Additional Hypotheses Research Articles

Abstract PO5-19-09: Trial in progress: A prospective randomized, controlled study to evaluate device efficacy for cutting and/or coagulation of tissue during mastectomy procedures

Abstract Background/Purpose: The ConMed HelixAR Electrosurgical Generator with Argon Beam Coagulation Technology (CHEST) trial aims to focus on patients undergoing mastectomy, either unilateral or bilateral, with immediate breast reconstruction including breast implants, tissue expander placement, or autologous flap. The study design follows the standard of care procedure with device efficacy being measured between two devices regularly used in the operative setting: the HelixAR Electrosurgical Generator (HEG) and the Conventional Electrosurgical Coagulation (CEC) systems. The need for safe alternative surgical tools is increasing as the number of women needing surgical treatment increases. Allowing for the test and comparison of these standardized devices gives an extent to the advantages of using one over the other. To evaluate the device effectiveness between the HelixAR Electrosurgical Generator and Conventional Electrosurgical Coagulation systems for cutting and/or coagulation of tissue during mastectomy and reconstruction surgery, we report the implementation in a randomized clinical trial. The study is powered to show superiority of the HEG to the CEC as it relates to the primary objective of time from post-mastectomy to hemostasis. The HEG is designed to deliver argon gas and high frequency electrical current compared to the CEC delivering high frequency electrical current only. The primary efficacy measure is the time it takes from post-mastectomy to hemostasis with the secondary effectiveness endpoints being infection, drain duration, total drain output, blood loss and device related adverse events. The study hypothesizes that the time for post-mastectomy hemostasis is significantly less for the HEG than the CEC. Additional hypotheses include overall less device related adverse events, lower blood loss, and reduced operative time in favor of the HEG. Methods: This is a prospective 1:1 randomized controlled study of the HEG versus the CEC for patients undergoing a mastectomy with reconstruction procedure. 82 patients will be enrolled and distributed in two arms of 41 patients with a primary objective to assess the device efficacy for cutting and coagulation. The subject population includes patients with breast cancer or high risk from genetic mutations and/or family history. Exclusion factors include known history of bleeding diathesis or coagulopathy, advanced refusal of blood transfusion, active systemic or cutaneous infection or inflammation. The enrolled patients will be followed for 2 months post-operatively. Results: The study is open with 53/82 (65%) patients enrolled at the time of the abstract submission. Of those, 26 subjects were randomized to the CEC and 27 to the HEG. 27 subjects have experienced an adverse or serious adverse event including bruising, infections, and wound dehiscence, none determined to be related to the device use. For the study, analysis will focus on the primary endpoint comparing post–mastectomy procedure time to hemostasis between the two devices. Conclusion: The CHEST trial demonstrates the feasibility of conducting a randomized controlled trial at a single center in a complex operative setting comparing two surgical modalities. The testing of these surgical devices provides rationale for the implementation of safe and regulated clinical trials. While both devices are FDA approved and regularly used, the standardization of device efficacy is becoming more prevalent as new innovations get introduced into the surgical setting. Citation Format: Jessica Montalvan, Ivan Marin, Logan Healy, Margarita Riojas-Barrett, Mary Bajomo, Elizabeth Bonefas, Alastair Thompson, Marco Maricevich, Sebastian Winocour, Stacey Carter. Trial in progress: A prospective randomized, controlled study to evaluate device efficacy for cutting and/or coagulation of tissue during mastectomy procedures [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-09.

A Comprehensive Study of the Langevin Boundary Value Problems with Variable Order Fractional Derivatives

The authors investigate Langevin boundary value problems containing a variable order Caputo fractional derivative. After presenting the background for the study, the authors provide the definitions, theorems, and lemmas that are required for comprehending the manuscript. The existence of solutions is proved using Schauder’s fixed point theorem; the uniqueness of solutions is obtained by adding an additional hypothesis and applying Banach’s contraction principle. An example is provided to demonstrate the results.

