Search

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.

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., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

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},β_{M1}^{p}=0.2∓1.2_{stat}±0.1_{BSR}∓0.3_{theo} in units of 10^{-4}  fm^{3}.

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.

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.

Introduction: Telecommunicator Assisted Cardiopulmonary Resuscitation (T-CPR) is independently associated with improved survival and improved functional outcome after adult Out of Hospital Cardiac Arrest (OHCA). The objective of this study was to evaluate whether there are racial and socioeconomic disparities in the provision of T-CPR instruction and subsequent CPR performance. Methods: We performed a retrospective review of a convenience sample of EMS agencies throughout the United States that utilized the Cardiac Arrest Registry to Enhance Survival (CARES) dispatch registry during the period 1/2014-12/2017. Data were collected by dispatch agencies after review of 9-1-1 OHCA audio recordings. Elements related to dispatcher CPR instruction, barriers to bystander CPR (BCPR) performance, patient race (White, Black, Hispanic-Latino, or other) and Utstein data were captured from the CARES database. These data were merged with census tract data from incident locations. The effects of race and income (Socioeconomic status, SES) on outcome were analyzed using multilevel logistic regression. Results: A total of 3,807 cases were identified from 37 dispatch agencies in 6 states. The sample was predominantly White (57.5%) and male (64.9%) with an average age of 60.3 ± 19.9. In the adjusted analysis, there were no differences in the odds of receiving CPR instruction by race (black vs white), OR = 0.96 (95% CI. 0.70, 1.32) or for increased income, (OR = 1.00, 95% CI 0.99, 1.02). There was a significant difference in receipt of T-CPR instruction by patient age, OR = 0.99 (95% CI, 0.98, 0.99). Subsequent utilization of T-CPR instruction to perform BCPR was less likely for patients that had a lower income, OR = 1.03 (95% CI 1.01, 1.05). There was also a decreased rate of BCPR provision by patient age OR = 0.99 (95% CI, 0.99, 1.00), but there was no difference in rate of BCPR provision by race, OR = 0.86 (95% CI 0.61, 1.23). Conclusion: We identified differences in age but not race or SES in the provision of T-CPR instruction by dispatch centers. We also identified decreased CPR provision by age and income after receipt of T-CPR instructions. In this sample, we found no evidence of racial disparities in the provision of T-CPR instruction or subsequent provision of BCPR.

Objectives: Dispatch-assisted cardiopulmonary resuscitation (DA-CPR) has been shown to improve cardiac arrest survival. Recent literature has proposed dispatch metrics for provision of this intervention. Our objectives are to: use the Cardiac Arrest Registry to Enhance Survival (CARES) to compare current practice to proposed DA-CPR guidelines; describe barriers to DA-CPR; and assess the association of DA-CPR with out-of-hospital cardiac arrest (OHCA) survival., Methods: We reviewed data from structured dispatch reviews of 911 OHCA calls from 1/1/14-12/31/15. Dispatch data including whether dispatch CPR instruction was given, and time intervals to CPR instruction and provision were linked with OHCA data elements from field cardiac arrest process and outcome data. Descriptive data on barriers to dispatch-caller instruction and measures of dispatcher performance were calculated. We compared outcome of patients who received bystander CPR prior to the 911 call (BCPR), after dispatcher CPR instructions (DA-CPR), and not until Emergency Medical Services (EMS) arrival (no BCPR)., Results: We identified 3335 cases from 32 dispatch agencies in 9 states that had dispatch and outcome data. CPR was performed prior to the 911 call by a bystander in 496 (14.9%) cases. Of all calls where the dispatcher talked to a bystander, dispatchers recognized cardiac arrest in 82.9% cases (1514/1827), with 31.6% calls recognized in <60 seconds. DA-CPR instructions were initiated in most (1320/1514, 87.2%) cases, and cardiac compressions were initiated in 73.7% (973/1320). DA-CPR was performed < two minutes in 21.4% of cases. In a multivariable analysis, BCPR (CPR prior to EMS arrival without instructions given) was associated with significantly improved patient survival (OR = 1.49, 95% CI 1.09, 2.04), and DA-CPR a non-significant improvement in survival to discharge (OR = 1.19, 95% CI 0.91, 1.56)., Conclusions: Temporal measures of dispatch performance were substantially below proposed national standards. In this population, OHCA was frequently recognized and DA-CPR performed but was not associated with a significant improvement in survival.

