bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of a defined daily dose fixed database for drug utilization research studies: The case of statins in Portugal
Authors: Abrantes Catarina , Tonin Fernanda S. , Reis‐Pardal Joana , Castel‐Branco Margarida , Furtado Claudia , Figueiredo Isabel V. , Fernandez‐Llimos Fernando
Published: February 2021

Aims

Given the discrepancies between PDDs (prescribed daily doses) and DDDs (defined daily doses), we aimed to assess the extent of error in the results of an 18‐year population‐level study on statin utilization in Portugal.

Methods

The Portuguese regulatory agency provided data for the period 2000–2018 on statin dispensing (C10AA). The DDDs were gathered from the ATC/DDD database. DDDs were calculated by the DDD year‐by‐year approach (DDDYEAR) and by the DDD last‐year approach (DDDLAST). PDDs were calculated according to the year‐by‐year approach (PDDYEAR). Statin annual utilization rates per 1000 inhabitants per day were also calculated. Percent errors were calculated for PDDYEAR and DDDYEAR units.

Results

The DDDYEAR approach revealed decreases in the consumption of atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin in 2009, when their DDD was modified. Conversely, the results from both DDDLAST and PDDYEAR approaches indicated gradual changes in the actual consumption of all statins in Portugal. Before 2009, atorvastatin, pravastatin and simvastatin utilization was greatly overestimated by DDDYEAR/1000 inhabitants/day. The average dose of lovastatin prescribed in the past 18 years (20 mg) was below the assigned DDDs during the study period, varying from 30 mg to 45 mg. Conversely, the PDD for fluvastatin was above the DDD values (ranging from 40 mg in 2000 to 70 mg in 2016). For atorvastatin, pravastatin and simvastatin, national PDDs were above the assigned DDD until the DDD modification in 2009.

Conclusions

A more dynamic system, based on national and annually updated DDDs, should be able to reduce discrepancies between DDDs and PDDs and the bias in utilization studies.
Population pharmacokinetic analysis of RO5459072, a low water‐soluble drug exhibiting complex food–drug interactions
Authors: Kratochwil Nicole A. , Stillhart Cordula , Diack Cheikh , Nagel Sandra , Al Kotbi Nada , Frey Nicolas
Published: February 2021

Aims

RO5459072, a cathepsin‐S inhibitor, Biopharmaceutics Classification System class 2 and P‐glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose‐dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis.

Methods

PK profiles in 39 healthy volunteers after first oral dosing (1–600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling.

Results

The PK of RO5459072 while fed was characterized by a 1‐compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first‐order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase.

Conclusion

The population PK model supported that dissolution‐ and solubility‐limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.
Arthritis in systemic lupus erythematosus is characterized by local IL-17A and IL-6 expression in synovial fluid
Authors: Sippl N , Faustini F , Rönnelid J , Turcinov S , Chemin K , Gunnarsson I , Malmström V
Published: February 2021

Arthritis is a common clinical feature of systemic lupus erythematosus (SLE) and is usually non-erosive, as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of lupus arthritis. Here, we aimed to explore the cytokine and cellular compartments in synovial fluids of SLE patients with arthritic manifestations. Acellular synovial fluid and paired serum samples from SLE patients (n = 17) were analyzed with cytokine bead array for T helper-associated cytokines. From two SLE patients, synovial fluid mononuclear cells (SFMC) could also be captured and were analyzed by multiparameter flow cytometry to dissect T cell, B cell, monocyte and dendritic cell phenotypes. SLE-derived SFMC were further stimulated in vitro to measure their capacity for producing interferon (IFN)-γ and interleukin (IL)-17A. All patients fulfilled the ACR 1982 classification criteria for SLE. Clinical records were reviewed to exclude the presence of co-morbidities such as osteoarthritis or overlap with RA. IL-17A and IL-6 levels were high in SLE synovial fluid. A clear subset of the synovial CD4+ T cells expressed CCR6+, a marker associated with T helper type 17 (Th17) cells. IL-17A-production was validated among CD4+CCR6+ T cells following in-vitro stimulation. Furthermore, a strong IFN-γ production was observed in both CD4+ and CD8+ cells. Our study shows high IL-17A and IL-6 levels in synovial fluids of patients with lupus arthritis. The Th17 pathway has been implicated in several aspects of SLE disease pathogenesis and our data also point to Th17 involvement for lupus arthritis.
Skin exposure to scented products used in daily life and fragrance contact allergy in the European general population ‐ The EDEN Fragrance Study
Authors: van Amerongen Cynthia C.A. , Ofenloch Robert F. , Cazzaniga Simone , Elsner Peter , Gonçalo Margarida , Naldi Luigi , Svensson Åke , Bruze Magnus , Schuttelaar Marie L.A.
Published: February 2021

Background

Fragrances are widely used in scented products used in daily life with the potential to induce skin sensitization.

Objective

To evaluate exposure to scented products and to explore associations between exposure and fragrance contact allergy.

