ALBERT

Beschreibung: Systems of activator–inhibitor reaction–diffusion equations posed on an infinite line are studied using a variety of analytical and numerical methods. A canonical form is considered, which contains all known models with simple cubic autocatalytic nonlinearity and arbitrary constant and linear kinetics. Restricting attention to models that have a unique homogeneous equilibrium, this class includes the classical Schnakenberg and Brusselator models, as well as other systems proposed in the literature to model morphogenesis. Such models are known to feature Turing instability, when activator diffuses more slowly than inhibitor, leading to stable spatially periodic patterns. Conversely in the limit of small feed rates, semi-strong interaction asymptotic analysis shows existence of isolated spike-like patterns. This paper describes the broad bifurcation structures that connect these two regimes. A certain universal two-parameter state diagram is revealed in which the Turing bifurcation becomes sub-critical, leading to the onset of homoclinic snaking. This regime then morphs into the spike regime, with the outer-fold being predicted by the semi-strong asymptotics. A rescaling of parameters and field concentrations shows how this state diagram can be studied independently of the diffusion rates. Temporal dynamics is found to strongly depend on the diffusion ratio though. A Hopf bifurcation occurs along the branch of stable spikes, which is subcritical for small diffusion ratio, leading to collapse to the homogeneous state. As the diffusion ratio increases, this bifurcation typically becomes supercritical and interacts with the homoclinic snaking and also with a supercritical homogeneous Hopf bifurcation, leading to complex spatio-temporal dynamics. The details are worked out for a number of different models that fit the theory using a mixture of weakly nonlinear analysis, semi-strong asymptotics and different numerical continuation algorithms.

Beschreibung: Whole transcriptome analyses have revealed that mammalian genomes are massively transcribed, resulting in the production of huge numbers of transcripts with unknown functions (TUFs). Previous research has categorized most TUFs as noncoding RNAs (ncRNAs) because most previously studied TUFs do not encode open reading frames (ORFs) with biologically significant lengths (〉100 amino acids). Recent studies, however, have reported that several transcripts harboring small ORFs (sORFs) that encode peptides shorter than 100 amino acids are translated and play important biological functions. Here, we examined the translational capacity of transcripts annotated as ncRNAs in human cells, and identified several hundreds of ribosome-associated transcripts previously annotated as ncRNAs. Ribosome footprinting and polysome profiling analyses revealed that 61 of them are potentially translatable. Among them, 45 were non-nonsense-mediated mRNA decay targets, suggesting that they are productive mRNAs. We confirmed the translation of one ncRNA, LINC00493, by luciferase reporter assaying and western blotting of a FLAG-tagged LINC00493 peptide. While proteomic analysis revealed that the LINC00493 peptide interacts with many mitochondrial proteins, immunofluorescence assays showed that its peptide is mitochondrially localized. Our findings indicate that some transcripts annotated as ncRNAs encode peptides and that unannotated peptides may perform important roles in cells.

Beschreibung: Synthetic binding proteins that have the ability to bind with molecules can be generated using various protein domains as non-antibody scaffolds. These designer proteins have been used widely in research studies, as their properties overcome the disadvantages of using antibodies. Here, we describe the first application of a phage display to generate synthetic binding proteins using a sweet protein, monellin, as a non-antibody scaffold. Single-chain monellin (scMonellin), in which two polypeptide chains of natural monellin are connected by a short linker, has two loops on one side of the molecule. We constructed phage display libraries of scMonellin, in which the amino acid sequence of the two loops is diversified. To validate the performance of these libraries, we sorted them against the folding mutant of the green fluorescent protein variant (GFPuv) and yeast small ubiquitin-related modifier. We successfully obtained scMonellin variants exhibiting moderate but significant affinities for these target proteins. Crystal structures of one of the GFPuv-binding variants in complex with GFPuv revealed that the two diversified loops were involved in target recognition. scMonellin, therefore, represents a promising non-antibody scaffold in the design and generation of synthetic binding proteins. We termed the scMonellin-derived synthetic binding proteins “SWEEPins.”

Beschreibung: HP1 (Heterochromatin Protein 1), a key factor for the formation of heterochromatin, binds to the methylated lysine 9 of histone H3 (H3K9me), and represses transcription. While the H3K9me mark and HP1 binding are thought to be faithfully propagated to daughter cells, the heterochromatin structure could be dynamically regulated during cell cycle. As evidenced by the well-known phenomenon called Position Effect Variegation (PEV), heterochromatin structure is dynamically and stochastically altered during developmental processes, and thus the expression of genes within or in the vicinity of heterochromatin could be affected by mutations in factors regulating DNA replication as well as by other epigenetic factors. Recent reports show that HP1 also plays an important role in the maintenance and transmission of chromosomes. Like many other factors ensuring faithful chromosome segregation, HP1 family proteins are subjected to posttranslational modifications, most notably phosphorylation, in a cell-cycle dependent manner. Recent studies identified a conserved phosphorylation site that profoundly affects the functions of HP1 during mitotic phase. In this commentary, we discuss dynamic regulation of HP1 protein by phosphorylation during transcriptional repression and cell cycle.

Beschreibung: We present a class of nonconforming virtual element methods for general fourth-order partial differential equations in two dimensions. We develop a generic approach for constructing the necessary projection operators and virtual element spaces. Optimal error estimates in the energy norm are provided for general linear fourth-order problems with varying coefficients. We also discuss fourth-order perturbation problems and present a novel nonconforming scheme which is uniformly convergent with respect to the perturbation parameter without requiring an enlargement of the space. Numerical tests are carried out to verify the theoretical results. We conclude with a brief discussion on how our approach can easily be applied to nonlinear fourth-order problems.

Beschreibung: This is the second paper reporting the results of a study investigating student choices of optional post-16 advanced-level (A-level) Mathematics and Further Mathematics qualifications in the UK and their impact on the transition from school to university mathematics. Here, the opinions of non-mathematics Science, Technology, Engineering and Mathematics (STEM) undergraduate students (all of whom had previously studied A-level Mathematics) were accessed via a survey and individual interviews. The study found that Further Mathematics qualifications are perceived as advantageous for non-mathematics STEM degrees by students once they are at university but not when making A-level choices. While the students often perceived mathematics positively, this appears to influence the choice of A-level Mathematics but not Further Mathematics. The lack of support from teachers and parents, the lack of perceived utility of Further Mathematics qualifications and a perception that Further Mathematics is only useful for studying a mathematics degree could all be factors affecting the uptake of Further Mathematics. The identified perceived impact of Further Mathematics on the university transition is linked to studying more pure mathematics which may give students a better understanding of how to apply mathematics in the context of their degree. Some comparisons between the findings in Parts 1 and 2 of the study are included which suggests that the Further Mathematics qualification is better serving students intending to study a non-mathematics STEM degree rather than mathematics itself.

