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BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes,evidence of an association with breast cancer is weak, underlying risk estimatesare imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing onsamples from 60,466 women with breast cancer and 53,461 controls. In separateanalyses for protein-truncating variants and rare missense variants in these genes,we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluatedmissense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2)were associated with a risk of breast cancer overall with a P value of less than0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D,and TP53) were associated with a risk of breast cancer overall with a P value ofless than 0.05 and a Bayesian false-discovery probability of less than 0.05. Forprotein-truncating variants in 19 of the remaining 25 genes, the upper limit ofthe 95% confidence interval of the odds ratio for breast cancer overall was lessthan 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios werehigher for estrogen receptor (ER)–positive disease than for ER-negative disease;for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, andRAD51D, odds ratios were higher for ER-negative disease than for ER-positivedisease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 wereassociated with a risk of breast cancer overall with a P value of less than 0.001.For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a riskof breast cancer overall, with the risk being similar to that of protein-truncatingvariants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimatesof the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)

Context:Optical interferometry is at a key development stage. ESO's VLTI has established a stable, robust infrastructure for long-baseline interferometry for general astronomical observers. The present second-generation instruments offer a wide wavelength coverage and improved performance. Their sensitivity and measurement accuracy lead to data and images of high reliability. Aims:We have developed MATISSE, the Multi AperTure mid-Infrared SpectroScopic Experiment, to access high resolution imaging in a wide spectral domain and explore topics such: stellar activity and mass loss; planet formation and evolution in the gas and dust disks around young stars; accretion processes around super massive black holes in AGN. Methods:The instrument is a spectro-interferometric imager covering three atmospheric bands (L,M,N) from 2.8 to 13.0 mu, combining four optical beams from the VLTI's telscopes. Its concept, related observing procedure, data reduction and calibration approach are the product of 30 years of instrumental research. The instrument utilizes a multi-axial beam combination that delivers spectrally dispersed fringes. The signal provides the following quantities at several spectral resolutions: photometric flux, coherent fluxes, visibilities, closure phases, wavelength differential visibilities and phases, and aperture-synthesis imaging. Results:We provide an overview of the physical principle of the instrument and its functionalities, the characteristics of the delivered signal, a description of the observing modes and of their performance limits. An ensemble of data and reconstructed images are illustrating the first acquired key observations. Conclusion:The instrument has been in operation at Cerro Paranal, ESO, Chile since 2018, and has been open for science use by the international community since April 2019. The first scientific results are being published now., 24 pages, 26 figures, submitted to Astronomy & Astrophysics

Because of limited ability to visually discriminate targeted tissue from surrounding tissue the demand for new image guided surgery, such as fluorescence guidance, has increased. Fluorescence is the spontaneous emission of light radiation from a substance that is electronically excited by a light source. Meaning that light needs to go in first and a light-sensitive camera is required to detect the emitted light. Different types of fluorescent dyes are in use. The light absorbance and emission aspects of these dyes dictate the spectrum that needs to be visualized, for example near-infrared. Fluorescent dyes can be used as a free dye or bound (conjugated) to small molecules like proteins or peptides. When conjugated with a tumor specific molecule it can target different types of cancer. This way fluorescence guidance in node dissection can avail in real-time visualization of the lymphatic pathway, identification of sentinel node(s) or tumor containing tissue. A limiting factor of fluorescence is the tissue penetration of about 15 mm. (Tumor specific) hybrid tracers combining fluorescent with radioactive properties to unite acoustic and visual guidance could therefore hold great promise for the future.

Multi-year droughts in Mediterranean climates may shift the water balance, that is, the partitioning rule of precipitation across runoff, evapotranspiration, and subsurface storage. Mechanisms causing these shifts remain largely unknown and are not well represented in hydrologic models. Focusing on measurements from the headwaters of California s Feather River, we found that also in these mixed rain snow Mediterranean basins a lower fraction of precipitation was partitioned to runoff during multi-year droughts compared to non-drought years. This shift in the precipitation runoff relationship was larger in the surfacerunoff-dominated than subsurface-flow-dominated headwaters (39% vs. 18% decline of runoff, respectively, for a representative precipitation amount). The predictive skill of the Precipitation Runoff Modeling System (PRMS) hydrologic model in these basins decreased during droughts, with evapotranspiration (ET) being the only water-balance component besides runoff for which the drop in predictive skill during drought vs. non-drought years was statistically significant. In particular, the model underestimated the response time required by ET to adjust to interannual climate variability, which we define as climate elasticity of ET. Differences between simulated and data-driven estimates of ET were well correlated with accompanying data-driven estimates of changes in sub-surface storage (1S, r D 0:78). This correlation points to shifts in precipitation runoff relationships being evidence of a hysteretic response of the water budget to climate elasticity of ET during and after multi-year droughts. This hysteresis is caused by carryover storage offsetting precipitation deficit during the initial drought period, followed by vegetation mortality when storage is depleted and subsequent post-drought vegetation expansion. Our results point to a general improvement in hydrologic predictions across drought and recovery cycles by including the climate elasticity of ET and better accounting for actual subsurface water storage in not only soil, but also deeper regolith that stores water accessible to roots. This can be done by explicitly parametrizing carryover storage and feedback mechanisms capturing vegetation response to atmospheric demand for moisture.