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.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists., Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2., Design, Setting, and Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk., Exposures: Mutations of BRCA1 or BRCA2., Main Outcomes and Measures: Breast and ovarian cancer risks., Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers., Conclusions and Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

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.

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., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: The objectives of the study were to determine the impact of nocebo effects on adverse events (AEs) in drug trials in fibromyalgia syndrome (FMS) and painful diabetic peripheral neuropathy (DPN)., Methods: MEDLINE, CENTRAL, SCOPUS, and the databases of the U.S. National Institutes of Health and the Pharmaceutical Research and Manufacturers of America were searched until December 31, 2010. Randomized controlled trials with a parallel design of any drug therapy compared with pharmacological placebo in patients with FMS and DPN were included. Pooled estimates of nocebo effects (number of patients with at least 1 AE and dropping out due AEs) were calculated for placebo and true drug groups by a random effects model., Results: Fifty-eight FMS (62 DPN) trials included a total of 5065 (5095) patients in placebo groups. The quality of reporting the assessment strategy of AEs was poor in most trials. The pooled estimate of the event rate drop out rate due to AEs in placebo groups was 9.6 [95% confidence control (CI): 8.6-10.7] in placebo and 16.3 (95% CI: 14.1-31.2) in true drug groups of FMS trials and was 5.8 (95% CI: 5.1-6.6) in placebo and 13.2 (95% CI: 10.7-16.2) in true drug groups of DPN trials. Nocebo effects accounted for 72.0% (44.9) of the drop outs in true drug groups in FMS (DPN)., Discussion: Nocebo effects substantially accounted for AEs in drug trials of FMS and DPN. Standards to assess and report AEs should be defined by regulatory agencies. Strategies to minimize nocebo effects in both clinical trials and clinical practice should be developed.

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").

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.

The magnitude of placebo response and its predictors in fibromyalgia syndrome (FMS) and painful peripheral diabetic neuropathy (DPN) had not been studied. We performed a systematic review by searching MEDLINE, CENTRAL, SCOPUS, and the databases of the U.S. National Institutes of Health and the Pharmaceutical Research and Manufacturers of America until July 2010. We included randomised controlled trials of any pharmacological therapy compared with pharmacological placebo in patients with FMS and painful DPN. Pain values were converted to a 0 to 100 scale. We computed the pooled weighted mean difference (WMD) between pain baseline and end of treatment scores in placebo and active drug groups using a random effects model. A total of 72 studies (9827 patients) in FMS and of 70 studies in DPN (10,297 patients) were included. The pooled WMD in the FMS-placebo group was 7.69 (95% confidence interval [CI] 6.10 to 9.29) and 17.11 (95% CI 16.41 to 17.90) in painful DPN. The pooled WMD in the FMS-active drug group was 13.96 (95% CI 11.93 to 15.99) and in painful DPN was 22.54 (95% CI 20.49 to 24.58). The correlation between WMD in the placebo and active drug group in FMS was r=0.69 and painful DPN r=0.47. Placebo accounted for 45% of the response in the drug groups in FMS and for 62% in painful DPN. The placebo response was higher in painful DPN than in FMS (P<.001). The placebo response was not associated with age, sex, and race, but with year of study initiation, pain baseline, and effect size in active drug groups in both diseases., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives: Peutz-Jeghers syndrome (PJS) in children may present with anaemia, intussusception, or obstruction from an early age and surgery is common. Prophylactic polypectomy may reduce subsequent complications. Traditional barium enterography (BE) has poor sensitivity and requires significant radiation. We compared the performance of capsule endoscopy (CE) with BE in children with PJS., Materials and Methods: Children with PJS (ages 6.0-16.5 years) were prospectively recruited and underwent BE followed by CE, each reported by expert reviewers blinded to the alternate modality. Number of "significant" (>10 mm) and total number of polyps were recorded. Child preference was assessed using a visual analogue questionnaire. Definitive findings were assessed at laparotomy or enteroscopy, when performed., Results: There was no significant difference for >10 mm polyp detection. Six polyps were found in 3 children by both modalities: 3 polyps in 2 children at CE, 3 polyps in 1 child at BE (P=0.50). Re-review of 1 CE identified 3 polyps that were missed in 1 child at initial reading. Significantly more <10 mm polyps were identified by CE than BE: 61 vs 6 (P=0.02). CE was significantly more comfortable than BE (median score CE 76 [interquartile range 69-87] vs BE 37 [interquartile range 31-68], P=0.03) and was the preferred investigation in 90% (P=0.02)., Conclusions: CE is a feasible, safe, and sensitive test for small bowel polyp surveillance in children with PJS. It is significantly more comfortable than BE and is the preferred test of most children for future surveillance. There is a learning curve for reporting CE studies in PJS and appropriate training is essential.

