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Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) inWe analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (In RVA tests,These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in

Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole-exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombination (HR) and tumor suppression. One PALB2 variant showed disease cosegregation in a family with four affected people or obligate gene carrier. Chordoma cases had a significantly increased burden of rare variants in both genes when compared to population-based controls. Four of the six PALB2 variants identified from chordoma patients modestly affected HR function and three of the 11 BRCA2 variants caused loss of function in experimental assays. These results, together with previous reports of abnormal morphology and Brachyury expression of the notochord in Palb2 knockout mouse embryos and genomic signatures associated with HR defect and HR gene mutations in advanced chordomas, suggest that germline mutations in PALB2 and BRCA2 may increase chordoma susceptibility. Our data shed light on the etiology of chordoma and support the previous finding that PARP-1 inhibitors may be a potential therapy for some chordoma patients.

How should the medical team approach care for a very preterm infant with a significant painful and life-limiting condition when the parents wish to pursue all life-sustaining therapies? Here, we discuss a case of an infant born at 28 weeks’ gestation with a diagnosis of Carmi syndrome (junctional epidermolysis bullosa and pyloric atresia). While the medical team felt that a do-not-resuscitate order and redirection to comfort care were appropriate, the family held on to hope for recovery and wished to continue with full intensive care measures.

Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio [HR], 2.13; 95% confidence interval[CI], 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA.

PURPOSE: This scoping review explores how virtue and care ethics are incorporated into curricular design and how these factors relate to the development of humanistic patient care. METHOD: Our team identified citations in the literature emphasizing virtue ethics and care ethics (in PubMed, NLM Catalog, WorldCat, EthicsShare, EthxWeb, Globethics.net, Philosopher’s Index, and ProQuest Central) lending themselves to constructs of humanism pedagogy. Our exclusion criteria consisted of non-English articles, those not addressing virtue and care ethics and humanism in medical pedagogy, and those not addressing aspects of character in health ethics. We examined in a stepwise fashion whether citations: 1) Contained definitions of virtue and care ethics; 2) Implemented virtue and care ethics in health care pedagogy; and 3) Evidenced patient-directed caregiver humanism. RESULTS: 796 citations were identified, 88 intensively reviewed, and the final 25 analyzed in-depth. By first identifying multiple key themes with subsequent translation in virtue and care ethics (reciprocal translation), we developed a line of argument synthesis utilizing nine themes associated with virtue/care ethics, curricula, and humanism education. CONCLUSIONS: This research identified a line of argument synthesis regarding how virtue and care ethics can potentially promote humanism and identified themes that facilitate and impede this mission.

Low oxidation-state iron- and cobalt catalysis has been enabled using tetrafluoroborate activation across 5 reaction classes and seven ligand frameworks using a single catalysis protocol., The widespread adoption of earth-abundant metal catalysis lags behind that of the second- and third-row transition metals due to the often challenging practical requirements needed to generate the active low oxidation-state catalysts. Here we report the development of a single endogenous activation protocol across five reaction classes using both iron- and cobalt pre-catalysts. This simple catalytic manifold uses commercially available, bench-stable iron- or cobalt tetrafluoroborate salts to perform regiodivergent alkene and alkyne hydrosilylation, 1,3-diene hydrosilylation, hydrogenation, [2π + 2π]-cycloaddition and C–H borylation. The activation protocol proceeds by fluoride dissociation from the counterion, in situ formation of a hydridic activator and generation of a low oxidation-state catalyst.

A precatalyst activation strategy has been developed for earth-abundant metal catalysis enabled by counterion dissociation and demonstrated through alkene hydroboration. Commercially available iron and cobalt tetrafluoroborate salts were found to catalyze the hydroboration of aryl and alkyl alkenes with good functional group tolerance (Fe, 12 substrates; Co, 13 substrates) with three structurally distinct ligands. Key to this endogenous activation was counterion dissociation to generate fluoride which indirectly activates the precatalyst by reaction with pinacol borane.

Purpose To describe 3 cases of herpes simplex virus (HSV) vesicular blepharitis that progressed to infectious epithelial keratitis despite treatment with oral acyclovir, but responded to topical antiviral therapy. Methods Retrospective review of a small case series. Results One adult and 2 children presented with unilateral HSV vesicular blepharitis without evidence of corneal involvement. Each patient was placed on a therapeutic dose of oral acyclovir. While taking oral antiviral therapy, the patients developed HSV infectious epithelial keratitis, which was treated with trifluridine 1% solution 9 times daily in the adult and ganciclovir 0.15% ophthalmic gel 5 times daily in the 2 children. All 3 cases showed resolution of epithelial keratitis within 3 to 10 days after initiation of topical antiviral treatment while oral acyclovir was continued. Conclusions Oral antiviral therapy alone may not adequately prevent progression of infectious ocular HSV blepharoconjunctivitis. Topical antiviral therapy appeared to enable resolution of HSV epithelial keratitis that arose during oral acyclovir treatment.