Atrial fibrillation is a widespread disease of growing clinical, economic and social importance. Interventional therapy for atrial fibrillation offers encouraging results, with pulmonary vein isolation (PVI) as the established cornerstone. Yet, the challenge to create durable transmural lesions remains, leading to recurrence of atrial fibrillation in long-term follow-up even after multiple ablation procedures in 20% of patients with paroxysmal atrial fibrillation and approximately 50% with persistent atrial fibrillation. To overcome these limitations, innovative tools such as the cryoballoon and contact force catheters have been introduced and have demonstrated their potential for safe and effective PVI. Furthermore, advanced pharmacological and pacing manoeuvres enhance evaluation of conduction block in PVI.

Background: Revision of an acetabular component that has failed after a total hip arthroplasty in which a bulk femoral head autogenous graft or allograft was used as a structural graft for acetabular reconstruction is an uncommon but complex and challenging procedure. We previously reported the results for seventy hips at an average of 16.5 years after a total hip arthroplasty in which an acetabular reconstruction had been performed with a femoral head graft. In the present study, we evaluated a subset of nine hips from that series that had a subsequent revision of the acetabular component without cement. The purpose of the current study was to assess the usefulness of the bone graft in this revision. Methods: The nine patients (nine hips) were followed clinically and radiographically for an average of seventy-six months (range, sixty-one to 114 months) after the index revision. In six hips the autogenous femoral head graft previously had been bolted to the lateral side of the ilium, and in one hip the femoral head allograft had been affixed in this manner. In the two remaining hips, the allograft had been placed within the acetabulum. The hips were classified according to the extent of acetabular bone loss, with use of criteria described previously. Three hips had stage-I bone loss; four, stage-II; and two, stage-IIIB. A porous-coated hemispherical acetabular component was inserted without cement and fixed with screws in each hip. At least 70 percent of the porous coating was in contact with viable bone. Results: At the time of the latest follow-up after the index revision, all nine acetabular components were functioning well without loosening or osteolysis and none had been revised. The average Harris hip score was 77 points (range, 61 to 98 points) compared with 49 points (range, 27 to 96 points) preoperatively. One hip had had revision of the femoral stem, and another had had exchange of the acetabular liner because of recurrent dislocations. There was no additional resorption of the residual bulk graft that was in contact with the metal shell in any hip. Conclusions: In this small series of complex acetabular revisions, the healed hulk graft provided valuable additional bone stock for the support of an acetabular component that was inserted without cement. Insertion of the acetabular component into the available bone, which consisted in major part of host bone and in minor part of united revascularized bulk graft, resulted in a well functioning hip after an intermediate duration of follow-up. In all except two hips, the enlarged bone stock allowed insertion of a a larger acetabular component than had been used previously.

We report lattice QCD results on the axial charges of ground and excited nucleon states of both parities. This is the first study of these quantities with approximately chiral (CI) fermions. Two energy levels in the range of the negative parity resonances N*(1535) and N*(1650) are observed and we determine the axial charge for both. We obtain a small axial charge for one of them, which is consistent with the chiral symmetry restoration in this state as well as with the small axial charge of the N*(1535) predicted within the quark model. This result agrees with the findings of Takahashi et al. obtained with Wilson quarks which violate chiral symmetry for finite lattice spacing. At the same time for the other observed negative parity state we obtain a large axial charge, that is close to the axial charge of the nucleon. This is in disagreement both with the quark model prediction as well as with the chiral restoration but allows for an interpretation as an s-wave {\pi} N state.