Replication Study to Evaluate the Effects of Awe on Humility

This paper replicates Stellar and Colleagues’ 2018 study involving an experimental manipulation of awe using standardized video induction, as well as proposing and testing out an additional hypothesis. The previous study hypothesized that watching an awe-inducing video would lead participants to write fewer strengths before writing their weaknesses. In addition to the replication, we hypothesized that participants with higher scores of depressive symptomatology (DS) would list fewer strengths due to diminished self-concept and self-efficacy. Ninety-four undergraduate psychology students were recruited from McGill University ranging from 18 to 35 years of age. Participants were randomly assigned to either the awe-inducing or neutral video condition, and then filled out measures of humility, emotional reactions, and DS. In contradiction with the original study, participants in the awe condition and the neutral condition did not significantly differ in their ratio of disclosed strengths to weaknesses, therefore no significant correlations were found between awe and humility or humility and depression. Additionally, results indicated that participants with greater DS did not list fewer strengths compared to those scoring lower on the CES-D. We were unable to directly replicate the original study and thus rejected our alternate hypothesis. This study had various potential limitations, among which are the possibilities of self-report bias, issues regarding convenience sampling, and bias due to time constraints. The current study advances the literature by including depression relating to awe and humility. Further research is needed, to differentiate lab-induced awe from natural experiences of awe and identify possible moderating factors on humility.

Breaking Barriers, Building Businesses, and International Markets: Strategies of Female Innovators in the Chinese Market

In China, which in the past was dominated by state-owned and male-led ventures, female entrepreneurs are now increasingly popular. However, the specific pathways to internationalization for female-owned firms in China and their contribution to the country’s economic growth remain unexplored. Based on the principles of the resource-based approach, the article explores the innovative strategies used by Chinese female-owned firms to overcome resource constraints, formal and informal institutional barriers to business internationalization (entering the global markets through indirect exports). The article puts forward and empirically tests 5 sets of hypotheses according to which Chinese female-owned firms are: 1) more efficient in internationalization through indirect export strategies; 2) more inclined to digital innovation; 3) not focused on innovation conversion, but rather on successful adaptation of existing offerings for international markets or efficiency gains; 4) do not prioritize innovation in communication technologies, focusing more on innovation to reach customers, build relationships and enter international markets; 5) use the female business ecosystem to obtain safer pathways to innovation, such as external partnerships or adapting existing technologies, rather than focusing on investing internal R&D with elevated risk. Within each block, 2 additional hypotheses were put forward. They consider the impact of the relevant factor (digital innovation, innovation conversion, communication innovation, internal innovation) on indirect exports and its role in mediating the relationship between female ownership and the success of business internationalization. The study is based on a sample of 2,700 Chinese firms surveyed from November 2011 to March 2013 using the World Bank Enterprise Surveys China 2012 (a comprehensive recoding was performed, adhering to established practices in quantitative research). The control variables are the location of the respondent company in the capital/province, city size and firm size. The study used two types of factor analysis – Exploratory (EFA, including Promax rotation, oblique rotation method) and Confirmatory (CFA, Alpha Cronbach test, full path analysis model, including both direct and indirect effects, Monte Carlo method). SPSS 29 software was used for the data sample and AMOS 26.0 for the modeling process. A direct positive relationship was found between female ownership and indirect exports in China and digital ecosystem innovations, as well as between communication innovations and indirect exports. A significant negative direct relationship was found between female ownership and communication innovations, between digital ecosystem innovations and indirect exports, and between internal innovations on indirect exports. It also reveals the absence of a significant direct impact of innovation conversion on indirect exports. Mediating effects were also confirmed for communication and digital ecosystem innovations; partially for internal innovations; not confirmed for innovation conversion.