The micro-environment in this study refers to the air space and environment around a person that directly impacts their thermal sensation. This study aims at evaluating the performance of a newly developed micro-environmental control system (μX) designed to cool the occupants locally for thermal comfort when the temperature in the ambient unoccupied space is raised from 23.9 °C to 26.1 °C in summer to reduce the HVAC cooling load. The μX was tested first with a 20-segment thermal manikin wearing summer clothing in a full-scale stainless-steel chamber and then with human participants in a climate chamber. Results show that the heat loss by the manikin increased with the distance between the μX air supply diffuser and the manikin and decreased with the clothing insulation. Changing the air delivery angle from 0° to 10° from the horizontal direction resulted in additional heat loss from the manikin. The heat loss from the manikin was found to be positively correlated with the supply air flow rate, but negatively correlated with the supply air temperature. However, the overall cooling efficiency dramatically increased with the supply air temperature. Overall, both the manikin test and the human participant test showed that the μX was able to cool the occupant in a room of expanded temperature set-point, and the Clothing Independent Thermal Comfort Model gave a consistent prediction with the human participant test. However, slight thermal discomfort was reported when the μX was used due to the effect of clothing, season, metabolic rate and local draught.

Background: Prospective validation of breast cancer risk models integrating classical risk factors and genetic variants is required for risk-stratified prevention and screening strategies. The objective of this study was to validate a breast cancer risk model integrating classical risk factors and a 313-variant polygenic risk score (PRS) in multiple prospective cohort studies, and to project five-year risk of breast cancer in six different countries. Methods: The study population included 7,529 cases and 230,103 controls from 14 prospective cohort studies in Australia, Germany, the Netherlands, Sweden, UK, and USA. We used the Individualized Coherent Absolute Risk Estimator (iCARE) tool for risk model building, validation, and risk projection. Expected five-year risk of invasive or in situ breast cancer was compared to observed risk, overall and within deciles of expected risk using goodness of fit statistics. We evaluated calibration of the relative risk through meta-analysis across cohorts, and of the absolute risk within each cohort. Model discrimination was evaluated using the area under the curve (AUC), and percentages of women crossing risk thresholds. Projections of five-year risk distributions were estimated for women of European ancestry aged 50-70 years in the general populations of these six countries. Results: Analysis showed overall good calibration of the integrated iCARE-based model relative risk for both women younger than 50 years (χ2=14.9, P=0.09) and aged 50 years or older (χ2=14.6, P=0.10), with a small overestimation of risk for women in the highest decile of expected risk (RR = 3.5 expected vs 2.3 (95% CI 1.6 to 3.2) observed for women Conclusions: Five-year risk predictions from a model with classical risk factors and PRS are well calibrated and provide substantial risk stratification across multiple cohorts in six different countries. Further studies are needed to evaluate the clinical utility of the validated model for risk stratified screening and prevention of breast cancer. Citation Format: Parichoy Pal Choudhury, Amber Wilcox, Chi Gao, Brian Carter, Anika Husing, Mark Brook, Mikael Eriksson, Kara Martin, Chris Scott, Min Shi, Thomas Ahearn, Michael Jones, Nick Orr, Minouk Schoemaker, Kamila Czene, Jenny Chang-Claude, Jacques Simard, Doug Easton, Marjanka K. Schmidt, Dale Sandler, Clarice R. Weinberg, Celine Vachon, Roger Milne, Per Hall, Anthony Swerdlow, Rudolph Kaaks, Myrto Barrdahl, Mia Gaudet, Antonis Antoniou, Peter Kraft, Montserrat Garcia-Closas, Nilanjan Chatterjee. Validation of breast cancer risk model incorporating classical risk factors and polygenic risk scores in 14 prospective cohort studies in 6 countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 962.

An operationally simple hydrosilylation of alkenes is developed using a stable Fe(II)-precatalyst with in situ activation by iPr2NEt.