Beschreibung: Background Benign breast disease (BBD) is a strong breast cancer risk factor but identifying patients that might develop invasive breast cancer remains a challenge. Methods By applying machine-learning to digitized H&E-stained biopsies and computer-assisted thresholding to mammograms obtained circa BBD diagnosis, we generated quantitative tissue composition metrics and determined their association with future invasive breast cancer diagnosis. Archival breast biopsies and mammograms were obtained for women (18-86 years of age) in a case-control study, nested within a cohort of 15,395 BBD patients from Kaiser Permanente Northwest (1970-2012), followed through mid-2015. Cases (n = 514) who developed incident invasive breast cancer and controls (n = 514) were matched on BBD diagnosis age and plan membership duration. All statistical tests were 2-sided. Results Increasing epithelial area on the BBD biopsy was associated with increasing breast cancer risk (Odds ratio [OR]Q4 vs Q1=1.85, 95% confidence interval [CI] = 1.13-3.04; Ptrend=0.02). Conversely, increasing stroma was associated with decreased risk in non-proliferative, but not proliferative, BBD (Pheterogeneity=0.002). Increasing epithelium-to-stroma proportion [ORQ4 vs Q1=2.06, 95% CI = 1.28-3.33; Ptrend=0.002) and percent mammographic density (MBD) (ORQ4 vs Q1=2.20, 95% CI = 1.20-4.03; Ptrend=0.01) were independently and strongly predictive of increased breast cancer risk. In combination, women with high epithelium-to-stroma proportion/high MBD had substantially higher risk than those with low epithelium-to-stroma proportion/low MBD [OR = 2.27, 95% CI = 1.27-4.06; Ptrend=0.005), particularly among women with non-proliferative (Ptrend=0.01) versus proliferative (Ptrend=0.33) BBD. Conclusion Among BBD patients, increasing epithelium-to-stroma proportion on BBD biopsies and percent MBD at BBD diagnosis were independently and jointly associated with increasing breast cancer risk. These findings were particularly striking for women with non-proliferative disease (comprising approximately 70% of all BBD patients), for whom relevant predictive biomarkers are lacking.

Beschreibung: We study the selection of adjustment sets for estimating the interventional mean under a point exposure dynamic treatment regime, that is, a treatment rule that depends on the subject’s covariates. We assume a non-parametric causal graphical model with, possibly, hidden variables and at least one adjustment set comprised of observable variables. We provide the definition of a valid adjustment set for a point exposure dynamic treatment regime, which generalizes the existing definition for a static intervention. We show that there exists an adjustment set, referred to as optimal minimal, that yields the non-parametric estimator of the interventional mean with the smallest asymptotic variance among those that are based on observable minimal adjustment sets. An observable minimal adjustment set is a valid adjustment set such that all its variables are observable and the removal of any variable from it destroys validity. We provide similar optimality results for the class of observable minimum adjustment sets, that is, valid observable adjustment sets of minimum cardinality among the observable adjustment sets. Moreover, we show that if either no variables are hidden or if all the observable variables are ancestors of either treatment, outcome, or the variables that are used to decide treatment, a globally optimal adjustment set exists. We provide polynomial time algorithms to compute the globally optimal, optimal minimal, and optimal minimum adjustment sets. Because static interventions can be viewed as a special case of dynamic regimes, all our results also apply for static interventions.

Beschreibung: Databases play a fundamental role in today’s world, being used by most companies, especially those that offer services through the Internet. Today there is a wide variety of database models, each adapted for use according to the specific requirements of each application. Traditionally, the relational models with centralized architectures have been used mostly due to their simplicity and general-purpose query language, which made relational systems suitable for almost any application. However, with the growth of the Internet in recent decades, both in the number of users and in the amount of information, those centralized models began to suffer availability and scalability issues. To address those issues, the use of decentralized architectures and alternative database models began to arise, eventually replacing relational databases and centralized architectures when the requirements on availability and scalability are high. Those database models alternative to the traditional relational model are grouped under the name of NoSQL (Not only Structured Query Language). In this article, we present a NoSQL database developed as an end of degree work, with a flexible data model based on documents and a fully decentralized architecture based on the Gossip protocol for node discovery and a distributed hash table, in particular the rendezvous hashing algorithm, used to distribute and replicate the data across all the nodes. The main goals of the system are to achieve high availability (the data should be almost always accessible) and high scalability (the system should be able to scale by increasing the number of nodes to increase its capacity both on data and number of users). High availability is achieved thanks to the replication of the data, while high scalability is achieved by its decentralized architecture, which allows multiple entry points from the requests, and the data distribution, effectively increasing the database capacity by increasing the number of nodes.

Beschreibung: Background More than half of breast cancer cases are diagnosed among women aged younger than 62 years, which may result in employment challenges. This study examined whether cancer-related employment disruption was associated with increased financial hardship in a national U.S. study of women with breast cancer. Methods Women with breast cancer who were enrolled in the Sister or Two Sister Studies completed a survivorship survey in 2012. Employment disruption was defined as stopping work completely or working fewer hours after diagnosis. Financial hardship was defined as 1) experiencing financial problems paying for cancer care, 2) borrowing money/incurring debt, or 3) filing for bankruptcy because of cancer. Prevalence ratios and 95% confidence intervals for the association between employment disruption and financial hardship were estimated using multivariable Poisson regression with robust variance. Results We analyzed data from women employed at diagnosis (n = 1,628). Women were a median age of 48 years at diagnosis and 5.6 years from diagnosis at survey completion. Overall, 27.3% of women reported employment disruption (15.4% stopped working; 11.9% reduced hours), and 21.0% experienced financial hardship (16.0% had difficulty paying for care; 12.6% borrowed money/incurred debt; 1.8% filed for bankruptcy). In adjusted analysis, employment disruption was associated with nearly twice the prevalence of financial hardship (prevalence ratio = 1.93, 95% confidence interval = 1.58 to 2.35). Conclusions Women experiencing employment disruptions after breast cancer may be more vulnerable to financial hardship. Findings highlight the need to target risk factors for employment disruption, facilitate return to work or ongoing employment, and mitigate financial consequences after cancer.

Beschreibung: In this article we prove the following results: (i) Every hemimaximal set has minimal $c_{1}$-degree, i.e. if $B$ is hemimaximal and $A$ is a c.e. set such that $A le _{c_{1}} B$ then either $B leq _{{c}_{1}} A$ or $A$ is computable. (ii) The $sQ$-degree of a c.e. set contains either only one or infinitely many c.e. $c$-degrees. (iii) If $A,B$ are c.e. cylinders in the same $sQ_{1}$-degree and $A

Beschreibung: We propose some new mixed finite element methods for the time-dependent stochastic Stokes equations with multiplicative noise, which use the Helmholtz decomposition of the driving multiplicative noise. It is known (Langa, J. A., Real, J. & Simon, J. (2003) Existence and regularity of the pressure for the stochastic Navier--Stokes equations. Appl. Math. Optim., 48, 195--210) that the pressure solution has low regularity, which manifests in suboptimal convergence rates for well-known inf-sup stable mixed finite element methods in numerical simulations; see Feng X., & Qiu, H. (Analysis of fully discrete mixed finite element methods for time-dependent stochastic Stokes equations with multiplicative noise. arXiv:1905.03289v2 [math.NA]). We show that eliminating this gradient part from the noise in the numerical scheme leads to optimally convergent mixed finite element methods and that this conceptual idea may be used to retool numerical methods that are well known in the deterministic setting, including pressure stabilization methods, so that their optimal convergence properties can still be maintained in the stochastic setting. Computational experiments are also provided to validate the theoretical results and to illustrate the conceptual usefulness of the proposed numerical approach.

Beschreibung: We propose an internal calculus to check the satisfiability of a set of formulas in ${ oldsymbol {S4}}$. Our calculus directly supports model extraction and is designed so to implement a forward proof-search strategy that can be understood as a top-down construction of a model. We prove that the extracted models have minimal height.

