Dark matter axion search using a Josephson Traveling wave parametric amplifier.

We describe the first implementation of a Josephson Traveling Wave Parametric Amplifier (JTWPA) in an axion dark matter search. The operation of the JTWPA for a period of about two weeks achieved sensitivity to axion-like particle dark matter with axion-photon couplings above 10-13 Ge V-1 over a narrow range of axion masses centered around 19.84 µeV by tuning the resonant frequency of the cavity over the frequency range of 4796.7-4799.5 MHz. The JTWPA was operated in the insert of the axion dark matter experiment as part of an independent receiver chain that was attached to a 0.56-l cavity. The ability of the JTWPA to deliver high gain over a wide (3 GHz) bandwidth has engendered interest from those aiming to perform broadband axion searches, a longstanding goal in this field.

Search for a Dark-Matter-Induced Cosmic Axion Background with ADMX.

We report the first result of a direct search for a cosmic axion background (CaB)-a relativistic background of axions that is not dark matter-performed with the axion haloscope, the Axion Dark Matter eXperiment (ADMX). Conventional haloscope analyses search for a signal with a narrow bandwidth, as predicted for dark matter, whereas the CaB will be broad. We introduce a novel analysis strategy, which searches for a CaB induced daily modulation in the power measured by the haloscope. Using this, we repurpose data collected to search for dark matter to set a limit on the axion photon coupling of a CaB originating from dark matter cascade decay via a mediator in the 800-995 MHz frequency range. We find that the present sensitivity is limited by fluctuations in the cavity readout as the instrument scans across dark matter masses. Nevertheless, we suggest that these challenges can be surmounted using superconducting qubits as single photon counters, and allow ADMX to operate as a telescope searching for axions emerging from the decay of dark matter. The daily modulation analysis technique we introduce can be deployed for various broadband rf signals, such as other forms of a CaB or even high-frequency gravitational waves.

Proton Compton Scattering from Linearly Polarized Gamma Rays.

Differential cross sections for Compton scattering from the proton have been measured at scattering angles of 55°, 90°, and 125° in the laboratory frame using quasimonoenergetic linearly (circularly) polarized photon beams with a weighted mean energy value of 83.4 MeV (81.3 MeV). These measurements were performed at the High Intensity Gamma-Ray Source facility at the Triangle Universities Nuclear Laboratory. The results are compared to previous measurements and are interpreted in the chiral effective field theory framework to extract the electromagnetic dipole polarizabilities of the proton, which gives α_{E1}^{p}=13.8±1.2_{stat}±0.1_{BSR}±0.3_{theo},ß_{M1}^{p}=0.2∓1.2_{stat}±0.1_{BSR}∓0.3_{theo} in units of 10^{-4} fm^{3}.

Axion Dark Matter Experiment: Detailed design and operations.

Axion dark matter experiment ultra-low noise haloscope technology has enabled the successful completion of two science runs (1A and 1B) that looked for dark matter axions in the 2.66-3.1 µeV mass range with Dine-Fischler-Srednicki-Zhitnisky sensitivity [Du et al., Phys. Rev. Lett. 120, 151301 (2018) and Braine et al., Phys. Rev. Lett. 124, 101303 (2020)]. Therefore, it is the most sensitive axion search experiment to date in this mass range. We discuss the technological advances made in the last several years to achieve this sensitivity, which includes the implementation of components, such as the state-of-the-art quantum-noise-limited amplifiers and a dilution refrigerator. Furthermore, we demonstrate the use of a frequency tunable microstrip superconducting quantum interference device amplifier in run 1A, and a Josephson parametric amplifier in run 1B, along with novel analysis tools that characterize the system noise temperature.

Search for Invisible Axion Dark Matter in the 3.3-4.2 µeV Mass Range.

We report the results from a haloscope search for axion dark matter in the 3.3-4.2 µeV mass range. This search excludes the axion-photon coupling predicted by one of the benchmark models of "invisible" axion dark matter, the Kim-Shifman-Vainshtein-Zakharov model. This sensitivity is achieved using a large-volume cavity, a superconducting magnet, an ultra low noise Josephson parametric amplifier, and sub-Kelvin temperatures. The validity of our detection procedure is ensured by injecting and detecting blind synthetic axion signals.

A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.

Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.

Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline.