Methods

A cross‐sectional study on individuals from 18 to 74 years of age, who were randomly selected from the general population in five European countries. A random sample (N = 3119) was patch tested and interviewed on exposure to scented products.

Results

Female participants were strongly associated with exposure to scented products relative to male participants. Participants age 40 years and older showed an inverse association with exposure to scented products. Compared to Sweden, The Netherlands followed by Germany showed the highest overall exposure to scented products. Sensitive skin was associated with exposure to scented products and with fragrance allergy. In univariable regression analysis, exposure to leave‐on products and to specific scented product subgroups was significantly associated with fragrance allergy.

Conclusion

Exposure to scented products depends primarily on sex and age. Female sex and sensitive skin are relevant indicators for developing fragrance allergy. Because aggregate exposure, especially to scented leave‐on products, may enhance the prevalence of contact allergy to fragrances, further investigations into exposure amounts and frequencies is warranted.
Voltage‐gated calcium channel nanodomains: molecular composition and function
Authors: Gandini Maria A. , Zamponi Gerald W.
Published: February 2021

Voltage‐gated calcium (CaV) channels and their regulation by proteins at the synaptic cleft play a critical role in neurotransmission. These interactions fine‐tune the synaptic response through the regulation of Ca2+ entry into the presynaptic terminal and trigger the fusion of vesicles filled with neurotransmitters and peptides. Regulation of CaV channel intrinsic properties and their numbers at the active zones shape the timing and strength of synaptic function. Here, we provide an overview of a number of proteins reported to be part of CaV channel nanodomains at the synaptic cleft and the repercussions of these interactions for CaV channel trafficking, tethering at the active zone, and regulation of their biophysical properties. We summarize the current state of knowledge by which CaV channels are regulated at presynaptic sites.
Effects of sorghum biomass quality on ensilability and methane yield
Authors: Pasteris Andrea M. , Zapka Oliver , Plogsties Vincent , Herrmann Christiane , Heiermann Monika
Published: February 2021

Sorghum is currently being introduced in the temperate regions of Europe. It is characterized by good digestibility and high biomass yields, which make it a useful crop for anaerobic digestion. In this study, six commercial sorghum varieties comprising four different cultivars of Sorghum bicolorL. Moench and two interspecific sorghum hybrids (Sorghum sudanenseL. × S. bicolorL. Moench) were harvested on two different dates during the years 2016 and 2017 at two diverse soil‐climate sites in Germany. The fresh harvested material and silages were analyzed to examine the ensilability of the different varieties with contrasting maturity characteristics. Subsequently, methane production experiments were performed to determine the specific methane yield (SMY) of the samples. The sorghum fresh matter (FM) varied among the sorghum types, including the parameters total solids (TS; 22.69%–46.93%FM), water‐soluble carbohydrates (2.68%–11.38%TS), and nitrates (0%–0.35%TS). The excellent ensiling ability of all the sorghum types analyzed was confirmed by evaluating the fermentation profile (pH range of 3.7–4.6; dominant presence of lactic acid [LA]; acetic acid [AA] in the range of 0.70%–2.38%TS; insignificant amount of butyric acid). The SMY ranged between 231.25 and 321.31 Ln kg−1 VS and tended to decrease with the increasing harvest time and maturity. LA and AA were positively correlated with the SMY, while the neutral detergent fiber content was negatively correlated with it. The SMY—a key parameter reflecting the crop biomass quality for biogas production—was slightly higher for S. bicolorthan for the sorghum hybrids. However, the results of this study confirmed that if the final purpose is biomethanation, the ensilability of different sorghum types imposes no restriction. Furthermore, different sorghum types offer a wide harvest window, which can be useful for cropping schemes, ensiling, and methane production.
The toll of success: Female leaders in the “women‐friendly” Greek advertising agencies
Authors: Miliopoulou Georgia‐Zozeta , Kapareliotis Ilias
Published: February 2021

This paper examines the views and attitudes of senior female executives in Greek advertising agencies. Using intersectionality as a theoretic lens, the authors study the intersection of sex, age, profession, and ethnicity, within a patriarchal, Southern European society and a male dominated industry. Research findings from 12 interviews reaffirm the motherhood penalty but also demonstrate how successful women refuse to be part of the boys' club, deconstruct the male stereotype, and engage in fierce counter‐stereotyping while showing lack of solidarity and empathy toward other women. After years at the intersection of two male‐dominated cultural contexts, these women have limited visibility of the barriers they encounter and see themselves as an embodied exception proving the rule, not as agents of change. Thus, individual success leads to collective defeat and to the prevalence of male dominance. This research contributes by presenting the view of successful women in adverse intersections, who demonstrate accumulated frustration, lack of collective gender consciousness, and lack of a sense of self‐fulfillment. The paper calls for further research that combines intersectionality with emotional transfers and defense mechanisms; research that explores the influence of intersectional conscientiousness, especially in the southern context.
Heating stability, physical and chemical analysis of calcium silicate‐based endodontic sealers
Authors: Antunes T. B. M. , Janini A. C. P. , Pelepenko L. E. , Abuna G. F. , Paiva E. M. , Sinhoreti M. A. C. , Raimundo I. M. , Gomes B. P. F. A. , de‐Jesus‐Soares A. , Marciano M. A.
Published: February 2021

Aim

To evaluate possible modifications in root canal sealers subjected to a variety of heating conditions using vibrational spectroscopy and analysis of physical and chemical properties.

