bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure–response modeling of peficitinib efficacy in patients with rheumatoid arthritis
Authors: Toyoshima Junko , Kaibara Atsunori , Shibata Mai , Kaneko Yuichiro , Izutsu Hiroyuki , Nishimura Tetsuya 
Published: April 2021

AbstractThe aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28‐joint disease activity score based on C‐reactive protein (DAS28‐CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure–response models. The analysis incorporated results from three multicenter, placebo‐controlled, double‐blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28‐CRP measurements were modeled by a non‐linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure–response models of effect of peficitinib on duration‐dependent increase in ACR20 response rate and decrease in DAS28‐CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal Emax saturable of drug exposure in RA patients. The significant covariates were DAS28‐CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28–CRP model. The covariate effects were highly consistent between the two models. Our exposure–response models of peficitinib in RA patients satisfactorily described duration‐dependent improvements in ACR20 response rates and DAS28‐CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment.Clinical trial registrationNCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).
Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline
Authors: Dashwood Alexander , Cheesman Elizabeth , Wong Yee Weng , Haqqani Haris , Beard Nicole , Hay Karen , Spratt Melanie , Chan Wandy , Molenaar Peter 
Published: April 2021

AbstractOmecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the β1–adrenoceptor (AR) agonist (−)‐noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non‐failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t50%) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration‐effect curves were established to (−)‐noradrenaline at β1‐ARs in the absence or presence of OM. OM prolonged TPF and t50% in ventricular trabeculae (600 nM, 2 µM, p < .001). OM had no significant inotropic effect but reduced time dependent deterioration in contractile strength compared to control (p < .001). OM did not affect the generation of spontaneous contractions. The potency of (−)‐noradrenaline (pEC50 6.05 ± 0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 µM. Co‐incubation with (−)‐noradrenaline reduced TPF and t50%, reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 µM, preserved contractile force in left ventricular trabeculae, but imparted negative diastolic effects in trabeculae from human failing heart. (−)‐Noradrenaline reversed the negative diastolic effects, co‐administration may limit the titration of inotropes by reducing the threshold for ischemic side effects.
Direct healthcare professional communications: A quantitative assessment study
Authors: Alsaleh Hajar , Alshammari Thamir M. 
Published: April 2021

AbstractA retrospective observational study evaluated the direct healthcare professional communication (DHPC) letters disseminated by the Saudi Food and Drug Authority (SFDA) and their compliance with the pharmacovigilance guidelines. The study was utilized all DHPC letters available on the SFDA website, which is intended to communicate drug safety information to healthcare professionals (HCPs). Then, the letters were evaluated based on DHPC letter requirements approved in the European Medicines Agency (EMA) pharmacovigilance guidelines. Statistical analyses were conducted utilizing statistical analysis software (SAS® version 9.4). In June 2020, 169 letters were retrieved from the SFDA website. Most of the letters had the marketing authorization holder's logo (97%) and mentioned the date of letter issuance (98.8%). The most frequently discussed safety issues were hyperkalemia risk associated with combining renin–angiotensin–aldosterone system (RAAS) medications (10.6%) and cardiac risks (9%). Antineoplastic and immunosuppressant classes were associated with a majority of DHPC letters (15% for each category). A significant percentage of DHPC letters (10%) did not mention an agreement statement with SFDA, and 42 letters did not include marketing authorization holders (MAHs) contact information. The qualified persons responsible for pharmacovigilance and medical directors had signed most of the DHPC letters (51% and 46%, respectively). Many letters mentioned the details of reporting information to both SFDA and an MAH (82%). Moreover, 66% of the DHPC letters presented safety information within the 2‐page limit. In conclusion, the DHPC letters disseminated by MAHs in Saudi Arabia have an acceptable level of compliance with the guidelines.
Clinically relevant enantiomer specific R‐ and S‐praziquantel pharmacokinetic drug‐drug interactions with efavirenz and ritonavir
Authors: Mutiti Chenai Sheilla , Kapungu Nyasha Nicole , Kanji Comfort Ropafadzo , Stadler Nadina , Stingl Julia , Nhachi Charles , Hakim James , Masimirembwa Collen , Thelingwani Roslyn Stella 
Published: April 2021

AbstractWe conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R‐ and S‐PZQ in healthy male participants. This was toward evaluating the risk of drug‐drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non‐randomized, open‐label, single‐dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC‐MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T1/2, Cmin, and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p < .05), reducing the AUC by 4‐fold (1213.15 vs. 281.35 h·ng/ml for R‐PZQ and 5669 vs. 871.84 h·ng/ml for S‐PZQ). Ritonavir had no significant effect on R‐PZQ but increased the AUC 2‐fold for S‐PZQ (p < .05) (4154.79 vs. 7291.05 h·ng/ml). Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition, respectively.
Treatment for tetanus applying Kampo medicine: Administration of shakuyakukanzoto
Authors: Nakae Hajime , Irie Yasuhito , Satoh Kasumi , Kitamura Toshiharu , Kameyama Koumei , Nara Tasuku , Okuyama Manabu 
Published: April 2021