We evaluated a multiple consanguineous Turkish family with two children, a boy and a girl, affected by severe encephalopathy, hypotonia, microcephaly and retinal dystrophy by a combination of linkage analysis and Whole Exome Sequencing (WES). We analyzed the sequence data by two different bioinformatics pipelines which did not differ in overall processing strategy but involved differences in software used, minor allele frequency (MAF) thresholds and reference data sets, the usage of in-house control exomes and filter settings to prioritize called variants. Assuming autosomal recessive mode of inheritance, only homozygous variants present in both children were considered. The resulting variant lists differed partially (nine variants identified by both pipelines, ten variants by only one pipeline). Major reasons for this discrepancy were different filters for MAF and different variant prioritizations. Combining the variant lists with the results of linkage analysis and further prioritization by expression data and prediction tools, an intronic homozygous splice variant (c.1090-2A>G; IVS9-2A>G; p.?) in PGAP1 (Post-GPI Attachment To Proteins 1) was identified and validated by cDNA analysis. PGAP1 ensures the first step of maturation of GPI (glycosylphosphatidylinositol)-anchor proteins. Recently, a homozygous loss-of-function mutation in PGAP1 has been reported in one family with two children affected by a similar phenotype. The present report not only illustrates the possible influence of specific filtering settings on the results of WES but also confirms PGAP1 as a cause of severe encephalopathy.

The influence of grass silage-to-maize silage ratio and concentrate composition on methane emissions, performance and milk composition of dairy cows.

It is well-established that altering the proportion of starch and fibre in ruminant diets can alter ruminal and post-ruminal digestion, although quantitative evidence that this reduces enteric methane (CH4) production in dairy cattle is lacking. The objective of this study was to examine the effect of varying grass-to-maize silage ratio (70 : 30 and 30 : 70 DM basis), offered ad libitum, with either a concentrate that was high in starch or fibre, on CH4 production, intake, performance and milk composition of dairy cows. A total of 20 cows were allocated to one of the four experimental diets in a two-by-two factorial design run as a Latin square with each period lasting 28 days. Measurements were conducted during the final 7 days of each period. Cows offered the high maize silage ration had a higher dry matter intake (DMI), milk yield, milk energy output and lower CH4 emissions when expressed per kg DMI and per unit of ingested gross energy, but there was no difference in total CH4 production. Several of the milk long-chain fatty acids (FA) were affected by forage treatment with the most notable being an increase in 18:0, 18:1 c9, 18:2 c9 c12 and total mono unsaturated FA, observed in cows offered the higher inclusion of maize silage, and an increase in 18:3 c9 c12 c15 when offered the higher grass silage ration. Varying the composition of the concentrate had no effect on DMI or milk production; however, when the high-starch concentrate was fed, milk protein concentration and milk FAs, 10:0, 14:1, 15:0, 16:1, increased and 18:0 decreased. Interactions were observed for milk fat concentration, being lower in cows offered high-grass silage and high-fibre concentrates compared with the high-starch concentrate, and FA 17:0, which was the highest in milk from cows fed the high-grass silage diet supplemented with the high-starch concentrate. In conclusion, increasing the proportion of maize silage in the diets of dairy cows increased intake and performance, and reduced CH4 production, but only when expressed on a DM or energy intake basis, whereas starch-to-fibre ratio in the concentrate had little effect on performance or CH4 production.

Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients.

Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin-Frankfurt-Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6-6.3%) for the best group (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.

[Molecular genetic detection of minimal residual disease (MRD) in children with acute lymphoblastic leukemia]. / Molekulargenetischer Nachweis minimaler Resterkrankung (minimal residual disease, MRD) bei Kindern mit akuter lymphoblastischer Leukämie.

The treatment of acute lymphoblastic leukemia (ALL) in childhood and adolescence achieves nowadays cure rates of more than 80%. The detection of minimal residual disease (MRD) via molecular genetic methods provides - in comparison with conventional clinical and biological parameters - much more sensitive approaches to monitor individual treatment response. Here we will discuss the molecular background and technical developments in the framework of the BFM-study group.

[Placebo responders in randomized controlled drug trials of fibromyalgia syndrome : Systematic review and meta-analysis]. / Placeboresponder in randomisierten, kontrollierten Medikamentenstudien des Fibromyalgiesyndroms : Systematische Übersicht und Metaanalyse.