Methodology

EndoSequence BC Sealer HiFlow, Bio‐C Sealer, BioRoot RCS and AH Plus were analysed chemically using Raman spectroscopy (25–220 °C) and Fourier‐transform infrared spectroscopy (FT‐IR) (37–100 °C ). For FT‐IR, the materials were tested individually and mixed with root dentine powder. Scanning electron microscopy (SEM) and coupled energy dispersive spectroscopy (EDS) were used to evaluate surface and chemical elements. ISO 6876‐2012 and ASTM‐C266‐07 specifications were followed to evaluate flow, setting time (moist and dry), solubility and radiopacity. Also, pH analysis at 37 and 100 °C was performed. Shapiro–Wilk and Mixed ANOVA (within and between the effects of the subjects), Levene, and a post hoc analyses with Bonferroni correction were performed (P < 0.05).

Results

Vibrational spectroscopy revealed peaks of tricalcium silicate, dicalcium silicate and zirconium dioxide. Chemical changes in the Raman spectra during heating were discrete, as the inorganic content predominated the signalling for all root canal sealers. FT‐IR analysis exhibited spectral changes in water absorption for EndoSequence BC Sealer HiFlow and Bio‐C Sealer, probably related to dehydration. For BioRoot RCS and AH Plus, no significant chemical changes were observed. Bio‐C Sealer exhibited a band of polyethylene glycol only after heating to 100 °C, probably related to its thermal decomposition. SEM/EDS analysis corroborated the composition results observed in vibrational spectroscopy for all materials. Heating to 100 °C significantly changed the flowability of all calcium silicate‐based sealers with a wide variation in setting times at both temperatures, along with solubility levels above ISO standards. For all tested sealers, radiopacity fulfilled the requirements, and pH exhibited alkaline values.

Conclusions

The tested calcium silicate‐based sealers were affected by heating. Calcium silicate‐based root canal sealers had high solubility which is a concern for their clinical use. AH Plus was the only root canal sealer that was stable after heating.
Female awareness about the preconception use of folic acid supplements in childbearing age: A cross‐sectional study
Authors: Raad Sarah Emad , AbuAlhommos Amal Khaleel
Published: February 2021

Aims

Folic acid is required for the growth and development of the fetus. There is strong evidence that taking folic acid before pregnancy and during the first trimester reduces the risk of neural tube defects (NTDs). This study aimed to assess women's awareness of preconception folic acid supplementation and its importance to the mother and the fetus.

Methods

This was a cross‐sectional questionnaire study conducted in Saudi Arabia between January and April 2019. An electronic questionnaire tool was designed and distributed using Google Forms through social media (Facebook and WhatsApp) websites. Binary logistics regression was used to estimate odds ratios (ORs), with 95% confidence intervals (CIs) for predictors of poor levels of awareness about folic acid.

Results

A total of 514 women participated in this study. The age range for the study participants was 18‐45 years. Only 24.1% of the participants reported that they routinely took folic acid. The most commonly reported source of information about folic acid use was the doctor. The majority of the participants had poor awareness of folic acid use. Older age (30 years and above) and not taking regular folic acid supplements were important predictors of poor awareness of folic acid. Having a university degree or higher education was an important predictor of increased awareness about folic acid.

Conclusion

Our study found that the awareness of the Saudi women was poor in identifying the generic name of folic acid, recognising the sources of folic acid, the correct dose of folic acid, and the side effects of high doses of folic acid and that there was good knowledge about the importance of folic acid, the consequences of folic acid deficiency, and the belief that even non‐pregnant women and girls of childbearing age should take folic acid.
Combining host plant defence with targeted nutrition: key to durable control of hemiparasitic Striga in cereals in sub‐Saharan Africa?
Authors: Mwangangi Immaculate M. , Büchi Lucie , Haefele Stephan M. , Bastiaans Lammert , Runo Steven , Rodenburg Jonne
Published: February 2021

Host plant defence mechanisms (resistance and tolerance) and plant nutrition are two of the most widely proposed components for the control of hemiparasitic weeds of the genus Striga in tropical cereal production systems. Neither of the two components alone is effective enough to prevent parasitism and concomitant crop losses. This review explores the potential of improved plant nutrition, being the chemical constituent of soil fertility, to fortify the expression of plant inherent resistance and tolerance against Striga. Beyond reviewing advances in parasitic plant research, we assess relevant insights from phytopathology and plant physiology in the broader sense to identify opportunities and knowledge gaps and to develop the way forward regarding research and development of combining genetics and plant nutrition for the durable control of Striga.
Professional expertise in policy advisory systems: How administrators and consultants built behavioral insights in Danish public agencies
Authors: Laage‐Thomsen Jakob
Published: February 2021