Beschreibung: We study regularity in the context of connective ring spectra and spectral stacks. Parallel to that, we construct a weight structure on the category of compact quasi-coherent sheaves on spectral quotient stacks of the form $X=[operatorname{Spec} R/G]$ defined over a field, where R is a connective ${{mathcal{E}}_infty}$-k-algebra and G is a linearly reductive group acting on R. Under reasonable assumptions, we show that regularity of X is equivalent to regularity of R. We also show that if R is bounded, such a stack is discrete. This result can be interpreted in terms of weight structures and suggests a general phenomenon: for a symmetric monoidal stable $infty$-category with a compatible bounded weight structure, the existence of an adjacent t-structure satisfying a strong boundedness condition should imply discreteness of the weight-heart. We also prove a gluing result for weight structures and adjacent t-structures, in the setting of a semi-orthogonal decomposition of stable $infty$-categories.

Beschreibung: We show three basic properties of the image Milnor number µI(f) of a germ $fcolon(mathbb{C}^{n},S) ightarrow(mathbb{C}^{n+1},0)$ with isolated instability. First, we show the conservation of the image Milnor number, from which one can deduce the upper semi-continuity and the topological invariance for families. Second, we prove the weak Mond’s conjecture, which states that µI(f) = 0 if and only if f is stable. Finally, we show a conjecture by Houston that any family $f_tcolon(mathbb{C}^{n},S) ightarrow(mathbb{C}^{n+1},0)$ with $mu_I(,f_t)$ constant is excellent in Gaffney’s sense. For technical reasons, in the last two properties, we consider only the corank 1 case.

Beschreibung: We conjecture that the class of frame matroids can be characterized by a sentence in the monadic second-order logic of matroids, and we prove that there is such a characterization for the class of bicircular matroids. The proof does not depend on an excluded-minor characterization.

Beschreibung: This article deals with the approximate controllability of semilinear retarded integrodifferential equations with non-instantaneous impulses governed by Poisson jumps in Hilbert space. The existence of a mild solution is established by using stochastic calculus and a suitable fixed point technique. The approximate controllability of the proposed non-linear stochastic differential system is obtained by employing the theory of interpolation spaces and Fredholm theory. Finally, applications to the stochastic heat equation and retarded type stochastic Benjamin–Bona–Mahony equation are provided to illustrate the developed theoretical results.

Beschreibung: Long noncoding RNAs (lncRNAs) have been considered as novel regulators in oral squamous cell carcinoma (OSCC). Enhancer of zeste homolog 2 (EZH2) can act as an oncogene in OSCC. This study intended to investigate whether lncRNA PART1 can exert its role in OSCC by regulating EZH2. The expression of PART1 in OSCC samples, tumors tissues, or OSCC cell lines was detected by qRT-PCR. The proliferation and apoptosis of OSCC cells were detected by CCK-8 and flow cytometry assays, respectively. The expression of PART1 and EZH2 were highly expressed in clinical OSCC tumors and cell lines. The expression level of PART1 was positively correlated to the size, clinical stage, and node metastasis of OSCC patients. Functionally, PART1 knockdown inhibited proliferation and facilitated apoptosis of OSCC cells. Mechanically, FUS interacted with PART1 and EZH2. Additionally, PART1 knockdown reduced the mRNA expression of EZH2, which was offset by FUS overexpression. The overexpression of FUS abrogated the effects of PART1 silence on proliferation and apoptosis of OSCC cells. The in vivo experiment revealed that PART1 knockdown inhibited tumor growth of OSCC cells in nude mice. This study indicated that PART1 exerts a carcinogenic role in OSCC by enhancing the stability of EZH2 protein.

Beschreibung: Background Although it is well documented that adolescents and young adults (AYAs) with cancer have low participation in cancer clinical trials (CCTs), the underlying reasons are not well understood. We utilized the NCI Community Oncology Research Program (NCORP) network to identify barriers and facilitators to AYA CCT enrollment, and strategies to improve enrollment at community-based and minority/underserved sites. Methods We performed one-on-one semi-structured qualitative interviews with stakeholders (NCORP Site Principle Investigators, NCORP Administrators, Physicians involved in enrollment, Lead Clinical Research Associates or Clinical Research Nurses, Nurse Navigators, Regulatory Research Associates, Patient Advocates) in the AYA CCT enrollment process. NCORP sites that included high- and low-AYA enrolling affiliate sites and were diverse in geography and department representation (eg, pediatrics, medical oncology) were invited to participate. All interviews were recorded and transcribed. Themes related to barriers and facilitators and strategies to improve enrollment were identified. Results We conducted 43 interviews across 10 NCORP sites. Eleven barriers and 13 facilitators to AYA enrollment were identified. Main barriers included perceived limited trial availability and eligibility, physician gatekeeping, lack of provider and research staff time, and financial constraints. Main facilitators and strategies to improve AYA enrollment included having a patient screening process, physician endorsement of trials, an “AYA champion” on site, and strong communication between medical and pediatric oncology. Conclusions Stakeholders identified several opportunities to address barriers contributing to low AYA CCT enrollment at community-based and minority/underserved sites. Results of this study will inform development and implementation of targeted interventions to increase AYA CCT enrollment.

Beschreibung: Patients, practitioners, and policymakers are increasingly concerned about the delivery of ineffective or low-value clinical practices in cancer care settings. Research is needed on how to effectively de-implement these types of practices from cancer care. In this commentary, we spotlight the National Cancer Institute (NCI) Community Oncology Research Program (NCORP), a national network of community oncology practices, and elaborate on how it is an ideal infrastructure for conducting rigorous, real-world research on de-implementation. We describe key, multi-level issues that affect de-implementation and also serve as a guidepost for developing strategies to drive de-implementation. We describe optimal study designs for testing de-implementation strategies and elaborate on how and why the NCORP network is uniquely positioned to conduct rigorous and impactful de-implementation trials. The number and diversity of affiliated community oncology care sites, coupled with the overall objective of improving cancer care delivery, make the NCORP an opportune infrastructure for advancing de-implementation research while simultaneously improving the care of millions of cancer patients nationwide.

Beschreibung: Summary A problem of major interest in network data analysis is to explain the strength of connections using context information. To achieve this, we introduce a novel approach named network-supervised dimension reduction by projecting covariates onto low-dimensional spaces for revealing the linkage pattern, without assuming a model.We propose a new loss function for estimating the parameters in the resulting linear projection, based on the notion that closer proximity in the low-dimension projection renders stronger connections. Interestingly, the convergence rate of our estimator is shown to depend on a network effect factor which is the smallest number that can partition a graph in a way similar to the graph coloring problem. Our methodology has interesting connections to principal component analysis and linear discriminant analysis, which we exploit for clustering and community detection. The methodology developed is further illustrated by numerical experiments and the analysis of a pulsar candidates data in astronomy.

Beschreibung: The secreted glycoprotein Reelin plays important roles in both brain development and function. During development, Reelin regulates neuronal migration and dendrite development. In the mature brain, the glycoprotein is involved in synaptogenesis and synaptic plasticity. It has been suggested that Reelin loss or decreased function contributes to the onset and/or deterioration of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease. While the molecular mechanisms underpinning Reelin function remain unclear, recent studies have suggested that the specific proteolytic cleavage of Reelin may play central roles in the embryonic and postnatal brain. In this review, we focus on Reelin proteolytic processing and review its potential physiological roles.

