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}.

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.

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.

[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.

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.

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.

[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").

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.

bcr Rearrangement without juxtaposition of c-abl in chronic myelocytic leukemia.

Southern blot analysis detected a bcr gene rearrangement within leukemic cells of a Philadelphia chromosome-negative chronic myelocytic leukemia (CML) patient that led to transcription of a novel 7.3 kb bcr RNA species. Participation of the c-abl oncogene in this genomic recombination could be ruled out by in situ hybridization studies and Northern blot analysis.

Persistence of chronic myelocytic leukemia despite deletion of rearranged bcr/c-abl sequences in blast crisis.

We report on a Ph+ chronic myelocytic leukemia (CML) case, cytogenetically characterized by the occurrence of a second Philadelphia (Ph) chromosome in lymphoid blast crisis of T cell lineage. In situ hybridization analyses showed a deletion of translocated c-abl sequences, present on the Ph during chronic state, from both Ph in acute state. Moreover, Southern blot analyses of blastic cells exhibited a rearrangement within bcr, but a deletion of 5' bcr sequences, and Northern blots failed to detect the hybrid 8.5 kb bcr/c-abl transcript usually observed in Ph+ CML.

Severe combined immunodeficiency (SCID) in man: B cell-negative (B-) SCID patients exhibit an irregular recombination pattern at the JH locus.

Human severe combined immunodeficiency (SCID) patients were analyzed by a polymerase chain reaction assay for their recombination capability at the DHQ52-JH region of the immunoglobulin heavy chain locus. Five patients with B cells (B+ SCID) exhibited a recombination pattern also observed in healthy persons. In contrast, six patients lacking B cells (B- SCID) showed a grossly altered rearrangement pattern characterized by the (partial) absence of regular DHQ52-JH recombinations and the presence of abnormal rearrangements. These events were caused by deletions surpassing the boundaries of immunoglobulin coding elements and thus resemble the pattern of deletional recombinations previously described in SCID mice.

RAG mutations in human B cell-negative SCID.

Patients with human severe combined immunodeficiency (SCID) can be divided into those with B lymphocytes (B+ SCID) and those without (B- SCID). Although several genetic causes are known for B+ SCID, the etiology of B- SCID has not been defined. Six of 14 B- SCID patients tested were found to carry a mutation of the recombinase activating gene 1 (RAG-1), RAG-2, or both. This mutation resulted in a functional inability to form antigen receptors through genetic recombination and links a defect in one of the site-specific recombination systems to a human disease.

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.

Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case-control study.

We genotyped six folate metabolic pathway genes for 11 polymorphisms in 460 cases of childhood acute lymphoblastic leukemia (ALL) and 552 ethnically matched controls. None of the polymorphisms except the 66A>G (I22M) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene showed any effect on disease risk. The carriers of the G-allele were associated with a marginal decreased risk of ALL (gender-adjusted global P=0.03; multiple-testing corrected P=0.25). Analysis of four polymorphisms in the MTRR gene showed statistically significant differences in haplotype distribution between cases and controls (global P<0.0001). The haplotypes GCAC (odds ratio (OR) 0.5, 95% confidence interval (CI) 0.4-0.6) and ATAC (OR 0.5, 95% CI 0.3-0.6) were associated with a reduced risk and the haplotypes ACAC (OR 2.3, 95% CI 1.8-2.9) and GTAC (OR 1.8, 95% CI 1.4-2.3) with an increased risk. The genotype-combination analyses indicated that the best model stratifies cases and controls based on the 66A>G and the 524C>T polymorphisms in the MTRR gene (global P=0.03). Our results suggest that, besides a weak association of childhood ALL with the 66A>G polymorphism, haplotypes within the MTRR gene may, in part, account for population-based differences in risk.

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.

The proximal element of the beta globin locus control region is not functionally required in vivo.

In addition to local sequence elements the regulation of the high-level, development- and tissue-specific expression of the human beta globin gene cluster appears to require distant regulatory sequences which have been termed locus control region. In the chromatin of erythroid cells the locus control region is characterized by four DNaseI hypersensitive sites that are located 6-18 kb 5' of the epsilon globin gene. The definition of the sequences minimally required for locus control region activity is likely to further the understanding of its physiology and will be of interest for the development of somatic gene therapy strategies of the hemoglobinopathies. We present here the analysis of a family with a 3,030-bp deletion of sequences upstream of the epsilon globin gene including the most 3' locus control region element and cosegregating beta(0) thalassemia. The deletion is linked in cis to a structurally and functionally normal beta globin gene. The proximal element of the locus control region does not therefore appear to be necessary for beta globin gene activity in vivo.

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.

Comparison of radiologists' confidence in excluding significant colorectal neoplasia with multidetector-row CT colonography compared with double contrast barium enema.

The aim of this study was to compare the confidence of experienced radiologists in excluding colonic neoplasia with CT colonography (CTC) compared with barium enema. 78 patients (median age 70 years, range 61-87 years, 44 women) underwent same day CTC and barium enema. Two radiologists experienced in reporting barium enema assessed whether the examination had excluded a polyp 6 mm or greater as "yes", "probably" or "no" for each of 6 colonic segments. Two different radiologists experienced in CTC independently performed the same assessment on the CT datasets. Responses were compared using a paired exact test. Formal barium enema and CT reports were compared with any endoscopic examination performed within 1 year. Studies reporting polyps 6 mm+ in patients not subsequently undergoing endoscopy were reviewed by two independent observers. Radiologists stated they had confidently excluded a significant lesion in 314 (71%) and 382 (86%) of 444 segments with barium enema and CTC, respectively (p<0.001). Confidence was significantly higher with CTC in the in the descending and ascending colon (p = 0.02 and p<0.001, respectively), and caecum (p<0.001). 22 patients underwent some form of endoscopy. Of five patients with proven colorectal neoplasia (including two with cancer), CTC and barium enema correctly identified five and three, respectively. In 56 patients not undergoing endoscopy, CTC reported 17 polyps 6 mm+, of which 16 were retrospectively classified as definite or probable. 11 could not be identified on the barium enema, even in retrospect. Confidence in excluding polyps 6 mm or larger is significantly greater with CT colonography particularly in the proximal colon.