Recent work on consultants and academics in public policy has highlighted their transformational role. The paper traces how, in the absence of an explicit government strategy, external advisors establish different organizational arrangements to build Behavioral Insights in public agencies as a new form of administrative expertise. This variation shows the importance of the politico‐administrative context within which external advisors exert influence. The focus on professional expertise adds to existing understandings of ideational compatibility in contemporary policy advisory systems. Inspired by the sociology of professions, expertise is conceptualized as professionally constructed sets of diagnosis, inference, and treatment. The paper compares four Danish governmental agencies since 2010, revealing the central roles external advisors play in facilitating new policy ideas and diffusing new forms of expertise. This has implications for how we think of administrative expertise in contemporary bureaucracies, and the role of external advisors in fostering new forms of expertise.
The dynamics of Phytophthora infestans populations in the major potato‐growing regions of Asia – A review
Authors: Guha Roy Sanjoy , Dey Tanmoy , Cooke David E. L. , Cooke Louise R.
Published: February 2021

Asia is now the largest potato‐producing region of the world and late blight, caused by Phytophthora infestans, is the most important pathogen limiting production. This review documents, in both the historical and the current context, the population structure of P. infestans in the major areas of potato production in Asia. Information from diverse sources regarding the stated or inferred clonal pathogen lineages present, population changes, and possible migration routes of the pathogen into the countries of this region have been reviewed to aid researchers and those involved in managing late blight in Asia. The single most important factor for population change and resultant epidemics in this region has been found to be migration of pathogen genotypes from Europe and the Americas. Reducing the impact of such migration in the future will necessitate putting in place improved phytosanitary measures. To achieve this, data sharing using global networks such as AsiaBlight and EuroBlight is imperative.
The diagnostic and prognostic significance of flow cytometric bone marrow assessment in myelodysplastic syndromes according to the European LeukemiaNet recommendations in single‐centre real‐life experience
Authors: Majcherek Maciej , Kiernicka‐Parulska Jolanta , Mierzwa Anna , Barańska Marta , Matuszak Magdalena , Lewandowski Krzysztof , Komarnicki Mieczysław , Czyż Anna
Published: February 2021

Introduction

This analysis attempts to determine the diagnostic and prognostic value of bone marrow (BM) evaluation by multiparameter flow cytometry in patients with myelodysplastic syndrome (MDS).

Materials and methods

The study group consisted of patients who underwent diagnostic process in the years 2008‐2017 due to cytopenia and finally were diagnosed with MDS (n = 71). The comparative group included patients with cytopenia diagnosed in the same period, whose definitive diagnosis was other than MDS (n = 39). Flow cytometric evaluation of BM was performed following the recommendations of the European LeukemiaNet (ELN) in all patients.

Results

The median number of immunophenotypic abnormalities found on granulocytes in the MDS group was significantly higher compared to the comparative group [2 (range 0‐5) vs 0 (range 0‐2); P < .0001]. Similarly, the median Ogata score was significantly higher in the MDS group [2 (range 0‐4) vs 1 (range 0‐3); P < .0001]. Since the disturbances of the CD11b/HLA‐DR and CD11b/CD13 on granulocytes were significantly more common in MDS patients, the Ogata score was extended by these abnormalities, what resulted in its higher diagnostic sensitivity (82%) while preserving high specificity (87%). The positive correlation was found between risk score determined by the Revised International Prognostic Scoring System and the number of the BM immunophenotypic abnormalities (P = .017).

Conclusions

Our results indicate that the diagnostic usefulness of the Ogata score may be increased by including the abnormal expression of CD11b/HLA‐DR and CD11b/CD13 on granulocytes. Moreover, our findings suggest the prognostic significance of the number of BM cytometric abnormalities in MDS.
Effects of wrist position on eccentric exercise‐induced muscle damage of the elbow flexors
Authors: Lau Wing Yin , Blazevich Anthony J. , Newton Michael J. , Wu Sam Shi Xuan , Nosaka Kazunori
Published: February 2021

We tested the hypothesis that the magnitude of changes in indirect muscle damage markers would be greater after maximal elbow flexor eccentric exercise in the supinated (shorter biceps brachii) than neutral wrist (longer) position, and the difference in the magnitude would be associated with greater elongation over contractions for the supinated than neutral position, rather than the initial muscle length. Ten untrained men (21‐39 years) performed two bouts of 10 sets of 6 maximal isokinetic eccentric contractions of the elbow flexors in the supinated position for one arm and neutral position for the other arm separated by 2 weeks in a randomized order. Biceps brachii myotendinous junction (MTJ) movements during eccentric contractions were recorded by B‐mode ultrasonography, and the displacement from the start to end of each contraction was quantified. Peak torque (supinated: 367.8 ± 112.5 Nm, neutral: 381.5 ± 120.4 Nm) and total work (1816 ± 539 J, 1865 ± 673 J) produced during eccentric contractions were similar between conditions. The average MTJ displacement increased (P < .05) from the 1st set (8.0 ± 2.0 mm) to 10th set (15.8 ± 1.9 mm) for the supinated condition, but no such increase was found in the neutral condition (1st set: 5.1 ± 1.0 mm, 10th set: 5.0 ± 0.8 mm). Changes in indirect muscle damage markers (maximal voluntary isometric contraction torque, range of motion, serum creatine kinase activity, and muscle soreness) after exercise were greater (P < .05) for the supinated than neutral condition. These results suggest that the greater muscle damage marker changes for the supinated than neutral wrist position was associated with the greater muscle lengthening (strain).
Intestinal schistosomiasis among preschool and school‐aged children in a rural setting near Alexandria: initiative for elimination
Authors: Allam Amal Farahat , Salem Aziza , Elsheredy Amel , Dewair Musaad Mohammed , Ibrahim Heba Said , Farag Hoda Fahmy , Hagras Nancy Abd‐elkader , Shehab Amel Youssef
Published: February 2021