Beschreibung: We present a method for solving nonlinear eigenvalue problems (NEPs) using rational approximation. The method uses the Antoulas–Anderson algorithm (AAA) of Nakatsukasa, Sète and Trefethen to approximate the NEP via a rational eigenvalue problem. A set-valued variant of the AAA algorithm is also presented for building low-degree rational approximations of NEPs with a large number of nonlinear functions. The rational approximation is embedded in the state-space representation of a rational polynomial by Su and Bai. This procedure perfectly fits the framework of the compact rational Krylov methods (CORK and TS-CORK), allowing solve large-scale NEPs to be efficiently solved. One advantage of our method, compared to related techniques such as NLEIGS and infinite Arnoldi, is that it automatically selects the poles and zeros of the rational approximations. Numerical examples show that the presented framework is competitive with NLEIGS and usually produces smaller linearizations with the same accuracy but with less effort for the user.

Beschreibung: Background Major cancer organizations recommend depression screening in patients and survivors. The Patient Health Questionnaire-9 (PHQ-9) is often suggested, with limited information about its use. Methods Enrollment data collected from younger breast cancer survivors participating in a behavioral intervention trial were used to examine the relationship between PHQ-9 scores (range = 0-27), patient characteristics and responses to standardized psychosocial assessment tools. Major depressive disorder criterion was met if responses to the first two PHQ-9 items (range = 0-6) were 〉3. The sample was categorized by total PHQ-9 scores: 10 (moderate to severe depression). PHQ-9 category associations with medical, demographic, psychosocial and behavioral characteristics were examined using ANOVA for continuous variables and chi-square tests for categorical variables. Results 231 women met the study pre-screening eligibility criterion of mild depressive symptoms and enrolled in the study. On average, they were 45.2 years old and 2.6 years since diagnosis. At enrollment, 22.1% met the screening criterion for possible major depressive disorder; among those with PHQ-9 scores 〉10, 58.3% met this criterion. Anxiety, fatigue, insomnia, and intrusive thoughts about cancer were frequent and were associated with depressive symptom severity (all Ps

Beschreibung: Cellular liquid-liquid phase separation is a physiologically inevitable phenomenon in molecularly crowded environments inside cells and serves to compartmentalize biomolecules to facilitate several functions, forming cytoplasmic and nuclear RNA granules. Abnormalities in the phase separation process in RNA granules are implicated in the onset of several neurodegenerative diseases; the initial liquid-like phase-separated droplets containing pathogenic proteins are prone to aberrantly mature into solid-like droplets. RNAs are involved in the maturation of physiological and pathological RNA granules and are essential for governing the fate of phase-transition processes. Notably, RNA G-quadruplex (G4RNA), which is the secondary structure of nucleic acids that are formed in guanine-rich sequences, appears to be an advantageous scaffold for RNA-derived phase separation because of its multivalent interactions with RNAs and RNA-binding proteins. Here, we summarize the properties of RNA granules in physiological and pathological phase separation and discuss the potential roles of G4RNA in granules.

Beschreibung: Recently, post-selection inference on thousands of parameters has attracted considerable research interest. Specifically, Benjamini & Yekutieli (2005) considered constructing confidence intervals after selection. They proposed adjusting the confidence levels of marginal confidence intervals for the selected parameters to ensure control of the false coverage-statement rate. Although Benjamini-Yekutieli’s confidence intervals are widely used, they are uniformly inflated. In this article, two methods are proposed to narrow Benjamini-Yekutieli’s confidence intervals. The first method improves the confidence intervals by incorporating the selection event into the calculation. The second method further narrows confidence intervals in which some parameters are selected with very small probabilities, which results in underutilization of the target level for control of the false coverage-statement rate. A breast cancer dataset is analyzed to compare the methods.

Beschreibung: Summary We generalize the sign covariance introduced by Bergsma & Dassios (2014) to multivariate random variables and beyond. The new interpoint-ranking sign covariance is applicable to general types of random objects as long as a meaningful similarity measure can be defined, and it is shown to be zero if and only if the two random variables are independent. The test statistic is a U-statistic, whose large sample behavior guarantees that the proposed test is consistent against general types of alternatives. Numerical experiments and data analyses demonstrate the great empirical performance of the proposed method.

Beschreibung: In this work, we propose a variant of so-called informational semantics, a technique elaborated by Voishvillo, for two infectious logics, Deutsch’s ${mathbf{S}_{mathbf{fde}}}$ and Szmuc’s $mathbf{dS}_{mathbf{fde}}$. We show how the machinery of informational semantics can be effectively used to analyse truth and falsity conditions of disjunction and conjunction. Using this technique, it is possible to claim that disjunction and conjunction can be rightfully regarded as such, a claim which was disputed in the recent literature. Both ${mathbf{S}_{mathbf{fde}}}$ and $mathbf{dS}_{mathbf{fde}}$ are formalized in terms of natural deduction. This allows us to solve several problems: to develop a natural deduction calculus for ${mathbf{S}_{mathbf{fde}}}$ containing the standard form of disjunction elimination (in contrast to the calculus by Petrukhin), to introduce the first natural deduction calculus for $mathbf{dS}_{mathbf{fde}}$ and to reflect the fundamental symmetry between ${mathbf{S}_{mathbf{fde}}}$ and $mathbf{dS}_{mathbf{fde}}$ on proof-theoretical level forming a convenient basis for obtaining their well-known extensions $mathbf{K}^{mathbf{w}}_{mathbf{3}}$ and $mathbf{PWK}$.

Beschreibung: Background Breast cancer is the leading cause of cancer death among Hispanic women. The aim of our study was to estimate Cardiovascular disease (CVD) risk among Hispanic and non-Hispanic White (NHW) breast cancer survivors compared to their respective general population cohorts. Methods Cohorts of 17,469 breast cancer survivors (1,774 Hispanic and 15,695 NHW) in the Utah Cancer Registry diagnosed 1997–2016, and 65,866 women (6,209 Hispanic and 59,657 NHW) from the general population in the Utah Population Database were identified. Cox Proportional Hazards models were used to estimate hazard ratios (HRs) for CVD. Results The risk of diseases of the circulatory system was higher in Hispanic than NHW breast cancer survivors (HRHispanic =1.94, 99% confidence interval [CI] =1.49–2.53; H NHW =1.38, 99%CI = 1.33–1.43; P  heterogeneity=0.01) 1–5 years after cancer diagnosis, in comparison with their respective general population cohorts. Increased risks were observed for both Hispanic and NHW breast cancer survivors for diseases of the heart and the veins and lymphatics, compared to the general population cohorts. More than 5 years after cancer diagnosis, elevated risk of diseases of the veins and lymphatics persisted in both ethnicities. The CVD risk due to chemotherapy and hormone therapy was higher in Hispanic than NHW breast cancer survivors, but did not differ for distant stage, higher baseline comorbidities or baseline smoking. Conclusions We observed a risk difference for diseases of the circulatory system between Hispanic and NHW breast cancer survivors compared to their respective general population cohorts but only within the first 5 years of cancer diagnosis.

Beschreibung: In this study we consider a classic paradox of infinity and its variations and suggest how the sources of misleading intuition can be analysed using the concept of uniform convergence of functions. We then examine how six mathematics honour students engage with a variation of the paradox. Despite their advanced mathematical training, the participants experienced considerable difficulty in addressing the presented paradoxical situation. Drawing on data from written responses and individual interviews, we describe the students’ approaches in an attempt to reconcile their intuitive perceptions with their mathematical computations.