Utility of cell-based vaccines as cancer therapy: Systematic review and meta-analysis

ABSTRACT Cell-based therapeutic cancer vaccines use autologous patient-derived tumor cells, allogeneic cancer cell lines or autologous antigen presenting cells to mimic the natural immune process and stimulate an adaptive immune response against tumor antigens. The primary objective of this study is to perform a systematic literature review with an embedded meta-analysis of all published Phase 2 and 3 clinical trials of cell-based cancer vaccines in human subjects. The secondary objective of this study is to review trials demonstrating biological activity of cell-based cancer vaccines that could uncover additional hypotheses, which could be used in the design of future studies. We performed the systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The final review included 36 studies − 16 single-arm studies, and 20 controlled trials. Our systematic review of the existing literature revealed largely negative trials and our meta-analysis did not show evidence of clinical benefit from cell-based cancer-vaccines. However, as we looked beyond the stringent inclusion criteria of our systematic review, we identified significant examples of biological activity of cell-based cancer vaccines that are worth highlighting. In conclusion, the existing literature on cell-based cancer vaccines is highly variable in terms of cancer type, vaccine therapies and the clinical setting with no overall statistically significant clinical benefit, but there are individual successes that represent the promise of this approach. As cell-based vaccine technology continues to evolve, future studies can perhaps fulfill the potential that this exciting field of anti-cancer therapy holds.

Corrigendum to “The discriminant of compositum of algebraic number fields”

We point out that there is an error in the proof of Theorem 1.1 in [The discriminant of compositum of algebraic number fields, Int. J. Number Theory 15 (2019) 353–360]. We also prove that the result of this theorem holds with an additional hypothesis. However, it is an open problem whether the result of the theorem is true in general or not.

Range-wide contrast in management outcomes for transboundary Northeast Pacific sablefish

Sablefish (Anoplopoma fimbria) of the Northeast Pacific support a highly mobile, valuable fishery resource currently managed as three separate populations. Recent work has shown sablefish to be genetically mixed; have high movement rates; and have synchronous biomass trends, including recent declines. A management strategy evaluation was developed with stakeholders and scientists from three regions to investigate whether spatially-structured management paradigms might result in better conservation and economic outcomes. The management strategy evaluation includes a transboundary operating model to represent spatial population dynamics including movement and a delay-difference estimation method with varying spatial complexities and potential stratifications, and harvest control rules. Mismatches in the spatial scale of management and the underlying biological units pose a crucial risk of localized depletion in the southern U.S. West Coast. This study presents one of the first transboundary, spatially-explicit management strategy evaluations conditioned to actual data. These results underscore the importance of spatial management strategy evaluation tools and implications when regional management is conducted in isolation. Future work should incorporate additional spatial hypotheses and investigate the drivers of recruitment patterns range-wide.

Medical device report analyses from MAUDE: Device and patient outcomes, adverse events, and sex-based differential effects

Post-market medical device-associated failures and patient problems are reported in Medical Device Reports (MDRs) to the US Food and Drug Administration. Reports are accessible through Manufacturer and User Facility Device Experience (MAUDE), a database including both required and voluntary submissions. We present an overview of >10 million MDRs received from 2011 to 2021. Approximately 92% of reporting issues represent medical device physical or functional failures, categorized from 1704 codes related to medical device integrity or function. ∼8% were coded adverse events (AEs). Patient outcomes are reported via 998 patient codes in 19 medical specialties (cardiovascular, orthopedic, etc.). ∼40% of patient reports indicated “no health consequences”; however, a small number of devices had consistently high AE reports. While overall reports did not exhibit a sex-based dichotomy, ∼9% of the reported AEs occurred more frequently in females, many of which were related to immune effects. The analyses are subject to uncertainties and potential bias based on data available and data selected for analysis. However, such an overview of post-market MDR data, not previously published, fills a gap in understanding medical device issues and patient-based outcomes related to medical device use. Trends identified may be subjects of additional hypotheses, analysis, and research.