Objective

To assess the status of intestinal schistosomiasis among preschool‐aged (PSAC) and school‐aged children (SAC) and to compare the efficacy of praziquantel (PZQ) in both groups.

Methods

The study was conducted on 400 children; 103 PSAC and 297 SAC. Diagnosis of Schistosoma mansoni was based on triplicate Kato‐Katz thick smears from a single stool sample. To identify the missed cases by Kato‐Katz, 120 randomly selected negative cases (38 PSAC and 82 SAC) were screened by real‐time PCR. All S. mansoni‐positive cases by Kato‐Katz were treated by crushed PZQ tablets. Four weeks after treatment, the cure rate was assessed by Kato‐Katz smears and real‐time PCR.

Results

The prevalence of S. mansoni with Kato‐Katz was 7.8% among PSAC and 7.4% among SAC. Most of children (63.3%) had light‐intensity infection. The cure rate was 100% among PSAC by both techniques, and 91%, and 77.2% among SAC by Kato‐Katz and real‐time PCR, respectively. In the 120 stool samples screened by real‐time PCR, S. mansoni prevalence was 25%; 15.8% and 29.3% were among PSAC and SAC respectively. Treated cases showed a lower range of Ct values than untreated cases. Two melting temperature ranges (Tm = 83–87°C and 89–93°C) were recognised among uncured cases which may point to S. mansoni genetic variability.

Conclusion

Continuous monitoring and inclusion of PSAC in schistosomiasis control programmes are crucial. Real‐time PCR and other molecular tools are recommended for evaluation of the true prevalence, assessment of cure and further studies on genetic diversity.
A procedure to introduce point mutations into the Rubisco large subunit gene in wild‐type plants
Authors: Lin Myat T. , Orr Douglas J. , Worrall Dawn , Parry Martin A. J. , Carmo‐Silva Elizabete , Hanson Maureen R.
Published: February 2021

Photosynthetic inefficiencies limit the productivity and sustainability of crop production and the resilience of agriculture to future societal and environmental challenges. Rubisco is a key target for improvement as it plays a central role in carbon fixation during photosynthesis and is remarkably inefficient. Introduction of mutations to the chloroplast‐encoded Rubisco large subunit rbcL is of particular interest for improving the catalytic activity and efficiency of the enzyme. However, manipulation of rbcL is hampered by its location in the plastome, with many species recalcitrant to plastome transformation, and by the plastid's efficient repair system, which can prevent effective maintenance of mutations introduced with homologous recombination. Here we present a system where the introduction of a number of silent mutations into rbcL within the model plant Nicotiana tabacum facilitates simplified screening via additional restriction enzyme sites. This system was used to successfully generate a range of transplastomic lines from wild‐type N. tabacum with stable point mutations within rbcL in 40% of the transformants, allowing assessment of the effect of these mutations on Rubisco assembly and activity. With further optimization the approach offers a viable way forward for mutagenic testing of Rubisco function in planta within tobacco and modification of rbcL in other crops where chloroplast transformation is feasible. The transformation strategy could also be applied to introduce point mutations in other chloroplast‐encoded genes.
Gonadotrophin‐releasing hormone receptor autoantibodies induce polycystic ovary syndrome‐like features in a rat model
Authors: Li Hongliang , Guo Yankai , Zhang Gege , Deng Jielin , Fischer Hayley , Craig LaTasha B. , Yu Xichun , Kem David C.
Published: February 2021

New Findings

What is the central question of this study?

Is there a causal relationship between gonadotrophin‐releasing hormone (GnRH) receptor‐activating autoantibodies and polycystic ovary syndrome (PCOS)?

What is the main finding and its importance?

Induction of GnRH receptor‐activating autoantibodies in rats resulted in increased luteinizing hormone pulsatility and testosterone concentrations, disrupted oestrous cycles, increased atretic follicles, and activation of insulin signalling in the pituitary and ovary. These changes replicate those seen in humans with PCOS, suggesting that GnRH receptor‐activating autoantibodies might be involved in the pathogenesis of PCOS.