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.

In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) after 5 and 12 weeks of treatment, has evolved as a strong prognostic factor in children with acute lymphoblastic leukemia (ALL) treated according to the BFM regime. Individual treatment response may be influenced by copy number alterations (CNA) leading to altered gene expression. We aimed to evaluate CNA using high-resolution array-comparative genomic hybridization (array-CGH) in different treatment-response groups. Leukemic genomic profiles of 25 standard risk (MRD-SR) and 25 high risk (MRD-HR) patients were compared. CNAs were found in 46/50 patients (92%). The most significant difference was a gain of 1q23-qter because of an unbalanced t(1;19), found in 10/25 MRD-SR patients, but in none of the MRD-HR patients (P < 0.001). The most frequent CNAs in the MRD-HR group were deletions of genomic regions harboring the immunoglobulin genes (Ig), e.g., 2p11.2 in 60% of MRD-HR compared to 28% of MRD-SR (P = 0.045). Combining all Ig loci, significantly more MRD-HR than MRD-SR patients displayed deletions (17:8 patients, P = 0.02). Frequency of other CNAs, such as loss of 9p21 or gains of 21q, did not differ strongly between the two patient groups. This is the first study evaluating the clinical significance of CNA as detected by array-CGH in childhood ALL and the first to suggest that such analyses may provide clinically important data. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

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.

A method of intact postmortem removal of the pelvic floor for imaging correlation studies, with minimal access disfigurement, is described. This consists of subcutaneous removal of both ischiopubic rami with division of the obturator membrane cranial to the origin of the levator ani muscles. The anatomical relationships of soft tissue surrounding the distal birth canal are thus preserved. The report discusses the need for, constraints on, and limitations of such studies in the unique problems of determining the dynamic anatomical configuration of the soft tissues of the pelvic floor. It illustrates the clinical relevance of initial studies, and reviews the background contributions of members of the group.

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 clinical management of patients with anorectal and pelvic floor dysfunction is often difficult. Evacuation proctography has evolved from a method to evaluate the anorectum for functional disorders to its current status as a practical method for evaluating anorectal dysfunction and pelvic floor prolapse. It has a high observer accuracy and yield of positive diagnosis. Clinicians find it of major benefit and has altered management from surgical to medical and vice versa in a significant number of cases.

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.

The extent measurement error on CT colonography influences polyp categorisation according to established management guidelines is studied using twenty-eight observers of varying experience to classify polyps seen at CT colonography as either 'medium' (maximal diameter 6-9 mm) or 'large' (maximal diameter 10 mm or larger). Comparison was then made with the reference diameter obtained in each patient via colonoscopy. The Bland-Altman method was used to assess agreement between observer measurements and colonoscopy, and differences in measurement and categorisation was assessed using Kruskal-Wallis and Chi-squared test statistics respectively. Observer measurements on average underestimated the diameter of polyps when compared to the reference value, by approximately 2-3 mm, irrespective of observer experience. Ninety-five percent limits of agreement were relatively wide for all observer groups, and had sufficient span to encompass different size categories for polyps. There were 167 polyp observations and 135 (81%) were correctly categorised. Of the 32 observations that were miscategorised, 5 (16%) were overestimations and 27 (84%) were underestimations (i.e. large polyps misclassified as medium). Caution should be exercised for polyps whose colonographic diameter is below but close to the 1-cm boundary threshold in order to avoid potential miscategorisation of advanced adenomas.