ABSTRACTAimSevere tetanus can be fatal, even with the latest drug treatments and artificial respiration. Nevertheless, combining Western and Kampo medicine may be beneficial for tetanus treatment.MethodsWe summarise the benefits of applying Kampo medicine in tetanus, especially referring to using shakuyakukanzoto (SKT) from the aspect of controlling myospasms. SKT is a Kampo formula used for the treatment of pain associated with sudden myospasms.ResultsSKT, kakkonto, daisaikoto, and daijokito have been used to successfully treat patients with generalised convulsions caused by generalised tetanus, without the use of a muscle relaxant. However, hypokalaemia, oedema, and hypertension caused by pseudo‐aldosteronism, which may result from an adverse reaction to licorice, should be monitored when using SKT.ConclusionA large randomised controlled trial may be necessary to establish a treatment for tetanus using both Western and Kampo medicines.
Searching for heavy Higgs in supersymmetric final states at the LHC
Authors: Adhikary Amit , Bhattacherjee Biplob , Godbole Rohini M. , Khan Najimuddin , Kulkarni Suchita 
Published: April 2021

Abstract
In this work, we analyse and demonstrate possible strategies to explore extended Higgs sector of the Minimal Supersymmetric Standard Model (MSSM). In particular we concentrate on heavy Higgs decays to electroweakinos. We analyse the Higgs to electroweakino decays in the allowed MSSM parameter space after taking into account 13 TeV LHC searches for supersymmetric particles and phenomenological constraints such as flavour physics, Higgs measurements and dark matter constraints. We explore some novel aspects of these Higgs decays. The final states resulting from Higgs to electroweakino decays will have backgrounds arising from the Standard Model as well as direct electroweakino production at the LHC. We demonstrate explicit kinematical differences between Higgs to electroweakino decays and associated backgrounds. Furthermore, we demonstrate for a few specific example points, optimised analysis search strategies at the high luminosity LHC (HL-LHC) run. Finally, we comment on possible search strategies for heavy Higgs decays to exotic final states, where the lightest chargino is long lived and leads to a disappearing track at the LHC.
Modularity of the displacement coefficients and complete plate theories in the framework of the consistent-approximation approach
Authors: Meyer-Coors Michael , Kienzler Reinhold , Schneider Patrick 
Published: April 2021

AbstractStarting from the three-dimensional theory of linear elasticity, we arrive at the exact plate problem by the use of Taylor series expansions. Applying the consistent-approximation approach to this problem leads to hierarchic generic plate theories. Mathematically, these plate theories are systems of partial-differential equations (PDEs), which contain the coefficients of the series expansions of the displacements (displacement coefficients) as variables. With the pseudo-reduction method, the PDE systems can be reduced to one main PDE, which is entirely written in the main variable, and several reduction PDEs, each written in the main variable and several non-main variables. So, after solving the main PDE, the reduction PDEs can be solved by insertion of the main variable. As a great disadvantage of the generic plate theories, there are fewer reduction PDEs than non-main variables so that not all of the latter can be determined independently. Within this paper, a modular structure of the displacement coefficients is found and proved. Based on it, we define so-called complete plate theories which enable us to determine all non-main variables independently. Also, a scheme to assemble Nth-order complete plate theories with equations from the generic plate theories is found. As it turns out, the governing PDEs from the complete plate theories fulfill the local boundary conditions and the local form of the equilibrium equations a priori. Furthermore, these results are compared with those of the classical theories and recently published papers on the consistent-approximation approach.
Simulation of the laser-material interaction of ultrashort pulse laser processing of silicon nitride workpieces and the key factors in the ablation process
Authors: Soltani Babak , Hojati Faramarz , Daneshi Amir , Azarhoushang Bahman 
Published: April 2021

AbstractUnderstanding the laser ablation mechanism is highly essential to find the effect of different laser parameters on the quality of the laser ablation. A mathematical model was developed in the current investigation to calculate the material removal rate and ablation depth. Laser cuts were created on the workpiece with different laser scan speeds from 1 to 10 mm s−1by an ultrashort pulse laser with a wavelength of about 1000 nm. The calculated depths of laser cuts were validated via practical experiments. The variation of the laser power intensity on the workpiece’s surface during laser radiation was also calculated. The mathematical model has determined the laser-material interaction mechanism for different laser intensities. The practical sublimation temperature and ablated material temperature during laser processing are other data that the model calculates. The results show that in laser power intensities (IL) higher than 1.5 × 109W cm−2, the laser-material interaction is multiphoton ionisation with no effects of thermal reaction, while in lower values ofIL, there are effects of thermal damages and HAZ adjacent to the laser cut. The angle of incidence is an essential factor in altering incidentILon the surface of the workpiece during laser processing, which changes with increasing depth of the laser cut.
Detrusor underactivity prevalence and risk factors according to different definitions in women attending urogynecology clinic
Authors: D’Alessandro Gloria , Palmieri Stefania , Cola Alice , Barba Marta , Manodoro Stefano , Frigerio Matteo 
Published: April 2021