Beschreibung: Background Fanconi anemia (FA) is a rare genetic disorder associated with hematological disorders and solid tumor predisposition. Owing to phenotypic heterogeneity, some patients remain undetected until adulthood, usually following cancer diagnoses. The uneven prevalence of FA cases with different underlying FA gene mutations worldwide suggests variable genetic distribution across populations. Here, we aim to assess the genetic spectrum of FA-associated genes across populations of varying ancestries and explore potential genotype-phenotype associations in cancer. Methods Carrier frequency and variant spectrum of potentially pathogenic germline variants in 17 FA genes (excluding BRCA1/FANCS, BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO) were evaluated in 3,523 Singaporeans and seven populations encompassing Asian, European, African and admixed ancestries from Genome Aggregation Database. Germline and somatic variants of 17 FA genes in seven cancer cohorts from The Cancer Genome Atlas (TCGA) were assessed to explore genotype-phenotype associations. Results Germline variants in FANCA were consistently more frequent in all populations. Similar trends in carrier frequency and variant spectrum were detected in Singaporeans and East Asians, both distinct from other ancestry groups particularly in the lack of recurrent variants. Our TCGA dataset exploration suggested higher germline and somatic mutation burden between FANCA and FANCC with head and neck and lung squamous cell carcinomas, as well as FANCI and SLX4/FANCP with uterine cancer, but the analysis was insufficiently powered to detect any statistical significance. Conclusion Our findings highlight the diverse genetic spectrum of FA-associated genes across populations of varying ancestries, emphasizing the need to include all known FA-related genes for accurate molecular diagnosis of FA.

Beschreibung: Paclitaxel (PTX) is the standard first-line treatment of ovarian cancer, but its efficacy is limited by multi-drug resistance. Therefore, it is crucial to identify effective drug targets to facilitate PTX-sensitivity for ovarian cancer treatment. Seventy PTX-administrated ovarian cancer patients were recruited in this study for gene expression and survival rate analyses. Muscleblind-like-3 (MBNL3) gain- and loss-of-function experiments were carried out in ovarian cancer cells (parental and PTX-resistant) and xenograft model. Cancer cell viability, apoptosis, spheroids formation, Nanog gene silencing were examined and conducted to dissect the underlying mechanism of MBNL3-mediated PTX-resistance. High expression of MBNL3 was positively correlated with PTX-resistance and poor prognosis of ovarian cancer. MBNL3 increased cell viability and decreased apoptosis in ovarian stem-like cells, through up-regulating Nanog. This study suggests the MBNL3-Nanog axis is a therapeutic target for the treatment of PTX-resistance in ovarian cancer management.

Beschreibung: Development of new and effective anti-influenza drugs is critical for prophylaxis and treatment of influenza A virus infection. A wide range of amphibian skin secretions have been identified to show antiviral activity. Our previously reported ESC-1GN, a peptide from the skin secretion of Hylarana guentheri, displayed good antimicrobial and anti-inflammatory effects. Here, we found that ESC-1GN possessed significant antiviral effects against influenza A viruses. Moreover, ESC-1GN could inhibit the entry of divergent H5N1 and H1N1 virus strains with the IC50 values from 1.29 to 4.59 μM. Mechanism studies demonstrated that ESC-1GN disrupted membrane fusion activity of influenza A viruses by interaction with HA2 subunit. The results of site-directed mutant assay and molecular docking revealed that E105, N50 and the residues around them on HA2 subunit could form hydrogen bonds with amino acid on ESC-1GN, which were critical for ESC-1GN binding to HA2 and inhibiting the entry of influenza A viruses. Altogether, these not only suggest that ESC-1GN maybe represent a new type of excellent template designing drugs against influenza A viruses, but also it may shed light on the immune mechanism and survival strategy of H. guentheri against viral pathogens.

Beschreibung: We devise a method for nonlinear time-dependent partial-differential-equation-constrained optimization problems that uses a spectral-in-time representation of the residual, combined with a Newton–Krylov method to drive the residual to zero. We also propose a preconditioner to accelerate this scheme. Numerical results indicate that this method can achieve fast and accurate solution of nonlinear problems for a range of mesh sizes and problem parameters. The numbers of outer Newton and inner Krylov iterations required to reach the attainable accuracy of a spatial discretization are robust with respect to the number of collocation points in time and also do not change substantially when other problem parameters are varied.

Beschreibung: In multicentre research, individual-level data are often protected against sharing across sites. To overcome the barrier of data sharing, many distributed algorithms, which only require sharing aggregated information, have been developed. The existing distributed algorithms usually assume the data are homogeneously distributed across sites. This assumption ignores the important fact that the data collected at different sites may come from various subpopulations and environments, which can lead to heterogeneity in the distribution of the data. Ignoring the heterogeneity may lead to erroneous statistical inference. In this paper, we propose distributed algorithms which account for the heterogeneous distributions by allowing site-specific nuisance parameters. The proposed methods extend the surrogate likelihood approach (Wang et al., 2017; Jordan et al., 2018) to the heterogeneous setting by applying a novel density ratio tilting method to the efficient score function. The proposed algorithms maintain the same communication cost as existing communication-efficient algorithms. We establish a non-asymptotic risk bound for the proposed distributed estimator and its limiting distribution in the two-index asymptotic setting which allows both sample size per site and the number of sites to go to infinity. In addition, we show that the asymptotic variance of the estimator attains the Cramér-Rao lower bound when the number of sites is in rate smaller than the sample size at each site. Finally, we use simulation studies and a real data application to demonstrate the validity and feasibility of the proposed methods.

Beschreibung: This paper deals with the global finite-time synchronization of a class of third-order chaotic systems with some intersecting nonlinearities, which cover many famous chaotic systems. First, a simple, continuous and dimension-reducible control by the name of the variable-substitution and feedback control is designed to construct a master–slave finite-time synchronization scheme. Then, a global finite-time synchronization criterion for the synchronization scheme is proven and the synchronization time is analytically estimated. Subsequently, the criterion and optimization technique are applied to the well-known brushless direct current motor (BLDCM) system and the classic Lorenz system, respectively, further obtaining some new optimized synchronization criteria in the form of algebra. Two numerical examples for the BLDCM system and a numerical example for the Lorenz system are simulated and analyzed to verify the effectiveness of the theoretical results obtained in this paper.

Beschreibung: Plasma membrane tubulin is an endogenous regulator of P-ATPases and the unusual accumulation of tubulin in the erythrocyte membrane results in a partial inhibition of some their activities, causing hemorheological disorders like reduced cell deformability and osmotic resistance. These disorders are of particular interest in hypertension and diabetes, where the abnormal increase in membrane tubulin may be related to the disease development. Phosphatidylserine is more exposed on the membrane of diabetic erythrocytes than in healthy cells. In most cells, phosphatidylserine is transported from the exoplasmic to the cytoplasmic leaflet of the membrane by lipid flippases. Here we report that phosphatidylserine is more exposed in erythrocytes from both hypertensive and diabetic patients than in healthy erythrocytes, which could be attributed to the inhibition of flippase activity by tubulin. This is supported by: (i)- the translocation rate of a fluorescent phosphatidylserine analog in hypertensive and diabetic erythrocytes was slower than in healthy cells, (ii)- the pharmacological variation of membrane tubulin in erythrocytes and K562 cells was linked to changes in phosphatidylserine translocation, (iii)- the P-ATPase-dependent phosphatidylserine translocation in inside-out vesicles from human erythrocytes was inhibited by tubulin. These results suggest that tubulin regulates flippase activity and hence the membrane phospholipid asymmetry.