Hydrologie und Wasserbewirtschaftung / BfG – Jahrgang: 56.2012,5 - ISSN 1439-1783

Employees’ perceptions of Management Development (MD) programs is the topic of this study. The purpose is to examine the influence of three important perceived characteristics of MD programs on relevant MD outcomes. The MD characteristics are: availability of role models, perceived control, and understanding the MD program. Outcomes are: participation in development activities, MD and job satisfaction, affective organizational commitment, perceived benefits of development activities, average salary growth, innovative behavior, and critical opinion sharing. Data are collected from 453 MD participants of seven organizations in the Netherlands. Findings show that perceived control has a positive relationship with MD satisfaction and extrinsic and organizational benefits of development activities. Understanding the MD program positively influences MD satisfaction and extrinsic benefits. Availability of role models has a positive relationship with intrinsic and organizational benefits.

QPACE is a novel parallel computer which has been developed to be primarily used for lattice QCD simulations. The compute power is provided by the IBM PowerXCell 8i processor, an enhanced version of the Cell processor that is used in the Playstation 3. The QPACE nodes are interconnected by a custom, application optimized 3-dimensional torus network implemented on an FPGA. To achieve the very high packaging density of 26 TFlops per rack a new water cooling concept has been developed and successfully realized. In this paper we give an overview of the architecture and highlight some important technical details of the system. Furthermore, we provide initial performance results and report on the installation of 8 QPACE racks providing an aggregate peak performance of 200 TFlops., Comment: 21 pages. Poster by T. Maurer and plenary talk by D. Pleiter presented at the "XXVII International Symposium on Lattice Field Theory", July 26-31 2009, Peking University, Beijing, China. Information on recent Green500 ranking added and list of authors extended

Purpose Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is used for (re)staging prostate cancer (PCa) and as a biomarker for evaluating response to therapy, but lacks established response criteria. A panel of PCa experts in nuclear medicine, radiology, and/or urology met on February 21, 2020, in Amsterdam, The Netherlands, to formulate criteria for PSMA PET/CT-based response in patients treated for metastatic PCa and optimal timing to use it. Methods Panelists received thematic topics and relevant literature prior to the meeting. Statements on how to interpret response and progression on therapy in PCa with PSMA PET/CT and when to use it were developed. Panelists voted anonymously on a nine-point scale, ranging from strongly disagree (1) to strongly agree (9). Median scores described agreement and consensus. Results PSMA PET/CT consensus statements concerned utility, best timing for performing, criteria for evaluation of response, patients who could benefit, and handling of radiolabeled PSMA PET tracers. Consensus was reached on all statements. PSMA PET/CT can be used before and after any local and systemic treatment in patients with metastatic disease to evaluate response to treatment. Ideally, PSMA PET/CT imaging criteria should categorize patients as responders, patients with stable disease, partial response, and complete response, or as non-responders. Specific clinical scenarios such as oligometastatic or polymetastatic disease deserve special consideration. Conclusions Adoption of PSMA PET/CT should be supported by indication for appropriate use and precise criteria for interpretation. PSMA PET/CT criteria should categorize patients as responders or non-responders. Specific clinical scenarios deserve special consideration.

Since its introduction to the diagnostic pathway for prostate cancer management, prostate-specific membrane antigen (PSMA)–ligand PET has demonstrated great potential. PSMA-ligand imaging is increasingly influencing therapeutic decision making, although its impact on patient outcomes still needs to be defined. One relatively new application, enabled through chemical and engineering efforts, is PSMA-guided surgery. This review highlights the potential of PSMA-guided surgery and discusses its implications in lymph node dissection in primary and recurrent prostate cancer.

Background We hypothesized that the residency status (rural area [RA] vs urban clusters [UC] vs urban areas [UA]) affects stage and cancer-specific mortality (CSM) in contemporary newly diagnosed prostate cancer (PCa) patients of all stages, regardless of treatment. Methods Newly diagnosed PCa patients with available residency status were abstracted from the Surveillance, Epidemiology, and End Results database (2004–2016). Propensity-score (PS) matching, cumulative incidence plots, multivariate competing-risks regression (CRR) models were used. Results Of 531,468 PCa patients of all stages, 6653 (1.3%) resided in RA, 50,932 (9.6%) in UC and 473,883 (89.2%) in UA. No statistically significant or clinically meaningful differences in stage at presentation or CSM were recorded. Conversely, 10-year other cause-mortality (OCM) rates were 27.2% vs 23.7% vs 18.9% (p p p Conclusion RA, and to a lesser extent UC, PCa patients are at higher risk of OCM than UA patients. Higher OCM may indicate shorter life expectancy and should be considered in treatment decision making.