement in the processing of IdUrd and BrdUrd in DNA, as well as the differential cytotoxicity and cell cycle effects of the halogenated dThd analogues compared with 6-TG. Therefore, IdUrd and BrdUrd may be used clinically to selectively target both MLH1- and MSH2-deficient, drug-resistant cells for radiosensitization.

Loss of DNA mismatch repair imparts defective cdc2 signaling and G(2) arrest responses without altering survival after ionizing radiation.

Our previous data demonstrated that cells deficient in MutL homologue-1 (MLH1) expression had a reduced and shorter G(2) arrest after high-dose-rate ionizing radiation (IR), suggesting that the mismatch re pair (MMR) system mediates this cell cycle checkpoint. We confirmed this observation using two additional isogenetically matched human MLH1 (hMLH1)-deficient and -proficient human tumor cell systems: human ovarian cancer cells, A2780/CP70, with or without ectopically expressed hMLH1, and human colorectal carcinoma cells, RKO, with or without azacytidine treatment to reexpress hMLH1. We also examined matched MutS homologue-2 (hMSH2)-deficient and -proficient human endometrial carcinoma HEC59 cell lines to determine whether hMSH2, and MMR in general, is involved in IR-related G(2) arrest responses. As in MLH1-deficient cells, cells lacking hMSH2 demonstrated a similarly altered G(2) arrest in response to IR (6 Gy). These differences in IR-induced G(2) arrest between MMR-proficient and -deficient cells were found regardless of whether synchronized cells were irradiated in G(0)/G(1) or S phase, indicating that MMR indeed dramatically affects the G(2)-M checkpoint arrest. However, unlike the MMR-dependent damage tolerance response to 6-thioguanine exposures, no significant difference in the clonogenic survival of MMR-deficient cells compared with MMR-proficient cells was noted after high-dose-rate IR. In an attempt to define the signal transduction mechanisms responsible for MMR-mediated G(2) arrest, we examined the levels of tyrosine 15 phosphorylation of cdc2 (phospho-Tyr15-cdc2), a key regulator of the G(2)-M transition. Increased phospho-Tyr15-cdc2 levels were observed in both MMR-proficient and -deficient cell lines after IR. However, the levels of the phospho-Tyr15-cdc2 rapidly decreased in MMR (hMLH1 or hMSH2)-deficient cell lines at times coincident with progress from the IR-induced G(2) arrest through M phase. Thus, differences in the levels of phospho-Tyr15-cdc2 after high-dose-rate IR correspond temporally with the observed differences in the IR-induced G(2) arrest, suggesting that MMR proteins may exert their effect on IR-induced G(2) arrest by signaling the cdc2 pathway. Although MMR status does not significantly affect the survival of cells after high-dose-rate IR, it seems to regulate the G(2)-M checkpoint and might affect overall mutation rates.