Beschreibung: Summary Autophagy, which is an evolutionarily conserved intracellular degradation system, involves de novo generation of autophagosomes that sequester and deliver diverse cytoplasmic materials to the lysosome for degradation. Autophagosome formation is mediated by approximately 20 core autophagy-related (Atg) proteins, which collaborate to mediate complicated membrane dynamics during autophagy. To elucidate the molecular functions of these Atg proteins in autophagosome formation, many researchers have tried to determine the structures of Atg proteins by using various structural biological methods. Although not sufficient, the basic structural catalog of all core Atg proteins was established. In this review article, we summarize structural biological studies of core Atg proteins, with an emphasis on recently unveiled structures, and describe the mechanistic breakthroughs in autophagy research that have derived from new structural information.

Beschreibung: Single-index models have gained increased popularity in time-to-event analysis owing to their model flexibility and advantage in dimension reduction. In this paper, we propose a semiparametric framework for the rate function of a recurrent event counting process by modelling its size and shape components with single-index models. With additional monotone constraints on the two link functions for the size and shape components, the proposed model possesses the desired directional interpretability of covariate effects and encompasses many commonly used models as special cases. To tackle the analytical challenges arising from leaving the two link functions unspecified, we develop a two-step rank-based estimation procedure to estimate the regression parameters with or without informative censoring. The proposed estimators are asymptotically normal, with a root-n convergence rate. To guide model selection, we develop hypothesis testing procedures for checking shape- and size-independence. Simulation studies and a data example on a hematopoietic stem cell transplantation study are presented to illustrate the proposed methodology.

Beschreibung: Summary We investigate estimation of a normal mean matrix under the matrix quadratic loss. Improved estimation under the matrix quadratic loss implies improved estimation of any linear combination of the columns under the quadratic loss. First, an unbiased estimate of risk is derived and the Efron–Morris estimator is shown to be minimax. Next, a notion of matrix superharmonicity for matrix-variate functions is introduced and shown to have analogous properties with usual superharmonic functions, which may be of independent interest. Then, we show that the generalized Bayes estimator with respect to a matrix superharmonic prior is minimax. We also provide a class of matrix superharmonic priors that includes the previously proposed generalization of Stein’s prior. Numerical results demonstrate that matrix superharmonic priors work well for low rank matrices.

Beschreibung: Block low-rank (BLR) matrices possess a blockwise low-rank property that can be exploited to reduce the complexity of numerical linear algebra algorithms. The impact of these low-rank approximations on the numerical stability of the algorithms in floating-point arithmetic has not previously been analysed. We present rounding error analysis for the solution of a linear system by LU factorization of BLR matrices. Assuming that a stable pivoting scheme is used, we prove backward stability: the relative backward error is bounded by a modest constant times $varepsilon $, where the low-rank threshold $varepsilon $ is the parameter controlling the accuracy of the blockwise low-rank approximations. In addition to this key result, our analysis offers three new insights into the numerical behaviour of BLR algorithms. First, we compare the use of a global or local low-rank threshold and find that a global one should be preferred. Second, we show that performing intermediate recompressions during the factorization can significantly reduce its cost without compromising numerical stability. Third, we consider different BLR factorization variants and determine the update–compress–factor variant to be the best. Tests on a wide range of matrices from various real-life applications show that the predictions from the analysis are realized in practice.

Beschreibung: Unobserved confounding presents a major threat to causal inference from observational studies. Recently, several authors suggest that this problem may be overcome in a shared confounding setting where multiple treatments are independent given a common latent confounder. It has been shown that under a linear Gaussian model for the treatments, the causal effect is not identifiable without parametric assumptions on the outcome model. In this note, we show that the causal effect is indeed identifiable if we assume a general binary choice model for the outcome with a non-probit link. Our identification approach is based on the incongruence between Gaussianity of the treatments and latent confounder, andnon-Gaussianity of a latent outcome variable. We further develop a two-step likelihood-based estimation procedure.

Beschreibung: Primary cilia are evolutionarily conserved microtubule-based organelles that protrude from the surface of almost all cell types and decode a variety of extracellular stimuli. Ciliary dysfunction causes human diseases named ciliopathies, which span a wide range of symptoms, such as developmental and sensory abnormalities. The assembly, disassembly, maintenance, and function of cilia rely on protein transport systems including intraflagellar transport (IFT) and lipidated protein intraflagellar targeting (LIFT). IFT is coordinated by three multisubunit protein complexes with molecular motors along the ciliary axoneme, while LIFT is mediated by specific chaperones that directly recognize lipid chains. Recently, it has become clear that several post-translational modification enzymes play crucial roles in the regulation of IFT and LIFT. Here we review our current understanding of the roles of these post-translational modification enzymes in the regulation of ciliary protein trafficking as well as their regulatory mechanisms, physiological significance, and involvement in human diseases.

Beschreibung: This paper proposes natural deduction systems for the representation of inferences in which several agents participate in deriving conclusions about what they believe or know, where belief and knowledge are understood in an intuitionistic sense. Multi-agent derivations in these systems may involve relatively complex belief (resp. knowledge) constructions which may include forms of nested, reciprocal, shared, distributed or universal belief/knowledge as well as attitudes de dicto/re/se. The systems consist of two main components: multi-agent belief bases which assign to each agent a subatomic system that represents the agent’s beliefs concerning atomic sentences and a set of multi-agent labelled rules for logically compound formulae. Derivations in these systems normalize. Moreover, normal derivations possess the subexpression property (a refinement of the subformula property) which makes them fully analytic. Relying on the normalization result, a proof-theoretic approach to the semantics of the intensional operators for intuitionistic belief/knowledge is presented which explains their meaning entirely by appeal to the structure of derivations. Importantly, this proof-theoretic semantics is autarkic with respect to its foundations as the systems (unlike, e.g. external/labelled proof systems which internalize possible worlds truth conditions) are not defined on the basis of a possible worlds semantics. Detailed applications to a logical puzzle (McCarthy’s three wise men puzzle) and to a semantical difficulty (Geach’s problem of intentional identity), respectively, illustrate the systems. The paper also provides comparisons with other approaches to intuitionistic belief/knowledge and multi-agent natural deduction.

Beschreibung: Background Prior research suggests a relationship between overall diet quality and breast cancer survival, though few studies have reported on this topic. We evaluated whether four dietary quality indices consistent with healthy eating recommendations around the time of breast cancer diagnosis were associated with risk of recurrence, cause-specific and all-cause mortality. Methods A total of 3,660 women diagnosed with invasive breast cancer were included. Diet was assessed an average of 2.3 (range = 0.7–18.7) months after diagnosis, from which four dietary quality indices were derived: the American Cancer Society guidelines (ACS), the alternate Mediterranean Diet Index (aMED), the Dietary Approaches to Stop Hypertension (DASH) and the 2015 Healthy Eating Index (HEI). Over 40,888 person-years of follow-up, 461 breast cancer recurrences and 655 deaths were ascertained. Cox models were used to estimate hazards ratios (HRs) and 95% confidence intervals (CIs). Results Adjusted comparisons between extreme quintiles showed all four dietary quality indices to be inversely associated with all-cause mortality, suggesting a 21%–27% lower risk (ACS HR = 0.73 [95%CI = 0.56–0.95], aMED HR = 0.79 [95%CI = 0.61–1.03], DASH HR = 0.76 [95%CI = 0.58–1.00], HEI HR = 0.77 [95%CI = 0.60–1.01]). Similar patterns were noted for non-breast cancer mortality (ACS HR = 0.69 [95%CI = 0.48–0.98], aMED HR = 0.73 [95%CI = 0.50–1.05], DASH HR = 0.55 [95%CI = 0.38–0.79], HEI HR = 0.67 [95%CI = 0.48–0.94]). None of the dietary quality indices were associated with recurrence or breast cancer-specific mortality. Conclusion Food intake patterns concordant with dietary quality indices consistent with recommendations for healthy eating may be beneficial for women with breast cancer.