Sentence Completion as a User Experience Research Method: Recommendations From an Experimental Study

Abstract The aim of this study is to investigate the use of the sentence completion technique (SCT) as a user experience (UX) research method. We conducted an online experiment (N = 400) to test the effect of sentence stem variations on sentence completion outcomes. Using a between-subjects design, half of the participants were exposed to impersonal sentence stems that did not include pronouns while the other half were exposed to stems formulated using first-person pronouns (PR). Additional hypotheses around stem formats (use of redundant stems, imaginative stems, two blanks stems, generic stems, stems prompting others’ perception) were tested using a within-subject design. The results do not support hypothesized differences between the pronoun and no pronoun condition. Findings however show that varying the format of the stem influences response behavior, as measured by variety, quantity and novelty of ideas, as well as the length of response. This study contributes to consolidating the use of SCT as a user research method and proposes actionable recommendations on how to create optimal sentence completion surveys in Human-Computer Interaction (HCI).

Role of M4 -receptor cholinergic signaling in direct pathway striatal projection neurons during dopamine depletion.

Direct pathway striatal projection neurons (dSPNs) are characterized by the expression of dopamine (DA) class 1 receptors (D1 R), as well as cholinergic muscarinic M1 and M4 receptors (M1 R, M4 R). D1 R enhances neuronal firing through phosphorylation of voltage-gate calcium channels (CaV 1 Ca2+ channels) activating Gs proteins and protein kinase A (PKA). Concurrently, PKA suppresses phosphatase PP-1 through DARPP-32, thus extending this facilitatory modulation. M1 R also influences Ca2+ channels in SPNs through Gq proteins and protein kinase C. However, the signaling mechanisms of M4 R in dSPNs are less understood. Two pathways are attributed to M4 R: an inhibitory one through Gi/o proteins, and a facilitatory one via the cyclin Cdk5. Our study reveals that a previously observed facilitatory modulation via CaV 1 Ca2+ channels is linked to the Cdk5 pathway in dSPNs. This result could be significant in treating parkinsonism. Therefore, we questioned whether this effect persists post DA-depletion in experimental parkinsonism. Our findings indicate that in such conditions, M4 R activation leads to a decrease in Ca2+ current and an increased M4 R protein level, contrasting with the control response. Nevertheless, parkinsonian and control actions are inhibited by the Cdk5 inhibitor roscovitine, suggesting Cdk5's role in both conditions. Cdk5 may activate PP-1 via PKA inhibition in DA depletion. Indeed, we found that inhibiting PP-1 restores control M4 R actions, implying that PP-1 is overly active via M4 Rs in DA-depleted condition. These insights contribute to understanding how DA-depletion alters modulatory signaling in striatal neurons. Additional working hypotheses are discussed.