Our purpose was to assess the effect of reader experience, fatigue, and scan findings on interpretation time for CT colonography. Nine radiologists (experienced in CT colonography); nine radiologists and ten technicians (both groups trained using 50 validated examinations) read 40 cases (50% abnormal) under controlled conditions. Individual interpretation times for each case were recorded, and differences between groups determined. Multi-level linear regression was used to investigate effect of scan category (normal or abnormal) and observer fatigue on interpretation times. Experienced radiologists (mean time 10.9 min, SD 5.2) reported significantly faster than less experienced radiologists and technicians; odds ratios of reporting times 1.4 (CI 1.1, 1.8) and 1.6 (1.3, 2.0), respectively (P

The purpose of this study was to determine if greater z-axis tumour coverage improves the reproducibility of quantitative colorectal cancer perfusion measurements using CT. A 65 s perfusion study was acquired following intravenous contrast administration in 10 patients with proven colorectal cancer using a four-detector row scanner. This was repeated within 48 h using identical technical parameters to allow reproducibility assessment. Quantitative tumour blood volume, blood flow, mean transit time and permeability measurements were determined using commercially available software (Perfusion 3.0; GE Healthcare, Waukesha, WI) for data obtained from a 5 mm z-axis tumour coverage, and from a 20 mm z-axis tumour coverage. Measurement reproducibility was assessed using Bland-Altman statistics, for a 5 mm z-axis tumour coverage, and 20 mm z-axis tumour coverage, respectively. The mean difference (95% limits of agreement) for blood volume, blood flow, mean transit time and permeability were 0.04 (-2.50 to +2.43) ml/100 g tissue; +8.80 (-50.5 to +68.0) ml/100 g tissue/min; -0.99 (-8.19 to +6.20) seconds; and +1.20 (-5.42 to +7.83) ml/100 g tissue/min, respectively, for a 5 mm coverage, and -0.04 (-2.61 to +2.53) ml/100 g tissue; +7.40 (-50.3 to +65.0) ml/100 g tissue/min; -2.46 (-12.61 to +7.69) seconds; and -0.23 (-8.31 to +7.85) ml/100 g tissue/min, respectively, for a 20 mm coverage, indicating similar levels of agreement. In conclusion, increasing z-axis coverage does not improve reproducibility of quantitative colorectal cancer perfusion measurements.

Background and Study Aims: Video capsule endoscopy has shown promise for the surveillance of significant small-bowel polyps in patients with Peutz-Jeghers syndrome. In this study the yield of significant small-bowel polyps by capsule endoscopy was compared to the yield of these polyps by barium follow-through in adults with Peutz-Jeghers syndrome., Patients and Methods: A total of 19 adults with Peutz-Jeghers syndrome who were undergoing surveillance underwent both capsule endoscopy and barium follow-through examinations, and the number of small-bowel polyps of at least 1 cm in diameter that were detected was recorded for each method. The two methods were assessed in terms of comfort and convenience for the patients and their preferred future surveillance method, using a questionnaire., Results: Capsule endoscopy detected a median of four significant small-bowel polyps while barium follow-through detected a median of one (P = 0.008). There was a trend towards more participants having at least one significant small-bowel polyp detected by capsule endoscopy than was the case with barium follow-through, though capsule endoscopy seemed to be less reliable for accurate sizing of polyps that were at the limit of clinical significance. Most participants expressed a preference for capsule endoscopy for future surveillance., Conclusions: Capsule endoscopy should replace barium follow-through for the surveillance of small-bowel polyps in adults with Peutz-Jeghers syndrome, but the findings of this study should be interpreted with caution until a more reliable means of sizing polyps by capsule endoscopy is available.

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.