Gonadotrophin‐releasing hormone receptor‐activating autoantibodies (GnRHR‐AAb) are associated with polycystic ovary syndrome (PCOS). In the present study, we examined the impact of GnRHR‐AAb on reproductive function in GnRHR‐immunized female rats. All immunized rats produced high titres of GnRHR‐AAb targeting a dominant epitope located in the central region of the second extracellular loop of the GnRHR. Increased pulsatile luteinizing hormone secretion and testosterone concentrations were found in immunized rats. These rats exhibited disrupted oestrous cycles, increased ovarian follicular atresia, and activation of insulin signalling in the pituitary and ovary, as indicated by increased mRNA expressions of insulin receptor substrate, phosphatidylinositol 3‐kinase and glucose transporter 1. No significant changes in inflammatory cytokines were detected in the ovarian tissue. These features mimic those observed in humans with PCOS. Our findings support the concept that chronic stimulation of the GnRHR by GnRHR‐AAb, with an associated increase in pituitary luteinizing hormone secretion and ovarian androgen overproduction, might represent a new aetiological mechanism for PCOS.
Monte Carlo Analysis Techniques Revisited
Authors: Suresh K.
Published: February 2021

The predominant engineering analysis techniques are the finite element, finite difference and boundary element methods. These techniques are global in that they attempt to solve field problems over an entire domain. Global techniques are, however, an ‘over-kill’ in the early stages of engineering design, when design parameters are fuzzy, and the functional viability of options can be determined through quick check-point analysis.

In this paper, we revisit two ‘discarded’ Monte Carlo (MC) analysis techniques: MC boundary sampling, and MC domain sampling, which can be employed for solving field problems at discrete points. These techniques can be (potentially) more effective than global techniques, especially in the early stages of engineering design, but are ignored in practice because they are computationally expensive if implemented conventionally. In this paper, we argue that an appropriate geometric representation (of the underlying domain) — specifically, ray-representations for boundary sampling, and Voronoi graphs for domain sampling — is critical for efficient implementation of each technique. Exemplary numerical results are also presented.
Similarity-Based Decision Support for Internet Enabled Supply-Web Interactions
Authors: Veeramani Raj , Viswanathan Narayanan , Joshi Shailesh M.
Published: February 2021

New approaches for decision making are emerging to support the use of the Internet for supply-web interactions in the manufacturing industry. In this paper, we discuss one such paradigm, namely similarity-based decision support. It recognizes that knowledge of similar experiences can support rapid and effective decision making in various forms of supply-web interactions. We illustrate this approach using two prototype systems, WebScout (an agent-based system for customer–supplier matchmaking in the job-shop machining industry context) and TOME (Treasury of Manufacturing Experiences — an Intranet application to aid manufacturability assessment in foundries).
Development of a Web-Based Controller for Remote Sensing and Control of Manufacturing Processes
Authors: Mok Swee M.
Published: February 2021

This paper introduces the concept of a networked controller that leverages the capability of web services. By doing so, it enables the implementation of a large set of factory monitoring and control equipment that is cost effective and manageable. By using the factory local area network for communication, and industrial computers based on standard hardware and software as the controller platform, cost is minimized. A networked solution based on Transmission Control Protocol / Internet Protocol (TCP/IP) allows the controller to communicate with factory engineers through their desktop computers as efficiently as it can with other computers. Engineers can set up each unit for its intended function by installing the appropriate sensors. Java applet technology is employed for remote setup and control. Controller requirements such as remote configuration, client processing, and data presentation are presented. A method for overcoming real time issues is proposed using a client/server design. A prototype was built to demonstrate some of the concepts. Discussions are then made on possible future work using a Finite State Machine design methodology to improve overall system reliability.
Visual Modelling of Products and Life-Cycle Activities
Authors: Grothe-Møller Thorkild
Published: February 2021

Decisions taken in the early phases of product development have great influence on the final product both seen from a design activity point of view and from a product life-cycle point of view. Most computerbased design support systems for engineering design like CAD-systems etc. are not made for the very first and crucial decisions.

The objective is to demonstrate that product modelling in interaction with a computer system using optimized graphical user interface can improve the designer’s basis for decision making in the early phases of the project.

This paper presents the software system called Modellizer, which is based on the design theory called Theory of Domains that can be used to expand the concept of product models from a bill-of-material representation to a genetic model capturing decisions and design concepts during design activities.

Modellizer has been implemented with a designer dedicated user interface, which supports product modelling and life-phase modelling in order to structure data and document based information.

Three different applications of Modellizer is demonstrated in the paper:

1) OSS Modellizer is a prototype for a shipyard, where the idea is to support the early modelling of ships by catching decisions during design meetings

2) Alulib is a commercial available application for promoting more and correct use of aluminum. Alulib is a library with product examples.

3) LCA Visualizer is a commercial available application for evaluation and visualization of the environmental burden of different design scenarios.