Abstract
Introduction and hypothesis
There is still no consensus on definitions of detrusor underactivity; therefore, it is difficult to estimate the prevalence. The primary objective of the study was to evaluate the prevalence of detrusor underactivity in a cohort of patients with pelvic floor disorders according to different proposed urodynamics definitions. The secondary objectives were to estimate the association between detrusor underactivity and symptoms, anatomy and urodynamic findings and to build predictive models.

Methods
Patients who performed urodynamic evaluation for pelvic floor disorders between 2008 and 2016 were retrospectively analyzed. Detrusor underactivity was evaluated according to Schafer’s detrusor factor, Abrams’ bladder contractility index and Jeong cut-offs. The degree of concordance between each method was measured with Cohenʼs kappa, and differences were tested using Student’s t test, Wilcoxon test and Pearson’s chi-squared test.

Results
The prevalence of detrusor underactivity among a cohort of 2092 women, concerning the three urodynamic definitions, was 33.7%, 37.0% and 4.1%, respectively. Age, menopausal status, voiding/bulging symptoms, anterior and central prolapse, first desire to void and positive postvoid residual were directly related to detrusor underactivity. Conversely, stress urinary incontinence, detrusor pressures during voiding and maximum flow were inversely associated. Final models for detrusor underactivity resulted in poor accuracy for all considered definitions.

Conclusions
The prevalence of detrusor underactivity varies depending on the definition considered. Although several clinical variables resulted as independent predictors of detrusor underactivity, instrumental evaluation still plays a key role in the diagnosis.
Diagnosis and treatment delay of head and neck cancers during COVID-19 era in a tertiary care academic hospital: what should we expect?
Authors: De Luca Pietro , Bisogno Antonella , Colacurcio Vito , Marra Pasquale , Cassandro Claudia , Camaioni Angelo , Cassandro Ettore , Scarpa Alfonso 
Published: April 2021

AbstractBackgroundSince the spreading of SARS-CoV-2 from China, all deferrable medical activities have been suspended, to redirect resources for the management of COVID patients. The goal of this retrospective study was to investigate the impact of COVID-19 on head and neck cancers’ diagnosis in our Academic Hospital.MethodsA retrospective analysis of patients treated for head and neck cancers between March 12 and November 1, 2020 was carried out, and we compared these data with the diagnoses of the same periods of the 5 previous years.Results47 patients were included in this study. We observed a significative reduction in comparison with the same period of the previous 5 years.ConclusionsOur findings suggest that the COVID-19 pandemic is associated with a decrease in the number of new H&N cancers diagnoses, and a substantial diagnostic delay can be attributable to COVID-19 control measures.
MicroRNAs in the aqueous humor of patients with different types of glaucoma
Authors: Kosior-Jarecka Ewa , Czop Marcin , Gasińska Karolina , Wróbel-Dudzińska Dominika , Zalewski Daniel P. , Bogucka-Kocka Anna , Kocki Janusz , Żarnowski Tomasz 
Published: April 2021

Abstract
Purpose
The aim of the study was to compare the frequency and the level of expression of selected miRNAs in the aqueous humor of patients with various types of glaucoma.

Methods
The studied group consisted of 42 patients with glaucoma: 19 with primary open-angle glaucoma (POAG), 14 with pseudoexfoliation glaucoma (PEXG), 9 with primary angle closure glaucoma (PACG), and the control group of 36 patients with senile cataract without glaucoma. The real-time polymerase chain reaction method was used to analyze the expression of miRNAs.

Results
There were no significant differences in the frequency and the level of miRNA expression between various types of glaucoma. There was a tendency for hsa-miR-6722-3p and hsa-miR-184 to be expressed more frequently in PEXG and hsa-miR-1260b in POAG. The expression levels of hsa-miR-1260b and hsa-miR-6515-3p were correlated with age in POAG. Target annotation and functional analyses showed that genes targeted by the most frequently expressed miRNAs (hsa-miR-1202, -1260b, -184, -187-5p, -6515-3p, -6722-3p, and hsa-mir-4634) are involved mainly in response to hypoxia, cardiovascular system development, and apoptosis.