Objective: The purpose of our study was to compare the effects of automated and manual carbon dioxide insufflation before CT colonography on distention and patient acceptance., Subjects and Methods: One hundred forty-one symptomatic subjects underwent CT colonography using either an automated device (n = 47) or a manual method (n = 94) for carbon dioxide insufflation. CT data sets were assessed retrospectively in consensus by two blinded observers who graded distention for six colonic segments using a 4-point scale. An additional assessment of the overall clinical adequacy of distention (yes/no) was also made, and any learning curve was sought. Each patient completed a validated 24-point patient questionnaire reflecting patient satisfaction and discomfort. Distention scores, clinical adequacy, and questionnaire responses were analyzed using ordered logistic regression, Fisher's exact test, and the Mann-Whitney test statistic, respectively., Results: Automated insufflation significantly improved distention overall (p = 0.001). For individual segments, distention was significantly improved in the sigmoid (p = 0.007) and descending (p < 0.001) colons when the patient was supine; and in the sigmoid (p = 0.02), descending (p = 0.001), and transverse (p = 0.02) colons when supine and prone positions were combined. No significant difference was seen in the clinical adequacy of distention, nor was there evidence of any learning curve for either insufflation method. Subjects were more weary after automated insufflation (p = 0.03), but no significant difference was seen for the remaining 23 questionnaire items or for feelings of bloating or discomfort., Conclusion: Automated carbon dioxide insufflation significantly improves colonic distention compared with manual insufflation. Benefit is greatest in the left colon, particularly when the patient is supine. Patient acceptance is similar to that for manual insufflation.

Aims: To compare the subjective acceptability of CT colonography in comparison with barium enema in older symptomatic patients, and to ascertain preferences for future colonic investigation., Materials and Methods: The study population comprised 78 persons aged 60 years or over with symptoms suggestive of colorectal neoplasia, who underwent CT colonography followed the same day by barium enema. A 25-point questionnaire was administered after each procedure and an additional follow-up questionnaire a week later. Responses were compared using Wilcoxon matched pairs testing, Mann-Whitney test statistics and binomial exact testing., Results: Participants suffered less physical discomfort during CT colonography (p = 0.03) and overall satisfaction was greater compared with barium enema (p = 0.03). On follow-up, respondents reported significantly better tolerance of CT colonography (p = 0.002), and were less prepared to undergo barium enema again (p < 0.001). Of 52 subjects expressing an opinion, all preferred CT to barium enema., Conclusion: Patient satisfaction was higher with CT colonography than barium enema. CT colonography caused significantly less physical discomfort and was overwhelmingly preferred by patients.

Aim: To investigate the feasibility of using multidetector-row computed tomography (CT) duodenography to stage duodenal polyposis in patients with familial adenomatous polyposis., Materials and Methods: Six patients underwent multidetector-row CT duodenography before upper gastrointestinal endoscopy. A single-blinded radiologist used a surface shaded three-dimensional endoluminal fly though and two-dimensional axial and multiplanar reformats to assign a score for maximum polyp size and number based on the Spigelman classification. Comparison was made with the corresponding Spigelman scores obtained from subsequent endoscopy., Results: CT duodenography was technically successful in five of six patients. The CT derived Spigelman score based on maximum polyp size was accurate in all five patients. The CT derived Spigelman score based on polyp number was accurate in only two cases: Polyp number was overestimated in one patient and underestimated in a further two. In retrospect, fine carpeting of tiny duodenal polyps was poorly visualized with CT., Conclusions: CT duodenography is technically feasible and accurately predicts maximum polyp size but CT estimates of polyp number are relatively inaccurate. CT duodenography potentially has a useful role for duodenal surveillance in those patients intolerant of conventional endoscopy.

Objective: Preoperative MRI of fistula in ano is becoming more common. This prospective study aimed to determine if a significant difference occurred in interpretation between one expert and one novice observer and to assess inter- and intraobserver agreement after both observers underwent a period of directed education. SUBJECTS AND METHODS. An outcome-derived reference standard was defined in 100 patients with suspected fistula in ano via a combination of preoperative MRI, surgical findings, and clinical outcome. The performances of a single expert and a single novice interpreter were compared with this reference standard both before and after a period of directed education, and inter- and intraobserver agreement was determined., Results: Initially the expert correctly classified significantly more fistulas than the novice (85% vs 63%, p = 0.024), but after directed education there was no significant difference, with good agreement for both the classification of the primary track (kappa = 0.71) and identification of extensions (k = 0.61). Intraobserver agreement was very good for the expert (kappa = 0.92) and novice (kappa = 0.88) for classification of the primary track and good (kappa = 0.64 and 0.74, respectively) for identification of extensions., Conclusion: The diagnostic accuracy for fistula in ano classification using MRI was significantly higher for one expert than for one novice, though this was rectified by a short period of directed education.