A simple alkylamine [(iPr)2NEt] has been used to activate an air- and moisture-stable iron(II) pre-catalyst for alkene and alkyne hydrofunctionalization reactions. This amine activation has enabled the highly operationally simple hydrosilylation and hydroboration of alkenes and alkynes using just 0.25–2 mol% iron catalyst and 1–25 mol% amine. Significantly, these reactions proceed in equal yield under both air and inert reaction conditions.

This study investigated the detoxification of a dilute acid pretreated Ponderosa pine slurry using the polyelectrolyte polyethyleneimine (PEI). The addition of polyelectrolyte to remove enzymatic and/or fermentation inhibitory compounds, that is, acetic acid, furfural, and 5-hydroxymethylfurfural (HMF), was performed either before or after enzymatic hydrolysis to determine the optimal process sequence. Negligible acetic acid, glucose, and xylose were removed regardless of where in the process the polymer addition was made. Maximum furfural and HMF separation was achieved with the addition of PEI to a clarified pre-enzymatic hydrolysis liquor, which showed that 88.3% of furfural and 66.4% of HMF could be removed. On the other hand, only 23.1% and 13.4% of furfural and HMF, respectively, were removed from a post-enzymatic hydrolysis sample; thus, the effects of enzymes, glucose, and wood solids on inhibitor removal were also investigated. The presence of solid particles >0.2 µm and unknown soluble components

BACKGROUND: The excellent fungicidal activity of [1,2,4]triazolo[1,5-a]pyrimidines suggested the search for further analogues with improved properties. RESULTS: A series of novel trisubstituted pyrido[2,3-b]pyrazines has been designed and prepared as 6,6-biheterocyclic analogues of related 5,6-bicyclic [1,2,4]triazolo[1,5-a]pyrimidines. Their fungicidal activity was evaluated against the plant pathogens Puccinia recondita Rob. ex Desm. f. sp. tritici (Eriks.) CO Johnston (wheat brown rust), Mycosphaerella graminicola (Fuckel) Schroter (Septoria tritici Rob., leaf spot of wheat) and Magnaporthe grisea (Hebert) Barr (Pyricularia oryzae Cav., rice blast). Structure–activity relationship studies revealed the advantage of a fluoro substituent in position 6 and of a secondary amine in position 8. CONCLUSION: 8-Amino-7-aryl-6-halogen-substituted pyrido[2,3-b]pyrazines have been prepared as 6,6-biheterocyclic analogues of similarly substituted triazolopyrimidine fungicides. A concise four-step synthesis route has been worked out to prepare these novel compounds from commercially available starting materials. [(R)-(1,2-Dimethylpropyl)]-[6-fluoro-7-(2,4,6-trifluorophenyl)pyrido[2,3-b]pyrazin-8-yl]amine showed excellent activity against three economically important phytopathogens. Copyright © 2009 Society of Chemical Industry

Brian Carter describes the very distinct architecture of the French-Canadian practice Saucier + Perrotte. He explains how a string of small, well-conceived Quebecoise arts centres in the 1990s provided a formative route to designing major institutional buildings in Montreal and beyond. Copyright © 2007 John Wiley & Sons, Ltd.

In this paper, the concepts of growing software applications by incremental development of heterogeneous micro-applications using cellular regeneration concepts are explored. The proposal is the move from homogeneous monolithic architectures to heterogeneous micro-architectures, to allow for application evolution. The focus is on growing legacy applications that will evolve to remain healthy. Cellular regeneration concepts are used to show that applications should always be regenerating, like cells living in an organism, to become resilient to events that cause disturbance and damage. Understanding regeneration can give insights into growing computational systems that are more resilient. A definition for micro-architectures and comparisons on how such an architecture differs from typical monolithic architectures are given. Concepts to allow applications to adapt to new and changing business and scientific computational needs are designed. Development and operation complexity is addressed to handle the increase in activity and tasks. We conclude with future states for micro-applications.