Beschreibung: Death receptors, members of the tumor necrosis factor receptor (TNFR) superfamily, are characterized by the presence of a death domain in the cytosolic region. TNFR1, Fas, and TNF-related apoptosis-inducing ligand receptors, which are prototypical death receptors, exert pleiotropic functions in cell death, inflammation, and immune surveillance. Hence, they are involved in several human diseases. The activation of death receptors and downstream intracellular signaling are regulated by various post-translational modifications, such as phosphorylation, ubiquitination, and glycosylation. Glycosylation is one of the most abundant and versatile modifications to proteins and lipids, and it plays a critical role in the development and physiology of organisms, as well as the pathology of many human diseases. Glycans control a number of cellular events, such as receptor activation, signal transduction, endocytosis, cell recognition, and cell adhesion. It has been demonstrated that oligo- and monosaccharides modify death receptors and intracellular signaling proteins, and regulate their functions. Here, we review the current understanding of glycan modifications of death receptor signaling and their impact on signaling activity.

Beschreibung: Background After resection of colorectal cancer liver metastases (CRLM) two main histopathological growth patterns can be observed; a desmoplastic and a non-desmoplastic subtype. The desmoplastic subtype has been associated with superior survival. These findings require external validation. Methods An international multicenter retrospective cohort study was conducted in patients treated surgically for CRLM at three tertiary hospitals in the US and the Netherlands. Determination of histopathological growth patterns was performed on hematoxylin & eosin stained sections of resected CRLM according to international guidelines. Patients displaying a desmoplastic histopathological phenotype (only desmoplastic growth observed) were compared to patients with a non-desmoplastic phenotype (any non-desmoplastic growth observed). Cut-off analyses on the extent of non-desmoplastic growth were performed. Overall (OS) and disease-free (DFS) survival were estimated using Kaplan-Meier and multivariable Cox analysis. All statistical tests were 2-sided. Results In total 780 patients were eligible. A desmoplastic phenotype was observed in 19.1% and was associated with microsatellite instability (14.6% versus 3.6%, p = .01). Desmoplastic patients had superior 5-year OS (73.4% [95% CI = 64.1–84.0] versus 44.2% [95% CI = 38.9–50.2], p 

Beschreibung: We conduct a study of the aliased spectral densities of Matérn covariance functions on a regular grid of points, providing clarity on the properties of a popular approximation based on stochastic partial differential equations. While others have shown that it can approximate the covariance function well, we find that it assigns too much power at high frequencies and does not provide increasingly accurate approximations to the inverse as the grid spacing goes to zero, except in the one-dimensional exponential covariance case.

Beschreibung: We consider harmonic sections of a bundle over the complement of a codimension 2 submanifold in a Riemannian manifold, which can be thought of as multivalued harmonic functions. We prove a result to the effect that these are stable under small deformations of the data. The proof is an application of a version of the Nash-Moser implicit function theorem.

Beschreibung: Background Duloxetine effectively treats aromatase inhibitor–associated musculoskeletal symptoms (AIMSS) in women with breast cancer but causes low-grade toxicities. This secondary analysis examines the relationship between adverse events (AE) and patient-perceived benefit, based on patient self-report that the treatment received was beneficial despite side effects. We hypothesized that duloxetine had a favorable effect on patient-perceived benefit, even among duloxetine-treated patients who experienced AEs and who, had they been treated with placebo, would have experienced none. Methods Principal stratification was used to estimate the effect of duloxetine versus placebo on patient-perceived benefit and FACT-ES functional quality of life (FQOL) in the randomized, double-blind trial SWOG S1202 (n = 289). Subgroups of patients were defined by observed and counterfactual (what would have occurred had they been randomized to the opposite study arm) experiences of AEs and the original primary outcome, reduction of average pain after 12 weeks of ≥ 2 points on the Brief Pain Inventory–Short Form. Results Duloxetine caused an estimated 23.4% (95% credible interval [CI] = 13.4% to 33.7%) of patients to experience an AE even though they would have experienced none on placebo. Those patients remained more likely to report that their received treatment was beneficial than comparable patients assigned placebo (73.3% vs 41.8%, respectively, 95%CI for difference = 15.4 to 47.2 percentage points), though there was no statistically significant effect of duloxetine on FQOL (11.3 vs 9.0, 95%CI for difference = -2.2 to + 6.7). Conclusion Duloxetine resulted in higher patient-perceived benefit, even among those who would have an AE on duloxetine but none on placebo. Treatment of AIMSS with duloxetine should be considered for appropriate patients.

Beschreibung: One of the most relevant issues of a social robot is its capability of catching the attention of a new acquaintance and empathize with her. The first steps towards a system which can be used by a social robot in order to be empathetic are illustrated in this paper. The system can analyze the Twitter ID of the new acquaintance, trying to detect the IAB (Interactive Advertising Bureau) Tier 1 categories that possibly can let arise in him/her a joyful feeling. Furthermore, it can retrieve news about that category and report them to the user, hopefully increasing his/her curiosity towards the system, improving the naturalness of the interaction. Moreover, the system is capable of querying Wikipedia in order to clarify any doubts that may arise in the user. A sample of a possible interaction is reported at the end of the paper.

Beschreibung: Space-filling designs are widely used in computer experiments. Inspired by the stratified orthogonality of strong orthogonal arrays, we propose a minimum aberration type criterion for assessing the space-filling properties of designs based on design stratification properties on various grids. A space-filling hierarchy principle is proposed as a basic assumption of the criterion. The new criterion provides a systematic way of classifying and ranking space-filling designs including various types of strong orthogonal arrays and Latin hypercube designs. Theoretical results and examples are presented to show that strong orthogonal arrays of maximum strength are favorable under the proposed criterion. For strong orthogonal arrays with the same strength, the space-filling criterion can further rank them based on their space-filling patterns.

Beschreibung: This paper studies alternative procurement modes for emergency supplies in the presence of a public sector and a private supplier. A key feature of such a supply chain is that the private supplier must consider commercial demand in addition to disaster demand. Three procurement modes are analysed: an option mode (OM), an order-before-disaster mode (OBDM) and a procurement-after-disaster mode (PADM). We provide the optimal decisions associated with these three modes. Theoretical results in the OM show that a large order is not always better for the private supplier. From theoretical and numerical comparative analyses, no mode is absolutely superior. For the public sector, there are two thresholds. When the disaster probability is less than the low threshold, the revenues of all procurement modes are the same; when the disaster probability is larger than the high threshold, the OBDM has the highest revenue; otherwise, the OM has the highest revenue. However, for the private supplier, the PADM always has the highest revenue.

