bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers for Hypoxia, HPVness, and Proliferation from Imaging Perspective
Authors: Sanduleanu Sebastian , Keek Simon , Hoezen Lars , Lambin Philippe
Published: June 2021

Recent advances in quantitative imaging with handcrafted radiomics and unsupervised deep learning have resulted in a plethora of validated imaging biomarkers in the field of head and neck oncology. Generally speaking, these algorithms are trained for one specific task, e.g. to classify between two or multiple types of underlying tumor biology (e.g. hypoxia, HPV status), predict overall survival (OS) or progression free survival (PFS), automatically segment a region of interest e.g. an organ at risk for radiotherapy dose or the gross tumor volume (GTV). Despite relatively good performances in external validation cohorts these algorithms still have not found their way into routine clinical practice. The reason this has not happened yet is complex, multifactorial, and can be usually divided into three categories: technical (a part of the algorithm or pre-processing step is not technically sound), statistical (mainly related to selection of subset of relevant biomarkers), and translational (not enough understanding by clinicians, not easily implementable within clinical workflow). We currently foresee that the next artificial intelligence (AI)-driven technique to find its way into clinical practice beside existing techniques (e.g. automatic organ at risk segmentation) will be the automatic segmentation of head and neck gross tumor volumes.
Innovation and Advances in Precision Medicine in Head and Neck Cancer
Authors: Watson Geoffrey Alan , Taylor Kirsty , Siu Lillian L.
Published: June 2021

The clinical utility of precision medicine through molecular characterization of tumors has been demonstrated in some malignancies, especially in cases where oncogenic driver alterations are identified. Next generation sequencing data from thousands of patients with head and neck cancers have provided vast amounts of information about the genomic landscape of this disease. Thus far, only a limited number of genomic alterations have been druggable, such asNTRKgene rearrangements in salivary gland cancers (mainly mammary analogue secretory carcinoma),NOTCHmutations in adenoid cystic cancers,HRASmutations in head and neck squamous cell cancers, and even a smaller number of these have reached regulatory approval status. In order to expand the scope of precision medicine in head and neck cancer, additional evaluation beyond genomics is necessary. For instance, there is increasing interest to perform transcriptomic profiling for target identification. Another advance is in the area of functional testing such as small interfering RNA and drug libraries on patient derived cell cultures. Liquid biopsies to detect specific tumor clones or subclones, or viral sequences such as HPV, are of great interest to enable non-invasive tracking of response or resistance to treatment. In addition, precision immuno-oncology is a tangible goal, with a growing body of knowledge on the interactions between the host immunity, the tumor and its microenvironment. Immuno-oncology combinations that are tailored to immunophenotypes of the host-tumor-microenvironment triad, personalized cancer vaccines, and adoptive cell therapies, among others, are in active development. Many therapeutic possibilities and opportunities lie ahead that ultimately will increase the reality of precision medicine in head and neck cancer.
Mechanisms of Cetuximab Resistance and How to Overcome It
Authors: De Pauw Ines , Boeckx Carolien , Wouters An
Published: June 2021

Deregulated or increased signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the development of various cancer types, including head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. However, after initially promising results of EGFR-targeted therapies, such as the monoclonal antibody cetuximab, it became clear that both intrinsic and acquired therapeutic resistance are major roadblocks in the field of personalised cancer treatments.

In order to unravel and overcome resistance to cetuximab, at least two strategies can be adopted.

Firstly, therapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signalling and/or mechanisms that can modulate EGFR-dependent signalling. In this chapter, we discuss which mechanisms of cetuximab resistance are already known and which ones deserve further investigation. This enhanced knowledge will guide us to rationally design and test novel combination therapies that overcome resistance to EGFR-targeting agents in cancer treatment.

Secondly, an urgent need remains to develop novel targeted treatments for single-agent or combined therapy use. In this view, due to the particular mode of activation of the EGFR receptor, involving ligand-induced homo- and heterodimerization of the four HER receptors, an increased inhibition scope of HER receptors most likely results in a more potent blockade of the HER network, preventing premature emergence of resistance and leading to a more pronounced therapeutic benefit. We discuss two multitargeted compounds, being MEHD7945A (duligotuzumab) and afatinib, in this chapter.