International audience; A 12 m loess–paleosol section (La Angostura) from Tafi del Valle, Tucumán, Argentina was studied using rock magnetic measurements, geochemistry, Mössbauer effect, particle size and Nd isotopes in order to elucidate changes in paleoenvironment at the site. Combining the results of these experiments allowed us to separate the effects of the two major controls (parent material and pedogenesis) on the measured parameters. Two behavior regimes were identified in the sediment: 1) in the lower half of the section pedogenic processes, though weak, dominate the variation of the sediment's physical properties, and 2) for the upper half of the section subtle changes in parent material control the majority of the measured parameters, even those typically controlled by pedogenesis, e.g., clay fraction. Applying rock magnetic, Mössbauer, and bulk geochemistry measurements in concert we calculated an iron budget for the loess. not, vert, similar80% of the iron in the sediment is in paramagnetic minerals; not, vert, similar20% of the iron is in hematite (not, vert, similar1.6% of the sediment's mass), and much less-than 1% of the total iron is present as magnetite/maghemite (not, vert, similar0.1% of the sediment's total mass). Neither the pedogenic formation nor the depletion of ferrimagnetic material with increasing pedogenesis was consistently observed in this sediment. Throughout the entire section the concentration of hematite is argued to be sensitive to in situ alteration, and it is further surmised to be sensitive to the available moisture at the site. Finally we present a curiosity: within the error of our chronology, the concentration of hematite seems to correlate with the coeval climate record from Antarctica (Vostok). It is possible that the sedimentary–magnetic record from La Angostura is a proxy for the strength of the South American summer monsoon.

The magnetization of sediments is acquired through complex processes involving a large number of physical, mineralogical and magnetic parameters. Despite many attempts, the degree to which these processes distort the record of the geomagnetic field as it is archived as a natural remanent magnetization (NRM) remains poorly documented. Among many other parameters, it is important to evaluate the amount of smoothing inherent to the signal, its relation with the field intensity and its variability in the sediment column. In order to address these problems, we performed new redeposition experiments using carbonate-rich, Ocean Drilling Program (ODP) Site 851, and clay-rich, ODP Site 854, sediments. We used a dilute solution of gelatin, which gels below 20°C, thereby allowing mechanical blocking of the magnetic grains. We observed two critical results: (1) The efficiency of detrital remanent magnetization (DRM) decreases with increasing sediment concentration for a given slurry. Sediment concentration is defined as: c=ms/(ms+mH2O), where ms and mH2O are the sediment and water mass, respectively. Higher c would then reflect greater compaction, lower water content and, presumably, greater depth in the sediment column. This effect reduces DRM efficiency nearly to zero for c> ∼50%. (2) Post-depositional remanent magnetization (pDRM) is important for c< ∼50%. pDRM is carried by grains covering the entire coercivity spectrum. By comparing the mean value of NRM divided by anhysteretic remanent magnetization from the previous magnetostratigraphic study at Site 851 with the relevant ratio derived from our redeposition experiments, we were able to estimate that pDRM was significant within the depth interval where ∼44%

Fluorination of electron rich aromatic systems with electrophilic fluorination reagents such as Selectfluor ® and Accufluor ® is a well-established process. Herein we report results from investigations into the use of such procedures to perform rapid, small-scale fluorinations under microwave irradiation. We have investigated the transformation with a range of different substrates and discuss the effects of two key factors, namely reaction time and choice of fluorination reagent. The use of Selectfluor ® in acetonitrile at 150 °C with microwave heating for 10 min affords products in comparable yields to those obtained by prolonged heating in acetonitrile at its reflux temperature.

In this paper, a very compelling proposition is presented, a novel approach for web development that is a hybrid of Single Page Applications (SPA) and server side applications. The proposed architecture lowers the entry to web development by providing a simplistic approach for development. The focus is on HTML, Java Script, Cascading Style Sheets, and Node.js. The architecture provides all the components required for students to start developing web applications and web services. The HTML Architecture, a Novel Development System (HANDS) is a hybrid approach leveraging the simplicity of plain old HTML pages, the AJAX injection of HTML from SPA frameworks, and the server side processing found in the Node.js framework. An open source starter kit and examples are provided.

The Pillreports.com database was mined in order to determine if the free-text fields in the database could be of use in differentiating regular pills from those that have been adulterated, i.e. contains ingredients not comparable to MDMA. The data was download and extracted using RapidMiner and Xpath queries. A Naive Bayes and SVM binary classification model was created. Pre-processing techniques of tokenisation, n-gram creation, stop-word removal, stemming as well as feature selection by weights were applied to the data, resulting in a 15 point improvement in the model. In addition we are reporting on a comprehensive cluster analysis. Frequent terms and differences between clusters were visualised using word clouds. Clusters were compared with values contained in nominal fields. Model results and interpretation are provided at various preprocessing stages. Key phrase extraction is identified as an area of possible future work.