Until now Modellizer has been used in a number of companies and engineering academies and good results have been obtained.
A Virtual Prototyping System for Design for Assembly, Disassembly, and Service
Authors: Bauer Matthew D. , Siddique Zahed , Rosen David W.
Published: February 2021

Design for the life cycle practices enable the improvement of a product’s recycling, disassembly, and service characteristics, to name a few. In this paper, an approach to virtual prototyping is presented that supports product Design For Assembly, Disassembly, and Service (DFADS). The VP-DFADS system enables a designer to construct a product model, to interactively simulate an assembly, disassembly, or service process for that product, and to formulate and solve a simultaneous product/process design problem. Specific research objectives underlying this project include a reduction in VP model construction times, an improvement in information with which designers make DFADS decisions, and the development of a design synthesis method for DFADS. Although automated reasoning and synthesis technologies are outlined, the emphasis in this paper is on the integration of these technologies into the VP-DFADS system and on the usage of the system in supporting DFADS decisions. An application of the VP-DFADS system to automotive center console design illustrates the potential usefulness of the VP-DFADS approach.
A Computational Model for Geometric Dimensions and Tolerances Consistent With Engineering Practice
Authors: Kandikjan Tatjana , Shah Jami J.
Published: February 2021

Dimensioning and tolerancing (D&T) are inter-related tasks; the validity of the tolerance representation model is dependent on the dimension model. Geometric tolerances are used to refine dimension tolerances and control some aspects of form, orientation and position of part features. This paper presents a computable model for the representation of dimensions and tolerances, compatible with D&T practice. The model is implemented as a dimension and tolerance graph (DTG). Constrained entities are combined into progressively expanding clusters which can be used to represent datum references/ frames, features, patterns, or the entire part. Validation of all D&T relations is performed in a uniform way using the concept of degrees of freedom and Control Frames. The tolerance specification method proposed here supports all tolerance classes defined in the ANSI standard, as well as datum reference frames and special pattern clusters.
Numerical Analysis of Annular Flow of Yield-Power-Law Fluids
Authors: Hussain Quazi E. , Sharif Muhammad A. R.
Published: February 2021

Fully developed laminar axial flow of yield-power-law fluids in eccentric annuli has been investigated numerically. The annuli may be fully open or partially blocked. General non-orthogonal, boundary-fitted curvilinear coordinates have been used to accurately model the irregular annular geometry due to the presence of a flow blockage. A computer code has been developed using a second-order finite-difference scheme. An exponential model for the shear stress, valid for both yielded and unyielded regions of the flow, is used in the computation. The effects of pressure gradient, eccentricity, and blockage height on the flow rate have been studied and the results are presented. The flow rate is found to increase with increasing eccentricity for eccentric annuli without any blockage. For partially blocked eccentric annuli, the flow rate at a particular eccentricity decreases as the blockage height is increased.
Effect of Residual Stresses Caused by Thermal Treatment on Creep Crack Growth Rate in Aluminium Gas Cylinders
Authors: Ibrahim Raafat , Ischenko Dmitry
Published: February 2021

Aluminum gas cylinders, which are in common use for various purposes, are susceptible to creep crack growth. Residual stresses introduced during the quenching process in aluminum gas cylinders contribute to the development of cracks. This may result in leakage or fracture of the cylinders. Finite element studies were conducted to evaluate the effect of the quenching process on through thickness inelastic strain and the residual stress distributions in the neck area of gas cylinders. Numerical modeling and experimental studies confirmed that a high level of tensile residual stresses exists on the inner surface of aluminum gas cylinders’ neck which is susceptible to cracking. The relationship between the amount of residual stresses and cooling conditions was established. The obtained residual stress distributions were included in the calculation of the creep crack growth rates. It was shown that residual stresses caused by manufacturing processes have a significant effect on the creep crack growth rate.
Reliability Indexes Calculation of Industrial Boilers Under Stochastic Thermal Process
Authors: Rollot Olivier , Pendola Maurice , Lemaire Maurice , Boutemy Igor
Published: February 2021

This text sums up a research for the French Electric Company, EDF, which wants to know the influence of the temperature variability on the reliability of some of their boilers. These boilers are very complex structures whose behavior has to be modelized by the Finite Element Method, FEM. This work is an application of Finite Element Methods in a reliability context, that means the introduction of random data into a classical FEM, in order to determine the reliability of the structures. These random data may concern geometry, material characteristics of the structures or the loads the structure may carry. Then, it’s necessary to employ new methods to take into account these stochastic approaches and to obtain more efficient decision’s elements for a better control of the boilers.
Simulation and Optimization of the Dynamical Behavior of Rail Vehicle Systems
Authors: Dragos Robert , Eschenauer Hans A.
Published: February 2021

The present paper addresses the modeling of rail vehicles as multi-body systems and the simulation of their operation behaviour with respect to the frequency and time range. By means of chosen examples it is shown that the structural-dynamic properties of important vehicle subsystems like vehicle body or bogie frame gain a decisive influence on the system dynamics. A layout with respect to the driving properties has to consider, as optimally as possible, quality criteria determining ride comfort and safety over the entire speed range and for different modes of operation. This multicriteria optimization task is solved by means of numerical optimization procedures, applied to the example of a commuter train, where a substantial improvement of the passenger comfort could be achieved by varying the spring stiffnesses and damping constants, at the same time fulfilling all safety constraints.
The Motivation, Development and Applications of a Commercial Optimization Software Package Using DOE/RSM and NLP Methods
Authors: Tzannetakis Nikolas , Glassée Erwin , Cartuyvels Rudi , Migeot Jean-Louis
Published: February 2021