Beschreibung: The preferential conditional logic $ mathbb{PCL} $, introduced by Burgess, and its extensions are studied. First, a natural semantics based on neighbourhood models, which generalizes Lewis’ sphere models for counterfactual logics, is proposed. Soundness and completeness of $ mathbb{PCL} $ and its extensions with respect to this class of models are proved directly. Labelled sequent calculi for all logics of the family are then introduced. The calculi are modular and have standard proof-theoretical properties, the most important of which is admissibility of cut that entails a syntactic proof of completeness of the calculi. By adopting a general strategy, root-first proof search terminates, thereby providing a decision procedure for $ mathbb{PCL} $ and its extensions. Finally, semantic completeness of the calculi is established: from a finite branch in a failed proof attempt it is possible to extract a finite countermodel of the root sequent. The latter result gives a constructive proof of the finite model property of all the logics considered.

Beschreibung: Background Disparities in colon cancer outcomes have been reported across race and socioeconomic status which may reflect, in part, access to care. We sought to assess the influences of race and median household income (MHI) on outcomes among colon cancer patients with similar access to care. Methods We conducted a prospective, observational study of 1206 stage III colon cancer patients enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial. Race was self-reported by 1116 White and 90 Black patients at study enrollment; MHI was determined by matching 973 patients’ home zip codes with publicly-available United States Census 2000 data. Multivariate analyses were adjusted for baseline sociodemographic, clinical, dietary, and lifestyle factors. All statistical tests were 2-sided. Results Over a median follow-up of 7.7 years, the adjusted hazard ratios (HRs) for Blacks (compared to Whites) were 0.94 (95% confidence interval [CI] = 0.66–1.35; P = .75) for disease-free survival, 0.91 (95%CI = 0.62–1.35; P = .65) for recurrence-free survival, and 1.07 (95%CI = 0.73–1.57; P = .73) for overall survival. Relative to patients in the highest MHI quartile, the adjusted HRs for patients in the lowest quartile were 0.90 (95%CI, 0.67–1.19; Ptrend=0.18) for disease-free survival, 0.89 (95%CI = 0.66–1.22; Ptrend=0.14) for recurrence-free survival, and 0.87 (95%CI = 0.63–1.19; Ptrend=0.23) for overall survival. Conclusion In this study of patients with similar healthcare access, no statistically significant differences in outcomes were found by race or MHI. The substantial gaps in outcomes previously observed by race and MHI may not be rooted in differences in tumor biology, but in access to quality care.

Beschreibung: Background Branched-chain amino acids (BCAAs) are essential amino acids common throughout the US diet. While circulating BCAAs have been implicated in insulin resistance and some obesity-related cancers, the relationship between dietary intake of BCAAs and incident breast cancer is unknown. We sought to evaluate the association between long-term dietary intakes of BCAAs and invasive breast cancer risk. Methods Our analyses included 196,161 women from the Nurses’ Health Study and Nurses’ Health Study II longitudinal cohorts. Average intakes of total and individual BCAAs (isoleucine, leucine, valine) were estimated from repeated diet questionnaires and incident self-reported breast cancer cases were confirmed via medical record review. Cox proportional hazards models, adjusted for reproductive history, lifestyle, body mass index (BMI) and other breast cancer risk factors, were used to estimate hazard ratios and 95% confidence intervals. Results We observed 10,046 incident cases of breast cancer over a median of 20.8 years of follow-up. No associations between dietary intakes of total or individual BCAAs with breast cancer risk were observed. Compared with women in the bottom quintile of BCAA intake, the hazard ratio of breast cancer for those in the top quintile was 1.05 (95% confidence interval = 0.98 to 1.12; 2-sided Ptrend=0.20). Findings were consistent across molecular subtypes and according to type 2 diabetes diagnosis and BMI categories. Conclusions Dietary intakes of BCAAs are not likely a risk factor for breast cancer.

Beschreibung: Background Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a two-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods Our primary instrument included single nucleotide polymorphisms (SNPs) with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58,131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium; Colon Cancer Family Registry; and Colorectal Transdisciplinary study), lung cancer (n = 18,082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), MR-PRESSO, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer sub-type (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; p = 0.03), 3% increased risk of colon cancer (p = 0.02), 4% increased risk of proximal colon cancer (p = 0.01), and 3% increased risk of colorectal cancer among females (p = 0.04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

Beschreibung: Background Benign meningiomas are the most frequently reported central nervous system tumors in the United States (US), with increasing incidence in past decades. However, the future trajectory of this neoplasm remains unclear. Methods We analyzed benign meningioma incidence of cases identified by any means (eg, radiographically with or without microscopic confirmation) in US Surveillance Epidemiology and End Results (SEER) cancer registries among 35–84-year-olds during 2004–2017 by sex and race/ethnicity using age-period-cohort (APC) models. We employed APC forecasting models to glean insights regarding the etiology, distribution, and anticipated future (2018–2027) public health impact of this neoplasm. Results In all groups, meningioma incidence overall increased through 2010, then stabilized. Temporal declines were statistically significant overall and in most groups. JoinPoint analysis of cohort rate-ratios identified substantial acceleration in White men born after 1963 (from 1.1% to 3.2% per birth year); cohort rate-ratios were stable or increasing in all groups and all birth cohorts. We forecast that meningioma incidence through 2027 will remain stable or decrease among 55–84-year-olds but remain similar to current levels among 35–54-year-olds. Total meningioma burden in 2027 is expected to be approximately 30,470 cases, similar to the expected case count of 27,830 in 2018. Conclusions Between 2004–2017, overall incidence of benign meningioma increased and then stabilized or declined. For 2018–2027, our forecast is incidence will remain generally stable in younger age groups but decrease in older age groups. Nonetheless, the total future burden will remain similar to current levels because the population is aging.

Beschreibung: Background Having a child diagnosed with cancer is a devastating experience that may affect parentś mental health. We aimed to assess the risk of hospital contacts for psychiatric disorders in parents of children with cancer. Methods We conducted a nationwide population-based cohort study using Danish registry data. Parents of children diagnosed with cancer between 1982-2014 (n = 6,689 mothers, n = 5,509 fathers) were matched with comparison parents of cancer-free children (n = 67,544 mothers, n = 55,756 fathers). We used Cox proportional hazards models to estimate the risk of hospital contacts for any psychiatric disorder and specific disorders. Cox models were also used to investigate socio-demographic and cancer-related risk factors for psychiatric disorders. Results Incidence rates of hospital contacts for any psychiatric disorder were 426 per 100,000 person-years in mothers of children with cancer and 345 per 100,000 person-years in comparison mothers. For fathers the respective incidence rates were 260 and 262 cases per 100,000 person-years. Compared to parents of cancer-free children, mothers of children with cancer were at an increased risk of hospital contacts for any psychiatric disorder (HR = 1.23, 95%-CI = 1.12-1.36), while no elevated risk was seen in fathers (HR = 0.99, 95%-CI = 0.87-1.13). Among mothers, risks were particularly elevated for affective and stress-related disorders. Parents of deceased children and children diagnosed at a younger age were at particular risk of hospital contacts for psychiatric disorders. Conclusion Hospital contacts for psychiatric disorders were overall rare. Healthcare professionals should draw attention to subgroups of vulnerable parents to meet their needs of support and adequate treatment.