bluuebunny/crossref_metadata_2025_split huggingface dataset:
Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1
Authors: Vugmeyster Yulia , Grisic Ana-Marija , Wilkins Justin J. , Loos Anja H. , Hallwachs Roland , Osada Motonobu , Venkatakrishnan Karthik , Khandelwal Akash 
Published: September 2022

Abstract
Purpose
Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-β (TGF-β) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)–pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-β is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs).

Methods
The PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 (n = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration (Cavg), derived using a population PK model. The percentage of patients with trough concentrations associated with PD-L1 or TGF-β inhibition across various dosing regimens was derived.

Results
The probability of bleeding AEs increased with increasing Cavg; 50% dose reduction was chosen based on the integration of modeling and clinical considerations. The resulting AE management guidance to investigators regarding temporary or permanent treatment discontinuation was further refined with recommendations on restarting at RP2D or at 50% dose, depending on the grade and type of bleeding (tumoral versus nontumoral) and investigator assessment of risk of additional bleeding.

Conclusion
A pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.
Assessing the effectiveness of indirect questioning techniques by detecting liars
Authors: Perri Pier Francesco , Manoli Eleni , Christofides Tasos C. 
Published: September 2022

AbstractIn many fields of applied research, mostly in sociological, economic, demographic and medical studies, misreporting due to untruthful responding represents a nonsampling error that frequently occurs especially when survey participants are presented with direct questions about sensitive, highly personal or embarrassing issues. Untruthful responses are likely to affect the overall quality of the collected data and flaw subsequent analyses, including the estimation of salient characteristics of the population under study such as the prevalence of people possessing a sensitive attribute. The problem may be mitigated by adopting indirect questioning techniques which guarantee privacy protection and enhance respondent cooperation. In this paper, making use of direct and indirect questions, we propose a procedure to detect the presence of liars in sensitive surveys which allows researchers to evaluate the impact of untruthful responses on the estimation of the prevalence of a sensitive attribute. We first introduce the theoretical framework, then apply the proposal to the Warner randomized response method, the unrelated question model, the item count technique, the crosswise model and the triangular model. To assess the effectiveness of the procedure, a simulation study is carried out. Finally, the presence and the amount of liars is discussed in two real studies concerning racism and workplace mobbing.
Accurate computation of partial volumes in 3D peridynamics
Authors: Scabbia Francesco , Zaccariotto Mirco , Galvanetto Ugo 
Published: September 2022

AbstractThe peridynamic theory is a nonlocal formulation of continuum mechanics based on integro-differential equations, devised to deal with fracture in solid bodies. In particular, the forces acting on each material point are evaluated as the integral of the nonlocal interactions with all the neighboring points within a spherical region, called “neighborhood”. Peridynamic bodies are commonly discretized by means of a meshfree method into a uniform grid of cubic cells. The numerical integration of the nonlocal interactions over the neighborhood strongly affects the accuracy and the convergence behavior of the results. However, near the boundary of the neighborhood, some cells are only partially within the sphere. Therefore, the quadrature weights related to those cells are computed as the fraction of cell volume which actually lies inside the neighborhood. This leads to the complex computation of the volume of several cube–sphere intersections for different positions of the cells. We developed an innovative algorithm able to accurately compute the quadrature weights in 3D peridynamics for any value of the grid spacing (when considering fixed the radius of the neighborhood). Several examples have been presented to show the capabilities of the proposed algorithm. With respect to the most common algorithm to date, the new algorithm provides an evident improvement in the accuracy of the results and a smoother convergence behavior as the grid spacing decreases.
10-year follow-up of interventional electrophysiology: updated German survey during the COVID-19 pandemic
Authors: Eckardt Lars , Doldi Florian , Busch Sonia , Duncker David , Estner H. , Kuniss M. , Metzner A. , Meyer C. , Neuberger H.-R. , Tilz R. , Voss F. , Steven D. , Sommer P. 
Published: September 2022

Abstract
Introduction
This study provides an update of survey-based data providing an overview of interventional electrophysiology over the last decade. Overall infrastructure, procedures, and training opportunities in Germany were assessed.

Methods
By analyzing mandatory quality reports, German cardiology centres performing electrophysiological studies were identified to repeat a questionnaire from 2010 and 2015.

Results
A complete questionnaire was returned by 192 centers performing about 75% of all ablations in Germany in 2020. In the presence of the COVID-19 pandemic, a total of 76.304 procedures including 68.407 ablations were reported representing a 38% increase compared to 2015. The median number of ablations increased from 180 in 2010 to 377 in 2020. AF was the most common arrhythmia ablated (51 vs. 35% in 2010). PVI with radiofrequency point-by-point ablation (64%) and cryo-balloon ablation (34%) were the preferred strategies. Less than 50 (75) PVI were performed by 31% (36%) of all centres. Only 25 and 24% of participating centres fulfilled EHRA and national requirements for training centre accreditation, respectively. There was a high number of EP centres with no fellows (38%). The proportion of female fellows in EP increased from 26% in 2010 to 33% in 2020.

Conclusion
Comparing 2020, 2010 and 2015, an increasing number of EP centres and procedures were registered. In 2020, more than every second ablation was for therapy of AF. In the presence of an increasing number of procedures, training opportunities were still limited, and most centres did not fulfill recommended EHRA or national requirements for accreditation.

Graphical abstract
Chronic cigarette smoking is associated with increased arterial stiffness in men and women: evidence from a large population-based cohort
Authors: Hahad Omar , Schmitt Volker H. , Arnold Natalie , Keller Karsten , Prochaska Jürgen H. , Wild Philipp S. , Schulz Andreas , Lackner Karl J. , Pfeiffer Norbert , Schmidtmann Irene , Michal Matthias , Schattenberg Jörn M. , Tüscher Oliver , Daiber Andreas , Münzel Thomas 
Published: September 2022

Abstract
Background
Cigarette smoking is a threat to global human health and a leading cause of the cardiovascular disease (CVD) morbidity and mortality. Importantly, sex-specific differences in smoking-induced arterial stiffness, an early key event in the development of atherosclerotic CVD, remain still elusive. Thus, this study sought out to investigate sex-specific associations between smoking and measures of arterial stiffness.

Methods and results
Overall, 15,010 participants (7584 men and 7426 women aged 35–74 years) of the Gutenberg Health Study were examined at baseline during 2007–2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a standardized computer-assisted interview. Arterial stiffness and wave reflection were determined by stiffness index (SI) and augmentation index (AI). In the total sample, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Median cumulative smoking exposure was 22.0 pack-years in current male smokers and 16.0 in current female smokers. In general, multivariable linear regression models adjusted for a comprehensive set of confounders revealed that smoking status, pack-years of smoking, and years since quitting smoking were dose-dependently associated with markers of arterial stiffness. In sex-specific analyses, these associations were overall more pronounced in men and SI was stronger related to the male sex, whereas differences between men and women in the case of AI appeared to be less substantial.

Discussion
The present results indicate that chronic smoking is strongly and dose-dependently associated with increased arterial stiffness in a large population-based cohort regardless of sex but with a stronger association in men.
Post-mortem oxycodone blood concentrations of hospitalized cancer and surgery patients compared with fatal poisonings
Authors: Kriikku Pirkko , Kalso Eija , Ojanperä Ilkka 
Published: September 2022

AbstractOxycodone is a strong opioid drug commonly used to treat acute, cancer, and chronic non-malignant pain. In this study, all oxycodone-related medico-legal cases where death had occurred in a hospital or nursing home in Finland were investigated to determine the range of post-mortem (PM) oxycodone blood concentrations in a therapeutic setting. All toxicology cases in which oxycodone was detected in PM femoral blood during the 4-year period of 2016–2019 in Finland were retrieved from the national PM toxicology database. In this material, the 365 deceased hospital patient cases that met the study inclusion criteria were divided into four groups according to the cause and manner of death. The reference group of 121 fatal oxycodone poisoning cases comprised two groups: those with verified associated drug abuse and those without drug abuse. The median oxycodone concentration in PM blood was significantly higher in cancer patients (0.10 mg/L) than in patients with recent surgery (0.07 mg/L) or other disease (0.06 mg/L) (p < 0.05). In addition, the median oxycodone concentration was significantly lower in all hospital patient groups than in the poisoning groups, the latter displaying 0.38 mg/L (abuse) and 0.64 mg/L (no abuse) (p < 0.001). This study shows that half of the subjects in the cancer patient group had PM blood oxycodone concentrations above the typical clinical therapeutic plasma concentration range (0.005–0.10 mg/L). Appropriate medication of hospitalized surgery and cancer patients can result in concentrations of up to 0.2 and 0.6 mg/L, respectively, while higher concentrations are exceptional.
Muscle quantitative MRI as a novel biomarker in hereditary transthyretin amyloidosis with polyneuropathy: a cross-sectional study
Authors: Vegezzi Elisa , Cortese Andrea , Bergsland Niels , Mussinelli Roberta , Paoletti Matteo , Solazzo Francesca , Currò Riccardo , Ascagni Lucia , Callegari Ilaria , Quartesan Ilaria , Lozza Alessandro , Deligianni Xeni , Santini Francesco , Marchioni Enrico , Cosentino Giuseppe , Alfonsi Enrico , Tassorelli Cristina , Bastianello Stefano , Merlini Giampaolo , Palladini Giovanni , Obici Laura , Pichiecchio Anna 
Published: September 2022

Abstract
Background
The development of reproducible and sensitive outcome measures has been challenging in hereditary transthyretin (ATTRv) amyloidosis. Recently, quantification of intramuscular fat by magnetic resonance imaging (MRI) has proven as a sensitive marker in patients with other genetic neuropathies. The aim of this study was to investigate the role of muscle quantitative MRI (qMRI) as an outcome measure in ATTRv.

Methods
Calf- and thigh-centered multi-echo T2-weighted spin-echo and gradient-echo sequences were obtained in patients with ATTRv amyloidosis with polyneuropathy (n = 24) and healthy controls (n = 12). Water T2 (wT2) and fat fraction (FF) were calculated. Neurological assessment was performed in all ATTRv subjects. Quantitative MRI parameters were correlated with clinical and neurophysiological measures of disease severity.

Results
Quantitative imaging revealed significantly higher FF in lower limb muscles in patients with ATTRv amyloidosis compared to controls. In addition, wT2 was significantly higher in ATTRv patients. There was prominent involvement of the posterior compartment of the thighs. Noticeably, FF and wT2 did not exhibit a length-dependent pattern in ATTRv patients. MRI biomarkers correlated with previously validated clinical outcome measures, Polyneuropathy Disability scoring system, Neuropathy Impairment Score (NIS) and NIS-lower limb, and neurophysiological parameters of axonal damage regardless of age, sex, treatment and TTR mutation.

Conclusions
Muscle qMRI revealed significant difference between ATTRv and healthy controls. MRI biomarkers showed high correlation with clinical and neurophysiological measures of disease severity making qMRI as a promising tool to be further investigated in longitudinal studies to assess its role at monitoring onset, progression, and therapy efficacy for future clinical trials on this treatable condition.
Can workplace intervention prolong work life of older workers? A quasi-experimental study
Authors: Neupane Subas , Kyrönlahti Saila , Oakman Jodi , Siukola Anna , Riekhoff Aart-Jan , Kuivalainen Susan , Nygård Clas-Håkan 
Published: September 2022

AbstractBackgroundWe aimed to evaluate the impact of a workplace senior program intervention on early exit from labor market and on the disability retirement among older employees and work-related physical factors associated with it.MethodsA total of 259 individuals aged 55 + years participated in the study (107 in intervention and 152 were controls). A questionnaire survey was conducted among Finnish food industry employees between 2003 and 2009 and the intervention “senior program” was provided between 2004 and 2009. The type of pension for the respondents who had retired by 2019 was obtained and dichotomized as statutory vs. early labor market exit. Disability pension was investigated as a separate outcome. Information on work-related factors was obtained from the survey. Cox regression analysis was used to estimate hazard ratios (HR) with their 95% confidence intervals.ResultsFifty-one employees had early labor market exit. Of them, 70% (n = 36) were control participants. Employees in the senior program worked for longer years (mean years 7.4, 95% CI 6.4–8.1) compared to the control (6.6, 95% CI 6.3–7.5). Sixty percent lower risk of early labor market exit (HR 0.40, 95% CI 0.19–0.84) and disability pension was found among employees in the senior program compared to the control group. Good work ability had a 94% lower risk (0.06, 95% CI 0.01–0.29) of early labor market exit and 85% lower risk (0.15, 95% CI 0.03–0.73) of disability pension compared to poor work ability. Employees with musculoskeletal pain had 4 times higher risk of disability pension compared to those without musculoskeletal pain.ConclusionsA workplace senior program intervention prolonged work life and had positive effect on reducing disability pension among older industrial workers.
Effects of inhaled nitric oxide (iNO) in pulmonary hypertension secondary to arteriovenous malformations: a retrospective cohort study from the European iNO registry
Authors: Chakkarapani Aravanan Anbu , Gupta Samir , Jamil Asma , Yadav Santosh Kumar , Subhedar Nim , Hummler Helmut D. 
Published: September 2022

Abstract
This study aims to assess the effects of inhaled nitric oxide (iNO) on oxygenation in the management of pulmonary hypertension (PH) secondary to arteriovenous malformations (AVMs) in neonates. This is a matched retrospective cohort study from January 1, 2013, to December 31, 2017. The European inhaled nitric oxide registry from 43 neonatal and pediatric ICUs in 13 countries across Europe was used to extract data. The target population was neonates treated with iNO for the management of PH. The cases (PH secondary to AVMs treated with iNO) were matched (1:4 ratio) to controls (PH without AVMs treated with iNO). The main outcome measure was the absolute change of oxygenation index (OI) from baseline to 60 min after starting iNO in cases and controls. The primary outcome of our study was that the mean absolute change in OI from baseline to after 60 min was higher among cases 10.7 (14), than in controls 6 (22.5), and was not statistically different between the groups. The secondary outcome variable — death before discharge — was found to be significantly higher in cases (55%) than in controls (8%). All the other variables for secondary outcome measures remained statistically insignificant. Conclusion: Infants with PH secondary to AVMs treated with iNO did not respond differently compared to those presented with PH without AVMs treated with iNO. Right ventricular dysfunction on echocardiography was higher in cases than controls (cases: 66.7% and controls: 28.6%) but was not statistically significant.