Conclusion
Hsa-miR-1260b was the most abundantly expressed among studied miRNAs and may be a potential biomarker of clinical status in PEXG and PACG.
Elterliche Reaktionen auf kindliche Schmerzen
Authors: Wallrath Maren K. , Geremek Adam , Rubel Julian , Lindner Clemens , Hechler Tanja 
Published: April 2021

Zusammenfassung
Hintergrund
Elterliche kognitiv-affektive und verhaltensbezogene Reaktionen können die Chronifizierung von kindlichen Schmerzen beeinflussen. Unklar ist, ob Mütter und Väter unterschiedlich reagieren und inwieweit Top-down- (elterliche Somatisierung, Angstsymptome) und Bottom-up-Variablen (kindliche schmerzbezogene Beeinträchtigung, Angstsymptome) die elterlichen Reaktionen modulieren.

Ziele der Arbeit
(1) Vergleich der Somatisierung, Angstsymptome und elterlichen Reaktionen (Katastrophisieren, Zuwendung) von Müttern und Vätern chronisch schmerzkranker Kinder und (2) Untersuchung des Einflusses von Top-down- und Bottom-up-Variablen auf die elterlichen Reaktionen.

Methode
Eltern-Kind-Triaden (Kind, Mutter, Vater; je N = 21, Gesamt‑N = 63; Kinder: 50 % weiblich, 11–19 Jahre, ∅15,14 Jahre) wurden während einer kinder- und jugendpsychiatrischen Behandlung ihrer chronischen Schmerzen hinsichtlich der kindlichen Schmerzen und Angstsymptome, elterlicher Somatisierung und Angstsymptome und elterlichen Reaktionen mit validierten Fragebögen erfasst.

Ergebnisse
Mütter und Väter unterschieden sich nicht in Somatisierung, Angstsymptomen und Reaktionen. Eltern katastrophisierten stärker, wenn ihre Kinder sowohl unter Angstsymptomen als auch unter stärkerer schmerzbezogener Beeinträchtigung litten. Elterliche Zuwendung war verstärkt, wenn Eltern selbst Angstsymptome angaben. Jüngere Kinder und Mädchen erhielten mehr Zuwendung.

Diskussion
Im Einklang mit vorherigen Studien zeigt sich, dass elterliche und kindliche Angstsymptome, nicht aber das elterliche Geschlecht als modulierende Faktoren der elterlichen maladaptiven Reaktionen eine Rolle spielen. Dies sollte in Prävention und Therapie von Kindern mit chronischen Schmerzen und deren Bezugspersonen berücksichtigt werden.
Diophantine equations in separated variables and polynomial power sums
Authors: Fuchs Clemens , Heintze Sebastian 
Published: April 2021

AbstractWe consider Diophantine equations of the shape $$ f(x) = g(y) $$

f
(
x
)
=
g
(
y
)

, where the polynomials f and g are elements of power sums. Using a finiteness criterion of Bilu and Tichy, we will prove that under suitable assumptions infinitely many rational solutions (x, y) with a bounded denominator are only possible in trivial cases.
Review: Hydrogeology of weathered crystalline/hard-rock aquifers—guidelines for the operational survey and management of their groundwater resources
Authors: Lachassagne Patrick , Dewandel Benoît , Wyns Robert 
Published: April 2021

AbstractHard rocks or crystalline rocks (i.e., plutonic and metamorphic rocks) constitute the basement of all continents, and are particularly exposed at the surface in the large shields of Africa, India, North and South America, Australia and Europe. They were, and are still in some cases, exposed to deep weathering processes. The storativity and hydraulic conductivity of hard rocks, and thus their groundwater resources, are controlled by these weathering processes, which created weathering profiles. Hard-rock aquifers then develop mainly within the first 100 m below ground surface, within these weathering profiles. Where partially or noneroded, these weathering profiles comprise: (1) a capacitive but generally low-permeability unconsolidated layer (the saprolite), located immediately above (2) the permeable stratiform fractured layer (SFL). The development of the SFL’s fracture network is the consequence of the stress induced by the swelling of some minerals, notably biotite. To a much lesser extent, further weathering, and thus hydraulic conductivity, also develops deeper below the SFL, at the periphery of or within preexisting geological discontinuities (joints, dykes, veins, lithological contacts, etc.). The demonstration and recognition of this conceptual model have enabled understanding of the functioning of such aquifers. Moreover, this conceptual model has facilitated a comprehensive corpus of applied methodologies in hydrogeology and geology, which are described in this review paper such as water-well siting, mapping hydrogeological potentialities from local to country scale, quantitative management, hydrodynamical modeling, protection of hard-rock groundwater resources (even in thermal and mineral aquifers), computing the drainage discharge of tunnels, quarrying, etc.