Despite the huge efforts to unravel the molecular landscape of HNSCC, the main clinically validated target remains EGFR. However, immune checkpoints, like programmed cell death protein 1 (PD-1), are gaining clinical approvals as well. We underscore the importance of adopting rational drug combinations to enhance the therapeutic effect of the EGFR-inhibitor cetuximab and highlight the ongoing search for predictive biomarkers, with the ultimate goal of delivering individualized cancer therapy to HNSCC patients.
Biomarkers for Immune Modulatory Treatment in Head and Neck Squamous Cell Carcinoma (HNSCC)
Authors: Rischin Danny
Published: June 2021

Immune checkpoint inhibitors have changed the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, only a minority of patients respond, hence the search for predictive biomarkers. Potential predictive biomarkers for immune checkpoint inhibitors discussed in this chapter include (1) Immune checkpoint ligand expression e.g., PD-L1, (2) biomarkers of a T-cell inflamed tumour microenvironment (TME) such as gene expression profiles of activated T cells, (3) biomarkers of tumour neoepitope burden such as tumour mutation burden (TMB) and (4) multidimensional quantitative techniques. At present only PD-L1 expression has been shown to have clinical utility in head and neck cancer. It enriches for populations more likely to respond, but the false positive predictive value remains high. In the pivotal Keynote−048 trial that established a role for pembrolizumab (anti-PD1) monotherapy and pembrolizumab + chemotherapy as treatment options in first-line R/M HNSCC, primary endpoints included overall survival in defined subgroups based on PD-L1 expression. In this trial the combined positive score (CPS) was used which takes into account PD-L1 expression in tumour and immune cells. Based on this trial regulatory approvals for first-line pembrolizumab in R/M HNSCC require assessment of PD-L1 expression using the CPS. Finally we discuss emerging evidence that locoregionally advanced HPV-associated oropharyngeal cancers that have high expression of CD103 positive CD8 T cells have an excellent prognosis and features that suggest increased probability of responding to anti-PD1/PD-L1, raising the possibility of incorporating these immune therapies as part of a de-escalation trial strategy.
The Surgical Approach to Elderly Patients with HNSCC
Authors: Dietz Andreas
Published: June 2021

Despite the fact that elderly people are the main incidental and continuously growing patient group with head and neck cancer, prospective trials focusing on special issues regarding head and neck surgery in elderlies are missing. To avoid complications during and after surgery in that patient category, comprehensive evaluation of functional status, comorbidities, performance status, social support and mental condition is mandatory. Regarding functional parameters, cardiac and respiratory conditions play a major role for any primary surgical procedure. Nevertheless, other comorbidities, medication and patients view on self-determination have carefully to be taken into consideration. It has repeatedly been shown that fit elderly individuals may benefit from intensive therapies like reconstructive surgery with microvascular free tissue transfer, concurrent chemoradiotherapy in the locoregionally advanced disease setting, and even from the standard first- and second-line palliative systemic therapies. Since it is well known that tolerance of systemic nonsurgical treatments in elderly people is less and therefore death from noncancer-related causes in that population is higher, moderate surgical procedures can be even more effective regarding quality of life in situations facing higher comorbidities, or functional constraints with limited life expectancy compared to nonsurgical standard approaches. Older people usually are at increased risk of postoperative complications. In particular, organ failure progresses much faster in multiple organ failure. The preoperative clarification of comorbidity for the avoidance of surgical complications is therefore of major importance. Close coordination with anesthesia and rapid postoperative mobilization are essential for this. Decision-making and treatment based on specific assessment in an experienced multidisciplinary team is key.
Living with a Brain AVM: A Quality of Life Assessment
Authors: Orosz Péter , Vadász Ágnes , Veres Dániel Sándor , Berentei Zsolt , Gubucz István , Nardai Sándor , Kis Balázs , Szikora István
Published: June 2021

Background and purpose: Brain arteriovenous malformations (AVM) are uncommon vascular lesions with the risk of hemorrhage, epileptic seizures, neurological deficits, and headache. Comparing the risks of the natural history and that of preventive treatment, a recent study has found observation more beneficial than treatment for unruptured AVMs. This study, however, did not consider the long-term impact of carrying a brain AVM on everyday activities. In this study we analyzed the Quality Of Life (QOL) of patients with untreated AVMs, a measure increasingly used in clinical trials to asses this kind of impact.

Methods: We enrolled 36 patients with unruptured, untreated brain AVM from our hospital database and measured their QOL retrospectively using the EQ-5D-5L questionnaire. As a control group we used the results of the Research Report, a nationwide study based on the quality of life of 5534 healthy Hungarians in 2002. Due to the low number of cases, statistical analysis could not be made.

Results: Headache proved to be the most common AVM-related sign in our cohort (40%, n = 17), with a female predominance; neurological deficit was detected in 33% (n = 14), while epileptic seizures occurred in 26% (n = 11), more commonly affecting male subjects. Anxiety and discomfort seemed to be the most prevalent influencing factors on QOL, especially in the youngest age group (18–34 years). Female subjects showed a greater dependence than men in all age groups, though males had a more significant impairment in their usual activities. Older patients were affected more significantly in their self-care and usual activities compared with the younger population.

Conclusions: Untreated AVMs have a significant negative impact on patients carrying unruptured brain AVMs, as proved by QOL assessment. Beside neurological deficits, this impact should also be considered in the therapeutic decision.
Surgical Simulation with Three-Dimensional Fusion Images in Patients with Arteriovenous Malformation
Authors: Hara Takayuki , Yoshino Masanori
Published: June 2021

In arteriovenous malformation (AVM) surgery, vessel structures should be well evaluated with angiography. However, with conventional angiography, it is sometimes difficult to distinguish each feeder and its feeding territory in the nidus. In this study, we used two software systems to create three-dimensional (3D) fusion images using multiple imaging modalities and evaluated their clinical use. In the AVM patient, data were obtained from 3D rotational angiography, rotational venography, computed tomography (CT), and magnetic resonance imaging (MRI) and superimposed into 3D fusion images using imaging software (iPLAN and Avizo). Virtual surgical fields that were quite similar to the real ones were also created with these software programs. Compared with fusion images by iPLAN, those by Avizo have higher resolution and can demarcate not only each feeder but also its supplying territory in the nidus with different colors.

In conclusion, 3D fusion images in AVM surgery are helpful for simulation, even though it takes time and requires special skill to create them.
Surgical Treatment of Unruptured Brain AVMs: Short- and Long-Term Results
Authors: Eliava Shalva , Gorozhanin Vadim , Shekhtman Oleg , Pilipenko Yuri , Kuchina Olga
Published: June 2021

Unruptured brain AVMs (bAVMs) remain a controversial subject for practicing neurosurgeons, especially in the light of ARUBA and other observational studies. This retrospective study aims to analyze our experience with unruptured bAVMs to see whether it is beneficial in the long-term and how it corresponds to large literature trials. The study comprised 160 adult patients with unruptured bAVMs surgically treated in Burdenko NMC (Moscow) in 2009–2017. Mean age: 33.4 ± 10лет. Clinical presentations were: seizures in 99 (61.9%), chronical headaches—49 (30.6%), ischemic symptoms—4 (2.5%), asymptomatic in 8 (5%) patients. Spetzler-Martin scale: I—18 pt. (11.3%), II—71 pt. (44.4%), III—60 pt. (37.5%), IV—11 pt. (6.8%). Good outcomes (mRS = 0–2) at discharge were achieved in 149 (93.1%), satisfactory (mRS—3)—9 (5.6%). Follow-up was complete for 97 (60.6%) patients, mean—59.3 (13–108 month). Excellent outcomes (mRS = 0–1) reached in 94.8%. For epilepsy patients, Engel I outcome was found in 50 (84.8%); for chronic headaches, 43 (66.1%) patients reported improvement. Postoperative visual field defects were followed in 22 of 55 (40%), complete recovery was reported in 6 (27%) and partial recovery in 8 (36%) patients. Overall, our results support the conclusion that surgery for low-grade bAVMs (S-M I–II) is a beneficial, low-risk option.
Maximum Nidus Depth as a Risk Factor of Surgical Morbidity in Eloquent Brain Arteriovenous Malformations
Authors: Ryu Bikei , Yamaguchi Koji , Ishikawa Tatsuya , Atsushi Fukui , Matsuoka Go , Eguchi Seiichiro , Kawashima Akitsugu , Okada Yoshikazu , Kawamata Takakazu
Published: June 2021

Background: Eloquent location of a brain arteriovenous malformation (BAVM) is known to increase the surgical risk. Surgical removal of such BAVMs is challenging. Useful indicators for the safe removal of eloquent BAVMs are needed. The aim of this study was to determine the surgical risk factors for these challenging entities.

Methods: The authors retrospectively reviewed 29 motor and/or sensory BAVM patients who underwent surgeries. The risk factors for surgical morbidity were analyzed. As a new risk factor, maximum nidus depth, was evaluated.

