Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes. Conclusions 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient

Treatment of blunt thoracic aortic injury in Germany—Assessment of the TraumaRegister DGU®

Purpose Using the data delivered by the German Trauma Register DGU® from 2002 till 2013, the value of different therapies of blunt thoracic aortic injury (BTAI) in Germany was analyzed. Methods Prospectively collected data of patients suffering from BTAI were retrospectively analyzed with focus on the different treatment modalities for grade I–IV injuries. Results 821 patients suffering from BTAI were identified: 51.6% (424) grade I injury, 35.4% (291) grade II or III injury and 12.9% (106) grade IV injury (77.5% men [44.94 ± 20.6 years]). The main patterns of injury were high- speed accidents and falls (78.0% [n = 640], 21.8% [n = 171] respectively). Significant differences between grade I and grade II/III as well as IV injuries could be assessed for the incidence of cardiopulmonary resuscitation, a Glasgow Coma Scale score below 8 and a systolic blood pressure below 90 mmHg (p-value: <0.001). In the primary admission subgroup, 44.1% (197/447) of the patients received best medical treatment, 55.9% received surgical intervention (250/447): Thereof 37.2% (93/250) received open surgery and 62.8% (147/250) had been treated by endovascular means. Significantly lower 24-h- and in-hospital-mortality rates were encountered after endovascular treatment for all gradings of BTAI (p-value: <0.001). Yet this subgroup of patients showed the lowest incidence of further severe injuries and cardiac arrest. Conclusion Endovascular therapy became the treatment of choice for BTAI in Germany. Patients who have been treated by surgical means showed the highest survival rate, especially endovascular therapy showed a favorable low mortality rate

Sequential conformational transitions and α-helical supercoiling regulate a sensor histidine kinase

Sensor histidine kinases are central to sensing in bacteria and in plants. They usually contain sensor, linker, and kinase modules and the structure of many of these components is known. However, it is unclear how the kinase module is structurally regulated. Here, we use nano- to millisecond time- resolved X-ray scattering to visualize the solution structural changes that occur when the light-sensitive model histidine kinase YF1 is activated by blue light. We find that the coiled coil linker and the attached histidine kinase domains undergo a left handed rotation within microseconds. In a much slower second step, the kinase domains rearrange internally. This structural mechanism presents a template for signal transduction in sensor histidine kinases

The Bose-Einstein correlation function C2(Q)C_2(Q) from a Quantum Field Theory point of view

We show that a recently proposed derivation of Bose-Einstein correlations (BEC) by means of a specific version of thermal Quantum Field Theory (QFT), supplemented by operator-field evolution of the Langevin type, allows for a deeper understanding of the possible coherent behaviour of the emitting source and a clear identification of the origin of the observed shape of the BEC function $C_2(Q)$. Previous conjectures in this matter obtained by other approaches are confirmed and have received complementary explanation.Comment: Some misprints corrected. To be publishe in Phys. Rev.

Incremental value of biomarker combinations to predict progression of mild cognitive impairment to Alzheimer’s dementia

Background The progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1–42 (Aβ42), amyloid-beta1–40 (Aβ40) levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia. Methods We used 115 complete datasets from MCI patients of the “Dementia Competence Network”, a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%. Results Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aβ40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80–0.83, and the four- parameter combination from AUC 0.81–0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone. Conclusion A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials

Nonperturbative Effects in Gluon Radiation and Photoproduction of Quark Pairs

We introduce a nonperturbative interaction for light-cone fluctuations containing quarks and gluons. The $\bar qq$ interaction squeezes the transverse size of these fluctuations in the photon and one does not need to simulate this effect via effective quark masses. The strength of this interaction is fixed by data. Data on diffractive dissociation of hadrons and photons show that the nonperturbative interaction of gluons is much stronger. We fix the parameters for the nonperturbative quark-gluon interaction by data for diffractive dissociation to large masses (triple-Pomeron regime). This allows us to predict nuclear shadowing for gluons which turns out to be not as strong as perturbative QCD predicts. We expect a delayed onset of gluon shadowing at $x \leq 10^{-2}$ shadowing of quarks. Gluon shadowing turns out to be nearly scale invariant up to virtualities $Q^2\sim 4 GeV^2$ due to presence of a semihard scale characterizing the strong nonperturbative interaction of gluons. We use the same concept to improve our description of gluon bremsstrahlung which is related to the distribution function for a quark-gluon fluctuation and the interaction cross section of a $\bar qqG$ fluctuation with a nucleon. We expect the nonperturbative interaction to suppress dramatically the gluon radiation at small transverse momenta compared to perturbative calculations.Comment: 58 pages of Latex including 11 figures. Shadowing for soft gluons and Fig. 6 are added as well as a few reference

Global maps of soil temperature.

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km &lt;sup&gt;2&lt;/sup&gt; resolution for 0-5 and 5-15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km &lt;sup&gt;2&lt;/sup&gt; pixels (summarized from 8519 unique temperature sensors) across all the world's major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications