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The computer vision algorithms used currently in advanced driver assistance systems rely on image-based RGB cameras, leading to a critical bandwidth–latency trade-off for delivering safe driving experiences. To address this, event cameras have emerged as alternative vision sensors. Event cameras measure the changes in intensity asynchronously, offering high temporal resolution and sparsity, markedly reducing bandwidth and latency requirements1. Despite these advantages, event-camera-based algorithms are either highly efficient but lag behind image-based ones in terms of accuracy or sacrifice the sparsity and efficiency of events to achieve comparable results. To overcome this, here we propose a hybrid event- and frame-based object detector that preserves the advantages of each modality and thus does not suffer from this trade-off. Our method exploits the high temporal resolution and sparsity of events and the rich but low temporal resolution information in standard images to generate efficient, high-rate object detections, reducing perceptual and computational latency. We show that the use of a 20 frames per second (fps) RGB camera plus an event camera can achieve the same latency as a 5,000-fps camera with the bandwidth of a 45-fps camera without compromising accuracy. Our approach paves the way for efficient and robust perception in edge-case scenarios by uncovering the potential of event cameras2.

We present a method for estimating dense continuous-time optical flow from event data. Traditional dense optical flow methods compute the pixel displacement between two images. Due to missing information, these approaches cannot recover the pixel trajectories in the blind time between two images. In this work, we show that it is possible to compute per-pixel, continuous-time optical flow using events from an event camera. Events provide temporally fine-grained information about movement in pixel space due to their asynchronous nature and microsecond response time. We leverage these benefits to predict pixel trajectories densely in continuous time via parameterized Bézier curves. To achieve this, we build a neural network with strong inductive biases for this task: First, we build multiple sequential correlation volumes in time using event data. Second, we use Bézier curves to index these correlation volumes at multiple timestamps along the trajectory. Third, we use the retrieved correlation to update the Bézier curve representations iteratively. Our method can optionally include image pairs to boost performance further. To the best of our knowledge, our model is the first method that can regress dense pixel trajectories from event data. To train and evaluate our model, we introduce a synthetic dataset (MultiFlow) that features moving objects and ground truth trajectories for every pixel. Our quantitative experiments not only suggest that our method successfully predicts pixel trajectories in continuous time but also that it is competitive in the traditional two-view pixel displacement metric on MultiFlow and DSEC-Flow. Open source code and datasets are released to the public.

AbstractSufficient cooling of plasma-facing materials remains an outstanding challenge in the design of fusion reactor blankets in commercial power demonstration plants. Due to its chemical inertness and low neutron interaction cross section, pressurized helium is a candidate coolant fluid for such systems; however, helium has a small thermal mass compared to liquid coolants, potentially reducing heat removal performance. To address this need, a number of heat transfer enhancements have been proposed to improve the cooling efficiency of such components, thereby decreasing pumping power needs and improving overall plant efficiency.Toward this end, a helium flow loop experiment (HFLE) has been designed and commissioned to test advanced passive heat transfer enhancements in unit-cell test sections, providing necessary data for model validation and subsequent system design. The HFLE is designed to provide flow of pressurized (up to 4 MPa) helium at flow rates up to 80 g/s, enabling heat transfer and pressure drop measurements in test pieces at Reynolds numbers in excess of 180 000. To explore the effects of novel and complex heat transfer enhancements, test sections are produced via additive manufacturing, providing geometries not typically obtainable by conventional machining.In this work, we present results from HFLE commissioning and the initial thermal-hydraulic tests of an additively manufactured rifled-rib test section. Results are compared to smooth pipe correlations, and plans are described for future HFLE measurements. These preliminary experiments indicate the utility of the HFLE for heat transfer enhancement testing and simulation validation activities.

Summary: Corporate income taxation and prudential regulation are complementary instruments for public policy in banking markets. The common deductibility of interest payments induces debt bias and causes banks to be excessively levered. A reduction in debt-bias can achieve two goals at the same time: It enhances resiliency by lowering the cost of equity and it enhances the global competitiveness of banks by strengthening their capital structure. Moreover, even reforms that are fiscally neutral in the short run will reduce the fiscal burden on bank rescue operations in the long-run.

Natural microbial communities are phylogenetically and metabolically diverse. In addition to underexplored organismal groups1, this diversity encompasses a rich discovery potential for ecologically and biotechnologically relevant enzymes and biochemical compounds2,3. However, studying this diversity to identify genomic pathways for the synthesis of such compounds4and assigning them to their respective hosts remains challenging. The biosynthetic potential of microorganisms in the open ocean remains largely uncharted owing to limitations in the analysis of genome-resolved data at the global scale. Here we investigated the diversity and novelty of biosynthetic gene clusters in the ocean by integrating around 10,000 microbial genomes from cultivated and single cells with more than 25,000 newly reconstructed draft genomes from more than 1,000 seawater samples. These efforts revealed approximately 40,000 putative mostly new biosynthetic gene clusters, several of which were found in previously unsuspected phylogenetic groups. Among these groups, we identified a lineage rich in biosynthetic gene clusters (‘CandidatusEudoremicrobiaceae’) that belongs to an uncultivated bacterial phylum and includes some of the most biosynthetically diverse microorganisms in this environment. From these, we characterized the phospeptin and pythonamide pathways, revealing cases of unusual bioactive compound structure and enzymology, respectively. Together, this research demonstrates how microbiomics-driven strategies can enable the investigation of previously undescribed enzymes and natural products in underexplored microbial groups and environments.

AbstractOne technique for mitigating disruptions in a tokamak is shattered pellet injection (SPI). SPI is a process in which a large solid pellet consisting of deuterium, neon, or argon is desublimated in a pipe gun barsrel and launched downstream. Pellets are shattered just before entering the plasma by an impact with an angled tube. Injection of these materials into the plasma radiates stored thermal energy, limits current decay rates, suppresses the generation of runaway electrons, and dissipates runaway electrons if necessary. A critical element of the SPI system is a fast-acting valve that releases high-pressure gas to dislodge and accelerate pellets directly, or indirectly via a mechanical punch. A prototype valve sized for the ITER SPI system has been designed and fabricated. A pulsed high-voltage power supply energizes the valve’s internal magnetic coil, which induces eddy currents in the adjacent flyer plate resulting in a repulsive force between the flyer plate and the coil. The flyer plate action lifts a valve seat, allowing high-pressure gas to flow from the valve plenum to the downstream (breech) location of the pellet or mechanical punch. All of the valve’s internal components are designed to operate in ITER-level static background magnetic fields.A study was conducted to optimize the downstream pressure response for a range of valve sizes and operating pressures. In particular, the study analyzes the breech pressure response associated with varying plenum pressures as well as varying breech volumes. A computational fluid dynamics simulation was built in STAR-CCM+ and validated against data from laboratory experiments. The resulting simulation outputs, in the form of downstream responses for a variety of initial plenum pressures and breech volumes, will be used as a complement to experimental data to ensure the pressure pulse is suitable for pellet survivability. These data, combined with studies on pellet shear strength and shock response, will be applied to optimization of overall operating parameters of the ITER SPI system.

AbstractA helium flow loop is being assembled at Oak Ridge National Laboratory to analyze heat transfer enhancement for systems such as blanket and divertor components. To efficiently identify optimum geometries for heat transfer enhancement in these applications, simulation work is performed to optimize test section designs that are built and tested in the helium flow loop that operates at 4 MPa and a mass flow rate of 100 g/s. Different ribbed geometries that examine rib shape, rib height, rib orientation, rib spacing, and three-dimensional orientation are modeled and simulated in STAR-CCM+ to compare their ability to remove heat and mitigate pressure drop. Following the simulations, models are selected and manufactured for the helium flow loop tests. Simulations initially focus on a hydrodynamic study to determine the appropriate mesh and physics models and then add a heat flux to analyze the heat transfer abilities of the models. The simulations are run in steady state and use a Reynolds-averaged Navier-Stokes k-ε turbulence model. The helium is modeled as an ideal gas. The simulation explores models of geometries that enhance the heat transfer and decrease pressure drop with an overall goal of increasing fluid collision with the wall. Enhanced geometries are simulated to select appropriate designs for manufacturing, and preliminary experimental results are used to validate the simulations. The factors that are being analyzed in the comparison between the experimental and the simulated results include matching thermocouple temperatures, pressure drop, roughness, and fluid velocity.

When perceived as threatening, social interactions have been shown to trigger the sympathoadrenal medullary system as well as the hypothalamic-pituitary-adrenal axis resulting in a physiologic stress response. The allostatic load placed on human health and physiology in the context of acute and chronic stress can have profound health consequences. The purpose of this study was to develop a protocol for a lab-based stress stimulus using social-evaluative threat. While several valid, stress-stimulating protocols exist, we sought to develop one that triggered a physiologic response, did not require significant lab resources, and could be completed in around 10 min. We included 53 participants (29 men and 24 women) and exposed them to a modified version of the Stroop Color-Word Interference Task during which the participants were made to feel they were performing the task poorly while the lead researcher feigned annoyance and frustration. After exposure to this Feigned Annoyance and Frustration (FAF) Test, both the men and women in this study demonstrated a statistically significant and clinically meaningful increase in subjective stress on the visual analog scale. Additionally, the men in this study demonstrated a statistically significant increase in heart rate and salivary α-amylase concentrations after exposure to the test. The women in this study did not demonstrate a statistically significant increase in the physiologic stress biomarkers. This protocol for the FAF Test shows promise to researchers with limited time and resources who are interested in experimentally activating the sympathoadrenal medullary system.

Based on extensive literature research, hypotheses have been derived in order to test the impact of success factors (independend varibles) on the success indicator ROA (return on assets). Those hypotheses have been tested quantitatively and have been validated by expert interviews. The result is a model containing ten success factors which have positive or negative correlations with the dependend variable. With this model it is possible to estimate the result of listed companies based on those ten factors.

AbstractBackgroundWhether Copeptin combined with high sensitivity troponin below the respective decision cut-offs improves rule-out of NSTEMI and may predict all-cause death at 30-day is under debate.MethodsData on 10,329 patients from 5 trials were pooled to evaluate the diagnostic and prognostic performance of an initial Copeptin below decision cut-off in combination with a (hs)-cTn below the uppler limit of normal (ULN) compared to a) the initial (hs)-cTn alone in the standard serial sampling strategy based on the 99th percentile and b) a single marker strategy (SMS) based on hs-cTn < limit of detection. Endpoints were sensitivities and negative predictive values (NPV) for rule-out of NSTEMI, 30-day all-cause mortality and rates of eligibility for DMS or SMS.ResultsNPV for NSTEMI was higher for DMS than for the initial cTn, regardless assay sensitivity. The highest NPVs were observed with DMS vs. hs-cTn (99.4% [95% CI: 99.0%–99.6%] vs. 98.8% [98.4%–99.1%],) , and improved performance was consistent across all important subgroups including presentation <3 h, again irrespective of assay sensitivity. The point estimate of all NPVs for all-cause death exceeded 99.75%. In the label populations, DMS versus SMS demonstrated comparably high NPVs for rule-out of NSTEMI (99.4% [99.0%–99.6%] vs. 99.9% [99.2%–100.0%]), very low mortality after rule-out (0.1% [0.0%–0.4% vs. 0.0% [0.0%–1.2%]), but eligibility for rule-out was 2.4-fold higher (61.4% [59.9%–62.9%] vs. 25.3% [23.7%–26.9%]) with DMS than SMS.ConclusionFindings from a large pooled cohort corroborate the safety of the dual marker strategy for instant rule-out of NSTEMI, extending evidence to hs-cTn. Copeptin below cut-off in combination with hs-cTn below ULN may be used in more than 2.4-times more patients presenting with suspected ACS than a single marker strategy based on very low hs-cTn, without the need to exclude very early presenters or other important subgroups.

We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1and BRCA2pathogenic variant carriers.

IMPORTANCE: Negative pressure wound therapy (NPWT) is an established treatment option, but there is no evidence of benefit for subcutaneous abdominal wound healing impairment (SAWHI). OBJECTIVE: To evaluate the effectiveness and safety of NPWT for SAWHI after surgery in clinical practice. DESIGN, SETTING, AND PARTICIPANTS: The multicenter, multinational, observer-blinded, randomized clinical SAWHI study enrolled patients between August 2, 2011, and January 31, 2018. The last follow-up date was June 11, 2018. The trial included 34 abdominal surgical departments of hospitals in Germany, Belgium, and the Netherlands, and 539 consecutive, compliant adult patients with SAWHI after surgery without fascia dehiscence were randomly assigned to the treatment arms in a 1:1 ratio stratified by study site and wound size using a centralized web-based tool. A total of 507 study participants (NPWT, 256; CWT, 251) were assessed for the primary end point in the modified intention-to-treat (ITT) population. INTERVENTIONS: Negative pressure wound therapy and conventional wound treatment (CWT). MAIN OUTCOMES AND MEASURES: The primary outcome was time until wound closure (delayed primary closure or by secondary intention) within 42 days. Safety analysis comprised the adverse events (AEs). Secondary outcomes included wound closure rate, quality of life (SF-36), pain, and patient satisfaction. RESULTS: Of the 507 study participants included in the modified ITT population, 287 were men (56.6%) (NPWT, 155 [60.5%] and CWT, 132 [52.6%]) and 220 were women (43.4%) (NPWT, 101 [39.5%] and CWT 119 [47.4%]). The median (IQR) age of the participants was 66 (18) years in the NPWT arm and 66 (20) years in the CWT arm. Mean time to wound closure was significantly shorter in the NPWT arm (36.1 days) than in the CWT arm (39.1 days) (difference, 3.0 days; 95% CI 1.6-4.4; P &lt; .001). Wound closure rate within 42 days was significantly higher with NPWT (35.9%) than with CWT (21.5%) (difference, 14.4%; 95% CI, 6.6%-22.2%; P &lt; .001). In the therapy-compliant population, excluding study participants with unauthorized treatment changes (NPWT, 22; CWT, 50), the risk for wound-related AEs was higher in the NPWT arm (risk ratio, 1.51; 95% CI, 0.99-2.35). CONCLUSIONS AND RELEVANCE: Negative pressure wound therapy is an effective treatment option for SAWHI after surgery; however, it causes more wound-related AEs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01528033

Macromolecular organic photocatalysts consisting of a completely conjugated network have broad and promising applications in visible light-promoted photoredox catalysis. Precise reproduction and control of exact conjugation length remains an important challenge for fully conjugated and macromolecular photocatalysts. Here, we introduce a new photocatalytic material based on classical PMMA copolymerised with defined electron donor and acceptor units with precisely controllable redox potential and conjugation length, creating a promising class of metal-free, stable and low-cost heterogeneous photocatalysts. Furthermore, swelling of the PMMA copolymer matrix in organic solvents led to enhanced substrate diffusion and thereby increased catalytic efficiency. High efficiency and selectivity was achieved for photocatalytic [4 + 2] cycloaddition reactions in air with low effective photocatalyst loading. The photocatalytic efficiency of the PMMA photocatalyst was comparable with the state-of-the-art metal or non-metal catalysts while facilitating easy recyclability.

Der Beitrag analysiert die Entwicklung der Hilfeformen der spanischen Caritas, die als religiöser Akteur mit sozialpolitischem Einfluss zwischen 2008 und 2016 auf den Einbruch der großen Depression und die Anpassungen des spanischen Wohlfahrtsstaatsregimes reagiert. Zunächst werden die Merkmale des mediterranen Wohlfahrtsstaatsregimes beschrieben, insbesondere die Staat-Kirchen-Kooperation im sozialen Bereich nach dem Subsidiaritäts-Prinzip und der Einfluss des spanischen Katholizismus, der sich produktiv auf den Wohlfahrtsstaat auswirkt. Ausgehend von der These, dass das jeweilige Wohlfahrtsstaatsregime einen nachhaltigen, strukturierenden Einfluss auf die Entwicklung und Ausformung des Dritten bzw. Nonprofit-Sektors hat, lässt sich das spanische Wohlfahrtsarrangement erklären, und es zeigt sich, wie die Krise den Sektor trifft. Gerade die sogenannten „singulären Organisationen“, wie die Caritasverbände, konnten unter diesen Umständen ihre Vorrangstellung behaupten und erweitern. Schließlich werden die Implikationen und Auswirkungen der Krise aus der Sicht von 25 befragten Mitarbeitenden in sechs diözesanen Organisationen und der Zentrale in Madrid sowie ihre unterschiedlichen Hilfeverständnisse untersucht. Dabei ist zu erkennen, dass auf lokaler Ebene Prozesse stattfinden, in denen Diözesan-Caritasorganisationen mit konträren Strategien auf die an sie gerichteten Erwartungen reagieren, bei einer gleichzeitigen Betonung der katholischen Identität der Organisation. Die analysierten Strategien lassen sich als Coping-Mechanismen verstehen, die zu einer verstärkten Hybridisierung der Organisationen führen.