BACKGROUND: The superiority of true drug treatment over placebo in reducing symptoms of fibromyalgia syndrome (FMS) is small. Drug placebo treatment of functional somatic syndromes (FSS) such as FMS has been discussed. We determined the magnitude of placebo responders in drug trials with FMS patients to substantiate further research on placebo treatment of FSS. MATERIAL AND METHODS: CENTRAL, MEDLINE, Scopus, and the databases of the U.S. National Institutes of Health and the Pharmaceutical Research and Manufacturers of America were searched for randomized, double-blind, placebo-controlled trials with a parallel design and treatment duration of ≥ 12 weeks in FMS patients from inception to 31 December 2010. The magnitude of placebo responders was assessed by the pooled estimate of patients with a 30% and 50% reduction in pain. RESULTS: Thirty studies with 3,846 patients on placebo were included. The pooled estimate of a 30% placebo pain reduction was 30.8% (95% confidence interval (CI) 29.4-32.3%) and of a 50% placebo pain reduction was 18.8% (95% CI 17.5-20.1%). The pooled estimate of the risk ratio of 30% pain reduction by true drug versus placebo was 1.38 (95% CI 1.27-1.49). The pooled estimate of the risk ratio of 50% pain reduction by true drug versus placebo response was 1.57 (95% CI 1.36-1.81). CONCLUSION: The magnitude of responders to placebo in drug trials of FMS is substantial. The efficacy, safety, and costs of drugs recommended for FMS therapy and open-label placebo should be compared in large multinational trials sponsored by public institutions. The English full-text version of this article is available at SpringerLink (under "Supplemental").

Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment.

Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n=45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell-receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL.

State of the art: an integrated approach to pelvic floor ultrasonography.

Surgical management of pelvic floor disorders depends on a comprehensive understanding of the structural integrity and function of the pelvic floor. For visualizing this region, ultrasonography has emerged as a procedure that is relatively easy to perform, cost-effective and widely available. In this review, pelvic floor ultrasonography, including two-dimensional (2D), three-dimensional (3D) and 4D imaging as well as transvaginal, endoanal and transperineal techniques, is discussed from a global and multicompartmental perspective, rather than using a compartmentalized approach. The role of the different sonographic modalities in the major disorders of the pelvic floor-urinary and fecal incontinence, pelvic organ prolapse and obstructed defecation syndrome-is evaluated critically.

Effect of intravenous contrast agent volume on colorectal cancer vascular parameters as measured by perfusion computed tomography.

AIM: To determine the effect of two different contrast agent volumes on quantitative and semi-quantitative vascular parameters as measured by perfusion computed tomography (CT) in colorectal cancer. MATERIALS AND METHODS: Following ethical approval and informed consent, eight prospectively recruited patients with proven colorectal adenocarcinoma underwent two separate perfusion CT studies on the same day after (a) 100 ml and (b) 50 ml of a 340 mg/ml iodinated contrast medium, respectively. Quantitative (blood volume, blood flow, permeability surface area product) and semi-quantitative (peak enhancement, time to peak enhancement) tumour vascular parameters were determined using commercial software based on distributed parameter analysis and compared using t-testing. RESULTS: Tumour blood volume, blood flow, and permeability surface area product were not substantially different following the injection of 100ml and 50 ml contrast medium: 6.12 versus 6.23 ml/100 g tissue; 73.4 versus 71.3 ml/min/100 g tissue; 15.6 versus 15.3 ml/min/100 g tissue for 100 and 50 ml, respectively; p>0.05. Tumour peak enhancement and time to peak were significantly greater following the injection of 100ml versus 50 ml contrast medium: 41.2 versus 28.5 HU; 16.1 versus 11.8 s for 100ml and 50 ml, respectively; p=0.002; p=0.0003. CONCLUSION: Quantitative parameters do not appear to change substantially with a higher contrast agent volume suggesting a combined diagnostic staging-perfusion CT study following a single injection is feasible for colorectal cancer.

Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia.

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (< or =10(-4)), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD > or =10(-3) at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.

Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting.

Minimal residual disease (MRD) diagnostics is used for treatment stratification in childhood acute lymphoblastic leukemia. We aimed to identify and solve potential problems in multicenter MRD studies to achieve and maintain consistent results between the AIEOP/BFM ALL-2000 MRD laboratories. As the dot-blot hybridization method was replaced by the real-time quantitative polymerase chain reaction (RQ-PCR) method during the treatment protocol, special attention was given to the comparison of MRD data obtained by both methods and to the reproducibility of RQ-PCR data. Evaluation of all key steps in molecular MRD diagnostics identified several pitfalls that resulted in discordant MRD results. In particular, guidelines for RQ-PCR data interpretation appeared to be crucial for obtaining concordant MRD results. The experimental variation of the RQ-PCR was generally less than three-fold, but logically became larger at low MRD levels below the reproducible sensitivity of the assay (<10(-4)). Finally, MRD data obtained by dot-blot hybridization were comparable to those obtained by RQ-PCR analysis (r(2)=0.74). In conclusion, MRD diagnostics using RQ-PCR analysis of immunoglobulin/T-cell receptor gene rearrangements is feasible in multicenter studies but requires standardization; particularly strict guidelines for interpretation of RQ-PCR data are required. We further recommend regular quality control for laboratories performing MRD diagnostics in international treatment protocols.