What is Known:• Arterioenous malformation (AVM) is a well-known cause of persistent pulmonary hypertension in newborns. Inhaled nitric oxide (iNO) is most commonly used as first-line therapy for pulmonary hypertension in newborns.• Around 40–50% of vein of Galen malformations (VOGMs) are found to have congestive heart failure in the neonatal period.

What is New:• Neonates may present with an isolated PH of the newborn as the main feature of the VOGMs. A large proportion of cases with AVMs have been associated with right ventricular cardiac dysfunction. • Results from one of the largest database registries in the world for iNO have been used to answer our research question.
A new homogenization scheme for beam and plate structures without a priori requirements on boundary conditions
Authors: Müller Maximilian , Klarmann Simon , Gruttmann Friedrich 
Published: September 2022

AbstractThis contribution picks up on a novel approach for a first order homogenization procedure based on the Irving-Kirkwood theory and provides a finite element implementation as well as applications to beam and plate structures. It does not have the fundamental problems of dependency from representative volume element (RVE) size in determining the shear and torsional stiffness for beams and plates, that is present in classic Hill-Mandel methods. Due to the possibility of using minimal boundary conditions whilst simultaneously reusing existing homogenization algorithms, creation of models and numerical implementation are much more straight forward. The presented theory and FE formulation are limited to materially and geometrically linear problems. The approach to determining shear stiffness is based on the assumption of a quadratic shear stress distribution over the height (and width in case of the beam), which causes warping of the cross-section under transverse shear loading. Results for the homogenization scheme are shown for various beam and plate configurations and compared to values from well known analytical solutions or computed full scale models.
Changes in coastal farming systems in a changing climate in Bangladesh
Authors: Hasan Md Kamrul , Kumar Lalit 
Published: September 2022

AbstractChanges in farming systems are dominated by changes in global climate and local environment, apart from the non-climatic drivers. Given the challenges in partitioning the contribution of climatic and non-climatic factors to the changes in farming systems, this paper aims to assess the types and changes of coastal farming systems, the farmer perceptions of the causes of the changes in farming systems, and the relationship between the influencing factors and perceptions. A structured interview schedule was used to collect data from 381 randomly selected coastal households during September–October 2018. The random forest classification model was applied to estimate the relative importance of the farmers’ characteristics on their perception of causes of changes in farming systems. This study reveals that the coastal farmers had mostly semi-subsistence type of mixed farming systems, which were going through dynamic changes in terms of their sizes and number of farmers. In general, the participation in rice, vegetables, and livestock farming was decreasing but increasing in fisheries, forestry, and fruit farming. Most (95.5%) of the farmers had to change at least one of the farming enterprises over the past decade (2009–2018) compared with the previous decade (1999–2008). About two-thirds of the farmers perceived that climate change had caused changes in their farming systems. Compared with the eastern coasts, the farmers in the western coasts tended to blame climate change to a higher extent for the effect on their agricultural activities. The random forest model outputs imply that the farmers who are younger in age and with less formal education, larger family, and smaller farmland should be supported with scientific knowledge on causes of changes in farming systems. This could help them more aware of climate change issues related to agriculture and increase their enthusiasm to take part in adaptive changes in farming systems.
Examining the role of soft dimensions on the implementation of ISO 14000 environmental management systems: a graph-theoretic approach
Authors: Ali Syed Mithun , Belal H. M. , Roy Sanjeeb , Rahman Md. Tayabur , Raihan Ahmed Shoyeb 
Published: September 2022

AbstractOrganizations worldwide are now embracing different standards while approaching environmental management systems (EMS) to be environmentally and economically sustainable. The ISO 14001 EMS has captured much attention by offering efficient environmental practices organization-wide and throughout the supply chain. Human factors (HFs) are crucial behind implementing ISO 14001 EMS since research articles about ISO 14001 strongly emphasize different HFs. This study proposes a framework that solely focuses on those HFs. Influential HFs are extracted through content analysis of related literature and categorized into 5 main HFs. Opinions from experts in the relevant field about interrelationships and inheritances of the HFs are collected and converted into quantitative data. Incorporating the graph theoretic and matrix approach (GTMA), the data delivered permanent values corresponding to the main HFs and their best and worst possible values. Among the main HFs, EMS Training has been found to have the most scopes for improvement, followed by Employee Empowerment and EMS Teamwork. This study demonstrates a framework about how to assess the role of HFs behind internalizing ISO 14001 EMS and enables organizations to go for competitive benchmarking and to define and adjust goals for environmental management.