A 37-yr-old woman presented to the gynecology clinic with abnormal uterine bleeding in the setting of known, large uterine fibroids. Preoperative endometrial biopsy identified atypical melanocytic cells concerning for uterine melanoma. Care was transferred to the gynecologic oncology service for hysterectomy. Intraoperative findings included macular, blue-black pigmentation of the peritoneum of the bladder and cervix, which was resected and sent for frozen section, confirming melanocytic neoplasia. The hysterectomy revealed multiple tan leiomyomas up to 12 cm, and a distinct 3 cm black, incompletely circumscribed mass in the endomyometrium composed of bland spindled cells with delicate melanin granules. The tumor cells were positive for Sox-10, BAP1, and Mart-1 (Melan-A) and negative for PRAME, PD-L1, and BRAFV600E by immunostains. Microscopic elements of similar melanocytes and melanophages were found in the cervix and bladder peritoneum. Molecular analysis of the uterine tumor identified a GNA11mutation but no TERTor BAP1mutation. The uterine melanocytic tumor has characteristic findings of a cellular blue nevus arising in association with dendritic melanocytosis of Mullerian and pelvic tissues, a rarely seen benign phenomenon that should be distinguished from malignant melanoma of the upper genital tract.

AbstractHigh-density graphitic foam is an ideal low-Z plasma-facing material for deuterium-deuterium plasma experiments where tritium codeposition is not an issue. However, like all carbon, graphitic foam suffers from a precipitous drop in thermal conductivity at high temperatures, >600°C. To mitigate these problems, functionally graded layers of tungsten can be deposited to a thickness of 2 to 4 mm onto the plasma side of the foam using chemical vapor deposition. The graphitic foam then acts as a high-conductivity heat sink at temperatures below 600°C for the thin high-Z armor coating. The overall component weighs 18 times less than a comparable volume of tungsten and lacks the coefficient of thermal expansion joining issues between the CuCrZr tubing and the tungsten. This paper discusses the coating development and characterization and presents the results of recent plasma exposures in W7-X. It also reports on computational fluid dynamics heat transfer modeling and preparations for high heat flux testing of mock-ups. This hybrid plasma-facing component (PFC) consisting of innovative engineered materials may be a cost-effective, actively cooled solution for the divertors and other PFCs in long-pulse machines like W7-X and WEST.

•Factors associated with higher quality of life in MS were.•University education, RRMS, shorter disease duration, less depression/psychological distress.•No significant effects for physical disability, cognitive impairment or fatigue.•Focusing treatment on mental comorbidity could increase quality of life in MS.

Ongoing climate change might, through rising temperatures, alter allergenic pollen biology across the northern hemisphere. We aimed to analyse trends in pollen seasonality and pollen load and to establish whether there are specific climate-related links to any observed changes.

Adrenocortical carcinoma (ACC) has a heterogeneous prognosis, and current medical therapies have limited efficacy in its advanced stages. Genome-wide multiomics studies identified molecular patterns associated with clinical outcome.