MODELING IN INVENTORY MANAGEMENT PROBLEMS UNDER UNCERTAINTY AND TAKING INTO ACCOUNT (INFLATION) RISKS

A model that can be used in the problems of inventory management under uncertainty and taking into account various types of risks, in particular, inflation risks, is presented and substantiated. The strategy of stock management under uncertain (stochastic) demand usually requires the creation of a certain reserve of a predetermined volume, and then the next deliveries of stocks are made. If at a certain point in time the total stock is reduced to the size of the reserve, then an urgent order for delivery of a new batch is made. If the fulfillment of the request requires a certain time (this process is not instantaneous!), then the request for its replenishment is submitted when the stock decreases to a level exceeding the predetermined amount of the reserve.  The study provides one of the simplest ways to solve the reserve problem, namely, applying the principle of guaranteed result, i.e. electing a large enough reserve that guarantees minimum risk, namely, compensation of any random deviations, which requires large costs for their storage and the like. This also leads to the so-called opportunity risk as large reserves are associated with the diversion of significant funds. In this connection, additional hypotheses are introduced in the paper, and the concept of acceptable risk - the probability that the need for reserves will not exceed the available reserve - is used as the basis for calculating the required reserve. The concept of risk coefficient is introduced, which expresses the probability that the need for reserves will be unsatisfactory due to the insufficiency of the reserve and will exceed its volume. The value of the risk coefficient can be equal to 5% or 1%.  The paper uses a modified formula for calculating the nominal rate of interest with inflation interest rate risk, which includes the following components: 1) real safe rate of interest; 2) inflation premium; 3) inflation risk premium; 4) investment project risk premium (reserve creation is a kind of investment); 5) synergistic premium for investment project and inflation risk; 6) synergistic premium for investment project and inflation risk; 7) liquidity premium (in fact, it is an assessment of liquidity risk). In the study the volumes of raw materials (components) reserve are determined, which leads to the reduction of risk degree; within the framework of M. Miller and D. Orr's model the volumes of cash reserves are determined, where inflation risks are taken into account in the value of missed opportunities (which is related to the content of cash reserves balance); in the task of reserves management under uncertainty and the risk caused by it, the total costs of maintaining the reserve per unit of time are minimized and the value of the optimal reserve together with the reserve is determined (within the framework of the modified model of V. Miller and D. Orr). The paper provides a rather simple method of accounting for possible risks arising in the creation of stocks (raw materials, cash, etc.), solved the problem of selecting a specific rational value of the risk coefficient (based on expert procedures and utility theory), which allows to reflect and take into account the attitude of decision-making subjects to risk. 

Patterns in the genetic structure of 49 lowland rain forest tree species co‐distributed on opposite sides of the northern Andes

AbstractThe Andes are a major dispersal barrier for lowland rain forest plants and animals, yet hundreds of lowland tree species are distributed on both sides of the northern Andes, raising questions about how the Andes influenced their biogeographic histories and population genetic structure. To explore these questions, we generated standardized datasets of thousands of SNPs from paired populations of 49 tree species co‐distributed in rain forest tree communities located in Panama and Amazonian Ecuador and calculated genetic diversity (π) and absolute genetic divergence (dXY) within and between populations, respectively. We predicted (1) higher genetic diversity in the ancestral source region (east or west of the Andes) for each taxon and (2) correlation of genetic statistics with species attributes, including elevational range and life‐history strategy. We found that genetic diversity was higher in putative ancestral source regions, possibly reflecting founder events during colonization. We found little support for a relationship between genetic divergence and species attributes except that species with higher elevational range limits exhibited higher dXY, implying older divergence times. One possible explanation for this pattern is that dispersal through mountain passes declined in importance relative to dispersal via alternative lowland routes as the Andes experienced uplift. We found no difference in mean genetic diversity between populations in Central America and the Amazon. Overall, our results suggest that dispersal across the Andes has left enduring signatures in the genetic structure of widespread rain forest trees. We outline additional hypotheses to be tested with species‐specific case studies.

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial

BC2001 showed combining chemotherapy (5-FU+mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). invasive loco-regional control (ILRC); secondary overall survival. Hypoxia affected overall survival (HR=1.30; 95% CI 0.99-1.70; p=0.062): more uncertainty for ILRC (HR=1.29; 95% CI 0.82-2.03; p=0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n=90, HR 1.69; 95% CI 0.99-2.89 p=0.057) but not conventional (n=207, HR 0.70; 95% CI 0.28-1.80, p=0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n=51; HR 14.2; 95% CI 1.7-119; p=0.015) but not conventional (n=24, HR 1.04; 95% CI 0.07-15.5, p=0.978) radiotherapy. Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. Cancer Research UK, NIHR, MRC.

Wrong hypotheses in the generalized RTBP

Generalized restricted three body problems consist of adding some extra hypotheses to the Restricted three body problem (RTBP) in order to have a new problem, not very different of the original RTBP. However, not any additional hypothesis is allowed; it must satisfy the laws of Physics. Among the several generalizations found in literature, we prove that at least there are two hypotheses that cannot be used, namely: 1) Perturbation in Coriolis and/or centrifugal forces, and 2) primaries are spheroids moving on elliptical orbits.