Results: Complete obliteration was achieved in 28 patients (96.6%). Postoperative transient and permanent neurological deteriorations were seen in nine patients (31.0%) and five patients (17.2%), respectively. In univariate analysis, maximum nidus depth (p = 0.0204) and asymptomatic onset (p = 0.0229) were significantly correlated with the total morbidity. In multivariate analysis, only maximum nidus depth was significantly correlated with total morbidity (p = 0.0357; odds ratio, 2.78598; 95% confidence interval, 0.8866–8.7535). The cut-off value for the maximum nidus depth was 36 mm for total morbidity (area under the curve [AUC], 0.7428) and 41 mm for permanent morbidity (AUC, 0.8833). The cutoff value of the maximum nidus size was 30 mm for total morbidity (AUC, 0.5785) and 30 mm for permanent morbidity (AUC, 0.7625). AUC was higher for the maximum nidus depth than it was for the maximum nidus size.

Conclusions: Maximum nidus depth was significantly associated with surgical morbidity of eloquent BAVMs. The maximum nidus depth is a novel and a simpler indicator of the risk of surgical morbidity.
Microneurosurgical Management of Posterior Inferior Cerebellar Artery Aneurysms: Results of a Consecutive Series
Authors: Del Maestro Mattia , Luzzi Sabino , Galzio Renato
Published: June 2021

Aneurysms of the posterior inferior cerebellar artery (PICA) are uncommon. The complex anatomy of PICA and its intimate relationships with medulla, lower cranial nerves, and jugular tubercle makes the surgical treatment of these aneurysms fascinating. The reported is study aimed at a critical review of the overall results of a personal series of PICA aneurysms, treated by the senior author, R. Galzio. Demographics, charts, videos, outcome, and follow-up of a cohort of PICA aneurysms managed in the last 10 years were retrospectively analyzed, focusing only upon those treated with microneurosurgery. Twenty-five patients, harboring a single aneurysm, were operated on. Fifteen aneurysms were ruptured. Nineteen were proximal, all of these being been treated through a far-lateral approach. Trans-condylar or trans-tubercular variants were rarely necessary and however reserved to peculiar cases. Twenty-three aneurysms underwent direct treatment consisting of clip ligation. At 6-month follow-up, 60% of patients had a modified Rankin Score (mRS) of 0–2. Given the high anatomical variability of both PICA and patients’ bony anatomy, a case-by-case meticulous preoperative imaging evaluation is mandatory for the choice of the most suitable and tailored surgical corridor which, in turn, is pivotal to achieve the best outcome.
Earthquake Physical Risk/Loss Assessment Models and Applications: A Case Study on Content Loss Modeling Conditioned on Building Damage
Authors: Akkar S.
Published: June 2021

This paper presents a novel approach to develop content fragility conditioned on building damage for contents used in residential buildings in Turkey. The approach combines the building damage state probabilities with the content damage probabilities conditioned on building damage states to develop the content fragilities. The paper first presents the procedure and then addresses the epistemic uncertainty in building and content fragilities to show their effects on the content vulnerability. The approach also accounts for the expert opinion differences in the content replacement cost ratios (consequence functions) as part of the epistemic uncertainty. Monte Carlo sampling is used to consider the epistemic uncertainty in each model component contributing to the content vulnerability. A sample case study is presented at the end of the paper to show the implementation of the developed content fragilities by calculating the average annual loss ratio (AALR) distribution of residential content loss over the mainland Turkey.
Seismic Fragility Relationships for Structures
Authors: Di-Sarno L. , Elnashai A. S.
Published: June 2021

Structural fragility assessment is a fundamental component of modern performance-based earthquake design and assessment processes. Major advances in fragility functions development and implementation have occurred over the past three decades.
Memoirs of the Fruits of Globalization: The Markets for Chinese Textiles in New Spain by Jean de Monségur
Authors: Fernandez de Pinedo Nadia , Thépaut-Cabasset Corinne
Published: June 2021

A revealing report produced by the French intelligence services of the beginning of eighteenth-century explores the production of luxury and fashion commodities and their distribution on a global scale. According to Jean de Monségur the main competitors in New Spain arrived through China commercial routes. On one hand, we intend to explore if the trade market in Mexico was reflecting or not European fashions, in particular French fashion so in vogue among European elites. On the other hand, some cultural aspects must be taking into account to discern how entangled Europe, Asia and the Americas were in 1700s underlying economic prestige and social status as in Europe. How cultural and symbolic message matters? Was New Spain contributing to develop an emerging hybrid consumer society?
The EU as an Anchor for Turkey’s Macroeconomic and Trade Policy
Authors: Akman Mehmet Sait , Çekin Semih Emre
Published: June 2021