This paper presents the motivation development and an application of a unique methodology to solve Industrial Optimization problems, using existing simulation software programs. In order to make this a reality, (1) a unique way of communicating with simulation programs, (2) parallel execution of multiple Designs dictated by an extensive library of Design of Experiment plans - sampling the Design Space with the minimum amount of function evaluations while capturing the Design behavior - (3) a Stochastic Interpolation Response Surface Modeling technique and (4) Non-Linear Programming techniques are the essential elements of this methodology. Finally an application from the automotive industry demonstrate the methodology.
Quality Utility: A Compromise Programming Approach to Robust Design
Authors: Chen Wei , Wiecek Margaret M. , Zhang Jinhuan
Published: February 2021

In robust design, associated with each quality characteristic, the design objective often involves multiple aspects such as “bringing the mean of performance on target” and “minimizing the variations”. Current ways of handling these multiple aspects using either the Taguchi’s signal-to-noise ratio or the weighted-sum method are not adequate. In this paper, we solve bi-objective robust design problems from a utility perspective by following upon the recent developments on relating utility function optimization to a Compromise Programming (CP) method. A robust design procedure is developed to allow a designer express his/her preference structure of multiple aspects of robust design. The CP approach, i.e., the Tchebycheff method, is then used to determine the robust design solution which is guaranteed to belong to the set of efficient solutions (Pareto points). The quality utility at the candidate solution is represented by means of a quadratic function in a certain sense equivalent to the weighted Tchebycheff metric. The obtained utility function can be used to explore the efficient solutions in the neighborhood of the candidate solution. The iterative nature of our proposed procedure will assist decision making in quality engineering and the applications of robust design.
Integrating Environmental Impact Assessment Into Product Design
Authors: Borland Nicholas , Wallace David , Kaufmann Heiner P.
Published: February 2021

This paper proposes a computer-based method for providing product designers with real-time environmental impact assessment. In this concurrent modeling approach, environmental experts build life cycle models, define their interfaces, and publish them as distributed objects on the internet. Traditional designers integrating these objects into their design model have access to the impact assessment methods provided. Communication between these models is the primary focus of this paper — methods for establishing and maintaining this communication are described in detail. A beverage container design example illustrates how this collaborative approach can be effective in determining tradeoffs between design alternatives.
Mastering Variant Variety Using the Variant Mode and Effects Analysis
Authors: Schuh Günther , Tanner Hans R.
Published: February 2021

Industrial enterprises see themselves confronted with a complexity of products and production processes, which became almost uncontrollable. Individualization and globalization of the demand will continue to increase, so that the existing variety of the product variants presumably cannot be reduced significantly. Attainable are however a strong weakening of the variety increase and a reduction of the internal complexity. Results from numerous analysis projects in the automobile industry show that substantial potentials (on the average 64%) for the reduction of the complexity are present in areas without impact on the degree of fulfillment of customer requirements (engine, axles, raw body, etc.). Even higher potentials are realizable by an intensive cooperation between manufacturers and suppliers.

This paper introduces the Variant Mode and Effects Analysis (VMEA), which is a proven method to reduce the number of variants and, therefore, the complexity and complexity-related costs throughout the whole development and manufacturing processes. The method includes a systematic analysis of market requirements and a systematic assignment of market requirements to product functions, modules and parts, thereby enabling the user to develop a modularized, market-oriented product structure designed for meeting the market demands with the smallest number of product variants possible. The results presented in this paper were obtained in a series of twenty cooperation projects involving ten medium-sized German manufacturers of cars and automotive supplies, among them Audi AG, BMW AG, Volkswagen AG, Volvo and Micro Compact Car.
Finding the Shape of a Flexible Blade for Free-Form Layered Manufacturing of Plastic Foam Objects
Authors: Horváth Imre , Vergeest Joris S. M. , Juhász Imre
Published: February 2021

The need for rapid, cost-effective and finish-less manufacturing of large sized, sculptured, physical models from various soft materials is increasing in several fields. For objects fabricated from plastic foams an advantageous approach is free-form, thick-layered manufacturing. Although it is technologically demanding, to achieve the best results (a) computer definition of the geometry has to be accurate, (b) the geometric model has to be directly sliced, (c) higher order approximation of the nominal shape is necessary, and (d) a quasi-free-form working out of the front surfaces of the layers is needed. The authors have developed the mathematical and/or technological fundamentals and process of free-form cutting based on heated flexible blades. The shape and the relative positions of the flexible blade are controlled continually as needed by the normal curvatures of the front faces of the layers. The paper elaborates on the computation methods for physically-based and geometrically-based modeling of flexible blades. The algorithms for approximating curve generation and curve matching are also presented. The paper extends to some of the most important aspects of the global thick-layered fabrication process.