In the first part of this study, attention was focused primarily on three organisations; first, the Society of Charitable Sisters, founded in 1814, a society unique in Catholic affairs of the time, being a voluntary self regulating society of lay women, married and single, who devoted their lives to assisting the impoverished in London; second, the Catholic Club founded by W.E. Andrews, also in 1814, with the purpose of bringing together the Catholic artisan and working class Catholics to collaborate in raising funds for a variety of charities; third the evolution of Catholic libraries in London from 1822, which generated unexpected and fruitful diversification. What became clear from the study of these three groups and others connected to them was the range and variety of the charities and the fact that many of these were established and run by people from the working and artisan classes, a large proportion of whom were Irish.

We have constructed a large, mosaic CCD camera called MOA-cam2 which has 4096 × 6144-pixelsto search for gravitational microlensing events. MOA-cam2 has three4096 × 2048-pixel SITe CCD chips, which have a very high quantum efficiency (nearly 80% in the wave region 500 to 800 nm),and three buttable sides. We have placed the threechips side by side with 100 μm dead space. MOA-cam2 has been installed on the 61 cm Boller and Chivens telescope of the MOA collaboration at the Mt. John University Observatory (MJUO) in NewZealand since July 1998. The field coverage is 0.92° × 1.38° per exposure. The technical details of MOA-cam2 and the first images obtained with the Boller and Chivens telescope are presented. MOA-cam2 introduces a second phase of research on gravitational microlensing by the MOA collaboration.

In the presence of substoichiometric quantities of a copper-bisphosphine complex, a variety of aldehydes and reactive ketones undergo pentafluorophenylation using pentafluorophenyl-trimethylsilane.

In this paper, a very compelling proposition is presented, a portable system for software development. The focus is on HTML, Java Script, CSS, Node.js, and SQLite. The system provides all the applications required for students to start developing web applications. The HTML Educational Node.js System (HENS) does not require installation or admin access allowing for portability. This environment is built using open source applications.

Peer review is a widely accepted instrument for raising the quality of science. Peer review limits the enormous unstructured influx of information and the sheer amount of dubious data, which in its absence would plunge science into chaos. In particular, peer review offers the benefit of eliminating papers that suffer from poor craftsmanship or methodological shortcomings, especially in the experimental sciences. However, we believe that peer review is not always appropriate for the evaluation of controversial hypothetical science. We argue that the process of peer review can be prone to bias towards ideas that affirm the prior convictions of reviewers and against innovation and radical new ideas. Innovative hypotheses are thus highly vulnerable to being "filtered out" or made to accord with conventional wisdom by the peer review process. Consequently, having introduced peer review, the Elsevier journal Medical Hypotheses may be unable to continue its tradition as a radical journal allowing discussion of improbable or unconventional ideas. Hence we conclude by asking the publisher to consider re-introducing the system of editorial review to Medical Hypotheses.

Intensive-care and palliative care teams may at first seem to be polar opposites — with one focusing on the utilization of advanced technologies directed towards saving or prolonging life, and the other focusing on providing comfort and support, accepting death as a likely outcome. However, the one place that provides a natural interface for these teams with different goals is the ICU. Here children and families face potential or inevitable death, and even alongside attempts to save or prolong life, they need the care that is at the heart of palliation. Where ICU and palliative care meet, children can receive the most advanced technology alongside skilled, holistic, supportive care, and both teams can work together with families to facilitate appropriate support as goals change. Palliative care is now increasingly being integrated into the care of patients and families in both the neonatal and paediatric ICU settings. With focused research aimed at healthcare service delivery, effective symptom management, and the role of palliative care consultants in the ICU, the potential to broaden and improve palliative care in the ICU will be further advanced for all children and their families. The surprise is not that these two services should be integrated, but rather that it has taken us so long to realize the importance of such integration.

Soybean mosaic virus (SMV) is the most common member of the viral genus Potyvirus to infect soybeans (Glycine max [L.] Merr.) worldwide. SMV has been traditionally controlled by the deployment of single dominant, strain specific resistance genes, referred to as Rsv genes. Rsv1 is the most widely used form of SMV resistance with nine different alleles conferring resistance only to the lower numbered less virulent strains, G1 to G3. Rsv3 gives resistance to higher numbered more virulent strains G5 to G7. Soybean lines containing Rsv4, are resistant to all seven currently recognized North American SMV strains. In this study, the recently released soybean whole genome sequence was used to design molecular markers for fine mapping Rsv3 to a ~150 kb genomic region containing four coiled-coil nucleotide-binding leucine-rich repeat proteins. In a related study a large population segregating at the Rsv3 locus was screened for resistance to facilitate future characterization of this region. The markers identified in this study will allow for more accurate marker-assisted selection of Rsv3. Master of Science