Navigation systems have the potential to facilitate intraoperative orientation and recognition of anatomical structures. Intraoperative accuracy of navigation in thoracoabdominal surgery depends on soft tissue deformation. We evaluated esophageal motion caused by respiration and pneumoperitoneum in a porcine model for minimally invasive esophagectomy. In ten pigs (20–34 kg) under general anesthesia, gastroscopic hemoclips were applied to the cervical (CE), high (T1), middle (T2), and lower thoracic (T3) level, and to the gastroesophageal junction (GEJ) of the esophagus. Furthermore, skin markers were applied. Three-dimensional (3D) and four-dimensional (4D) computed tomography (CT) scans were acquired before and after creation of pneumoperitoneum. Marker positions and lung volumes were analyzed with open source image segmentation software. Respiratory motion of the esophagus was higher at T3 (7.0 ± 3.3 mm, mean ± SD) and GEJ (6.9 ± 2.8 mm) than on T2 (4.5 ± 1.8 mm), T1 (3.1 ± 1.8 mm), and CE (1.3 ± 1.1 mm). There was significant motion correlation in between the esophageal levels. T1 motion correlated with all other esophagus levels (r= 0.51, p= 0.003). Esophageal motion correlated with ventilation volume (419 ± 148 ml) on T1 (r= 0.29), T2 (r= 0.44), T3 (r= 0.54), and GEJ (r= 0.58) but not on CE (r= − 0.04). Motion correlation of the esophagus with skin markers was moderate to high for T1, T2, T3, GEJ, but not evident for CE. Pneumoperitoneum led to considerable displacement of the esophagus (8.2 ± 3.4 mm) and had a level-specific influence on respiratory motion. The position and motion of the esophagus was considerably influenced by respiration and creation of pneumoperitoneum. Esophageal motion correlated with respiration and skin motion. Possible compensation mechanisms for soft tissue deformation were successfully identified. The porcine model is similar to humans for respiratory esophageal motion and can thus help to develop navigation systems with compensation for soft tissue deformation.

Although uncontrolled proteolytic activity mediated by activated neutrophils is a major reason for tissue damage, therapeutic approaches using protease inhibitors are inefficient. Here, we investigated the role of the immune complex-induced neutrophil adhesion and protease release in tissue damage. We show both in vitro and in vivo that immune complex-mediated neutrophil adhesion to the target tissue depends on β2integrins. Without affecting elastase or reactive oxygen species release, blocking of adhesion drastically inhibited tissue damage in an experimental model of autoantibody-mediated skin blistering disease. By using a cell-bound fluorescent resonance energy transfer-based elastase sensor, we detected elastase enzyme activity on the surface of adherent cells resistant to protease inhibitors. Inhibitor resistance was lost by CD18 blockade or deficiency in vitro and in vivo. Immune complex-induced neutrophil adhesion created an enclosed protected space between the cell and its target structure where proteinases and reactive oxygen species can execute their tissue-damaging effect. Because immune complex-induced neutrophil adhesion represents an indispensable step for tissue damage of many diseases, our findings may facilitate the development of strategies for the treatment of such disorders.

BackgroundWe previously showed that the BRCA1variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers.MethodsData were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.ResultsIn this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).ConclusionOur results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery.

IMPORTANCE: Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending. OBJECTIVES: To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk. DESIGN, SETTING, AND PARTICIPANTS: For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016. MAIN OUTCOMES AND MEASURES: FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history. RESULTS: In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27). CONCLUSIONS AND RELEVANCE: Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.

The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmbexpression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Zusammenfassung.Hintergrund: Patientinnen mit vulvären Neoplasien berichten über Informationsmangel, fehlende Förderung des Selbstmanagements und Lücken im Versorgungsprozess. Fragestellung: Können schriftliche Informationen oder eine Beratung basierend auf dem WOMAN-PRO II Programm bei Frauen mit vulvären Neoplasien die Patientenzufriedenheit sowie den Versorgungsprozess aus Sicht des Behandlungspersonals verbessern? Methode: Die Patientenzufriedenheit und der Versorgungsprozess wurden innerhalb der multizentrischen randomisiert kontrollierten Phase II-Studie (Clinical Trial ID: NCT01986725) als sekundäre Outcomes erfasst. Die Patientenzufriedenheit bewerteten 49 Frauen nach schriftlicher Information (n = 13) und Beratung (n = 36), in vier Spitälern (CH, AUT) mittels PACIC-S11. Den Versorgungsprozess bewerteten zehn Advanced Practice Nurses (APNs) mittels G-ACIC vor und nach der Implementierung der Beratung. Ergebnisse: Es konnten keine signifikanten Gruppenunterschiede identifiziert werden (p = 0,25). Nur wenige Aspekte wurden von allen Frauen hoch bewertet, z. B. die Gesamtzufriedenheit (M = 80,3 %) und die Zufriedenheit mit der Organisation (M = 83,0 %). Die Beurteilung der APNs des Versorgungsprozesses bei Patientinnen, die eine Beratung erhielten, verbesserte sich signifikant (p = 0,031). Schlussfolgerung: Es gibt Hinweise, dass die Interventionen in der Praxis zu einer höheren Patientenzufriedenheit und die Beratung zu einer optimierten Versorgung beitragen könnten. Die tief bewerteten Aspekte im PACIC-S11 und G-ACIC weisen auf Optimierungsmöglichkeiten im Versorgungsprozess hin.

Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdxand dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdxand dkomice when the dystrophic pathology was already well established. Later stage treatment of mdxor dkomice with BGP-15 did not improve maximal force of tibialis anterior (TA) muscles (in situ) or diaphragm muscle strips (in vitro). However, collagen deposition (fibrosis) was reduced in TA muscles of BGP-15–treated dkomice but unchanged in TA muscles of treated mdxmice and diaphragm of treated mdxand dkomice. We also examined whether BGP-15 treatment could ameliorate aspects of the cardiac pathology, and in young dkomice it reduced collagen deposition and improved both membrane integrity and systolic function. These results confirm BGP-15's ability to improve aspects of the dystrophic pathology but with differing efficacies in heart and skeletal muscles at different stages of the disease progression. These findings support a role for BGP-15 among a suite of pharmacological therapies for Duchenne muscular dystrophy and related disorders.

In order to optimally integrate the use of high-throughput sequencing (HTS) as a tool in clinical diagnostics of likely monogenic disorders, we have created a multidisciplinary “Genome Clinic Task Force” at the University Hospitals of Geneva, which is composed of clinical and molecular geneticists, bioinformaticians, technicians, bioethicists, and a coordinator. We have implemented whole exome sequencing (WES) with subsequent targeted bioinformatics analysis of gene lists for specific disorders. Clinical cases of heterogeneous Mendelian disorders that could potentially benefit from HTS are presented and discussed during the sessions of the task force. Debate concerning the interpretation of identified variants and the content of the final report constitutes a major part of the task force’s work. Furthermore, issues related to bioethics, genetic counseling, quality control, and reimbursement are also addressed. This multidisciplinary task force has enabled us to create a platform for regular exchanges between all involved experts in order to deal with the multiple complex issues related to HTS in clinical practice and to continuously improve the diagnostic use of HTS. In addition, this task force was instrumental to formally approve the reimbursement of HTS for molecular diagnosis of Mendelian disorders in Switzerland.

The crucial point in inorganic particle formation from biomass combustion is the temperature-dependent release of inorganic compounds, especially potassium (K). Currently, common wood fuels comprise of a comparatively low amount of K, but the increased usage of wood energy requires new feedstocks in the future. Potentially new feedstocks, such as short rotation coppice (SRC), fuels from agriculture (e.g., straw), or wood from broad-leafed trees of low rotation, contain usually high ash contents and/or high K concentrations. Apparently, these feedstocks will cause increased inorganic particle emissions from biomass combustion processes. The principle of a decreased firebed temperature as a primary measure aiming at a retention of K in the ashes of the firebed is a common approach for particle emission reduction and was investigated in several previous studies. The present study describes the usage of an ash-rich fuel from SRC pellets made from willow in a residential pellet boiler modified with an unique prototype of direct water-based firebed cooling. This test setup enables the study of the isolated impact of decreased firebed temperatures and its influence on the combustion process and emissions as well. A statistically significant effect of the firebed cooling on temperatures below the burner plate as on gaseous HCl and SO2was found. The high ash content of the used fuel limited the effectiveness of the applied direct firebed cooling in residential biomass combustion. The accumulation of a thick and thermal insulating ash layer above the burner plate decreased the heat transfer, limited the cooling efficiency, and revealed deviations from the expected particle formation process.