Objectives: This longitudinal observational study evaluated the effect of 8 years of uninterrupted treatment of tibolone on bone mineral density (BMD) in postmenopausal women with significant osteopenia or osteoporosis., Material and Methods: Subjects were 66 postmenopausal women (29 with moderate or severe osteopenia and 37 with osteoporosis) who took tibolone (2.5 mg nocte) uninterruptedly for over 8 years and who attended for annual BMD assessments. Their mean age was 66.7 (0.86) years (range 50-86 years). BMD measurements at the lumbar spine and proximal femur were performed annually by dual-energy X-ray absorptiometry (DEXA)., Results: During the 8 years of treatment with tibolone there was a significant increase in BMD at the spine (P < 0.001) and at the hip (P < 0.001). Women who did not have previous oestrogen therapy had significantly greater response to tibolone than those who had previous treatment with conventional hormone replacement therapy (HRT)., Conclusion: This long-term observational study provides evidence of the effectiveness of tibolone in postmenopausal women with moderate/severe osteopenia and osteoporosis in terms of a significant increase in BMD.

Rectal cancer is a common malignancy with a highly variable outcome. Local recurrence is dependent upon tumour stage and surgical technique. The role of pre-operative imaging is to determine which patients may be safely managed by surgery alone and which need additional therapy in order to facilitate surgery and improve outcome. This decision depends on the distinction between those with early and advanced disease. While trans-rectal ultrasound has traditionally been used to answer this question, a role for magnetic resonance imaging (MRI) is increasingly argued. This review will focus on the treatment options for rectal cancer and the clinical questions that subsequently arise for the radiologist to answer.

The German Multicenter Study Group for Adult ALL (GMALL) conducts since 1984 trials with risk adapted study design. The model of conventional prognostic factors comprises now WBC, age, immunophenotype, cytogenetics and molecular genetics. Risk stratification according to these factors allows a highly significant prediction of relapse risk in adult ALL. In the recent GMALL study minimal residual disease (MRD) was added to the risk model. Trials in childhood and adult ALL showed convincingly that MRD is a relevant and independent prognostic factor. It is of particular value in standard risk (SR) patients as defined by conventional factors. In the current GMALL study a risk stratification according to conventional factors is followed by a MRD based stratification in SR patients. Whereas high and very high risk patients receive a stem cell transplantation (SCT) in first CR after induction and first consolidation, SR patients receive cyclic consolidation therapy for one year with MRD monitoring. At the end of the first year a stratification according to course and level of MRD takes place. Treatment is stopped in patients with low risk whereas in high risk patients a SCT is planned. Patients who cannot be allocated to either group are treated as intermediate risk and receive one year of intensified maintenance therapy. Preliminary results show that MRD based risk stratification is feasible and that the treatment recommendations for MRD based risk groups are reasonable. In the future however an earlier identification of high risk patients (after 4 months) will be attempted.

The t(12;21) translocation resulting in the TEL-AML1 gene fusion is found in 25% of childhood B-cell precursor (BCP) acute lymphoblastic leukemias (ALL). Since TEL-AML1 has been reported to induce cell cycle retardation and thus may influence somatic recombination, we analyzed 214 TEL-AML1-positive ALL by PCR for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. As a control group, 174 childhood BCP ALL without a TEL-AML1 were used. The majority of TEL-AML1-positive leukemias had a higher number of Ig/TCR rearrangements than control ALL. They also had a more mature immunogenotype characterized by their high frequency of complete IGH, IGK-Kde, and TCRG rearrangements. While IGK-Kde and TCRG were more frequently rearranged on both alleles at higher age, IGH and TCRD rearrangements decreased in their incidence along with a decrease in biallelic IGH rearrangements. This suggests that the recombination process continues in these leukemias leading to ongoing rearrangements and possibly also deletions of antigen receptor genes. We here provide first evidence that somatic recombination of antigen receptor genes is affected by the TEL-AML1 fusion, and that further age-related differences are probably caused by the longer latency period of the prenatally initiated TEL-AML1-positive leukemias in older children.