P077 The Immunometabolic Bimodal Mechanism of NLRX1 Agonist NX-13 in a Pig Model of Ulcerative Colitis

Abstract Background In mouse models, NX-13 is an orally active, gut-restricted NLRX1 agonist that has been shown to reduce severity of disease in multiple UC models through a novel immunometabolic, bimodal mechanism. Most preclinical UC studies rely upon rodent models, the human gastrointestinal physiology, microbiome, and immune system bear a greater similarity to that of pigs. Therefore, we sought to expand and validate our preclinical NX-13 results in mice using the dextran sulfate sodium (DSS) pig model of colitis. Here, we describe the disease severity, cellular, and biomarker results, and confirm the immunometabolic MOA observed in other species. Methods Pigs were randomized by weight (n=6 per group) and were administered tablets of excipient alone (placebo), NX-13 10 mg, NX-13 50 mg, or NX-13 100mg once daily. Pigs were challenged with 1% DSS in drinking water for 6 days and monitored daily for weight gain (loss). Composite disease activity score (0-12) was taken based on the sum of three subscores (0-4) for rectal bleeding, stool consistency and overall health/activity. Necropsy was conducted on day 7. Feces were collected for fecal calprotectin (FCP) quantification. Colonic tissue was macroscopically scored and collected for analysis by flow cytometry, histopathology and gene expression. Results Oral NX-13 treatment protected against weight loss and reduced colitis development with differences as early as day 2, becoming significant between days 4 and 6 as disease worsens in placebo treated pigs (Fig1A). NX-13 yielded a dose-dependent improvement in macroscopic lesion severity and microscopic immune cell infiltration (Fig1B). Specifically, Th1 cells (Fig1C) and TNF producing myeloid cells in the colonic lamina propria were reduced by NX-13, as well as FCP levels in stool (Fig1D) and mRNA expression in the colon (Fig1E). Oral NX-13 treatment reduced inflammatory markers including TNF, monocyte and neutrophil chemo attractants, IL-6, and IL-23 (Fig3F). Additionally, NX-13 treatment affected markers specific to the bimodal immunometabolic MOA of NLRX1 activation, namely upregulation of NLRX1 and mitochondrial metabolism gene COX3 (Fig1G), and reduction of NFkB and NLRP3 (Fig1H). Conclusion NX-13 demonstrated fast and clinically meaningful improvement in disease activity, and significantly impacted on key inflammatory markers in a DSS colitis model in pigs. These results align with previous murine results and observations in the phase 1b clinical program. Therefore, they can be used to generate additional mechanistic hypotheses for translational studies in the ongoing NEXUS phase 2 trial in moderate to severe UC.

Ontogenetic shifts in body form in the bull shark Carcharhinus leucas.

Recent studies have uncovered mosaic patterns of allometric and isometric growth underlying ontogenetic shifts in the body form of elasmobranch species (shark and rays). It is thought that shifts in trophic and spatial ecology through ontogeny drive these morphological changes; however, additional hypotheses relating to developmental constraints have also been posed. The bull shark (Carcharhinus leucas) is a large-bodied coastal shark that exhibits strong ontogenetic shifts in trophic and spatial ecology. In this study, we utilise a large data set covering a large number of morphological structures to reveal ontogenetic shifts in the body form of C. leucas, stratifying analyses by sex and size classes to provide fine-scale, more ecomorphologically relevant results. Our results indicate shifts in functional demands across the body through ontogeny, driven by selective pressures relating to trophic and spatial ecology driving the evolution of allometry. We also find significant differences in scaling trends between life stages, and between the sexes, highlighting the importance of utilising large, diverse datasets that can be stratified in this way to improve our understanding of elasmobranch morphological evolution. Ultimately, we discuss the implications of these results for existing ecomorphological hypotheses regarding the evolution of specific morphological structures, and pose novel hypotheses where relevant.

Controlling a generalized Fokker–Planck equation via inputs with nonlocal action

This paper concerns an optimal control problem (P) related to a generalized Fokker–Planck equation. Basic properties of the solutions to the generalized FP equation are derived via a semigroup approach in the space H−1(Rd). Problem (P) is proven to be deeply related to a stochastic optimal control problem (PS) for a McKean–Vlasov equation. The existence of an optimal control is obtained for the deterministic problem (P). The existence of an optimal control is established for an approximating optimal control problem (Ph) related to a backward Euler approximation of the generalized FP equation (with a constant discretization step h). One proves under additional hypotheses that “(Ph) converges to (P)” in a certain sense. First order necessary conditions for (Ph) are derived as well.

Dose addition in mixtures of compounds with dissimilar endocrine modes of action in in vitro receptor activation assays and the zebrafish sexual development test

BackgroundHuman exposure to pesticides is being associated with feminisation for which a decrease of the anogenital distance (AGD) is a sensitive endpoint. Dose addition for the cumulative risk assessment of pesticides in food is considered sufficiently conservative for combinations of compounds with both similar and dissimilar modes of action (MoA). ObjectiveThe present study was designed to test the dose addition hypothesis in a binary mixture of endocrine active compounds with a dissimilar mode of action for the endpoint feminisation. MethodsCompounds were selected from a list of chemicals of which exposure is related to a decrease of the AGD in rats and completed with reference compounds. These chemicals were characterised using specific in vitro transcriptional activation (TA) assays for estrogenic and androgenic properties, leading to a final selection of dienestrol as an ER-agonist and flutamide, linuron, and deltamethrin as AR-antagonists. These compounds were then tested in an in vivo model, i.e. in zebrafish (Danio rerio), using sex ratio in the population as an endpoint in order to confirm their feminising effect and MoA. Ultimately, the fish model was used to test a binary mixture of flutamide and dienestrol. ResultsStatistical analysis of the binary mixture of flutamide and dienestrol in the fish sexual development tests (FSDT) with zebrafish supported dose addition.

Nonlinear Pauli equation

<abstract> <p>In the framework of the self-consistent Maxwell-Pauli theory, the non-linear Pauli equation is obtained. Stationary and nonstationary solutions of the nonlinear Pauli equation for the hydrogen atom are studied. We show that spontaneous emission and the related rearrangement of the internal structure of an atom, which is traditionally called a spontaneous transition, have a simple and natural description in the framework of classical field theory without any quantization and additional hypotheses. The behavior of the intrinsic magnetic moment (spin) of an EW in an external magnetic field is considered. We show that, according to the self-consistent Maxwell-Pauli theory, in a weak magnetic field, the intrinsic magnetic moment of an EW is always oriented parallel to the magnetic field strength vector, while in a strong magnetic field, depending on the initial orientation of the intrinsic magnetic moment, two orientations are realized: either parallel or antiparallel to the magnetic field strength vector.</p> </abstract>

Fixed point and endpoint theorems of multivalued mappings in convex $ b $-metric spaces with an application

<abstract><p>In this paper, we investigated several new fixed points theorems for multivalued mappings in the framework $ b $-metric spaces. We first generalized $ S $-iterative schemes for multivalued mappings to above spaces by means of a convex structure and then we developed the existence of fixed points and approximate endpoints of the multivalued contraction mappings using iteration techniques. Furthermore, we introduced the modified $ S $-iteration process for approximating a common endpoint of a multivalued $ \alpha_{s} $-nonexpansive mapping and a multivalued mapping satisfying conditon $ (E^{'}) $. We also showed that this new iteration process converges faster than the $ S $-iteration process in the sense of Berinde. Some convergence results for this iterative procedure to a common endpoint under some certain additional hypotheses were proved. As an application, we applied the $ S $-iteration process in finding the solution to a class of nonlinear quadratic integral equations.</p></abstract>