EU–Turkey relations have been subject to manifold ups and downs for decades. The EU’s role in Turkey’s domestic transformation has long been a matter of interest to the academic community. This chapter examines to what extent and under what conditions the EU has served as an anchor for the Turkish economy during the last two decades, focusing on the effects of the EU anchor on Turkey’s macroeconomic and trade policy. It finds that maintaining a European anchor after the Helsinki European Council helped Turkey realize much-desired comprehensive macroeconomic reforms, especially during times when the EU anchor was combined with another multilateral anchor. Nevertheless, the EU’s anchor-providing role has not been consistent and amidst changing political circumstances it is no longer considered an ‘elixir’ for the Turkish economy. The establishment of the Customs Union (CU) is revealed to have been a significant driver of the transformation of Turkey’s trade policy. While the trade partnership remains one of the few well-functioning aspects of the volatile bilateral dialogue between the EU and Turkey, the EU’s role in the trade policy arena is diminishing, and the upgrading of the CU remains vital to achieve further momentum and enhance mutual gains.
Current Trends and Future Prospects for EU–Turkey Relations: Conditions for a Cooperative Relationship
Authors: Reiners Wulf , Turhan Ebru
Published: June 2021

This chapter summarizes the key insights derived from a three-dimensional perspective on EU–Turkey relations that combines the analytical lenses of (1) theories and concepts, (2) institutions, and (3) policies. It furthermore reflects upon the different periodizations of the EU–Turkey relationship. On this basis, we offer a systematic survey of the conditions under which cooperative trends in EU–Turkey relations could be (re)invigorated. The analysis shows that despite the high potential for reciprocity inside and outside the accession framework, the relationship currently rests on unfavorable conditions for cooperation on both sides. Important enablers of cooperative behavior—trust, communication, reputation, fairness, enforcement, and common identity—cannot properly operate in the current setup. The chapter puts forward possible means to allow for these enablers to facilitate cooperative behavior in EU–Turkey relations in the future. It concludes by discussing the future trajectory of the relationship and pinpointing avenues for a future research agenda for EU–Turkey studies.
Historical Institutionalism and EU–Turkey Relations: Path Dependence and Critical Junctures in the Accession Process
Authors: Icoz Gülay , Martin Natalie
Published: June 2021

This chapter employs the perspective of historical institutionalism to analyze and explain why Turkey’s EU accession process endures even though it has not significantly progressed since it began. It argues that its temporal approach, the concepts of critical junctures and path dependence help explain the processes of stasis and change inherent within it. The chapter starts with an outline of historical institutionalism and contextualizes its conceptual and theoretical value for the analysis of EU–Turkey relations, arguing that an underlying path dependence in the accession process is the result of security considerations. The chapter continues by identifying several critical junctures which have intervened, and both expedited and hampered the process. The opposition of member states, the Arab Spring, and authoritarian drift within Turkey are important factors in this context. On this basis, the analysis shows how progress achieved has typically been countered by opposition, often related to human rights concerns. As a result, the accession process has stagnated but has endured at the same time as security interests and human rights concerns have balanced each other over time.
Differentiated Integration: An Alternative Conceptualization of EU–Turkey Relations
Authors: Tekin Funda
Published: June 2021

This chapter introduces the concept of differentiated integration and discusses its explanatory value in view of the EU–Turkey relationship. The major aim is to elaborate whether variable geometries as a form of differentiation constituting different and sometimes even overlapping forms of association and integration with different member and non-member states can provide a soft-landing from the fallout of Turkey’s EU accession process. The chapter sets out the many faces of differentiation and examines how the conceptual approach is perceived in the European and Turkish debates. The analysis also provides a concise overview on how differentiated integration is embedded in the logics of the main European integration theories. This conceptual discussion is complemented by a detailed outline of the variable geometries that already exist in EU–Turkey relations resulting from the three distinct forms of bilateral dialogue: accession process, functional cooperation, and cooperation in international organizations. The chapter concludes by linking the empirical findings back to the conceptual analysis, thereby discussing the limits of the explanatory value of the concept as well as highlighting the modernization of the Customs Union as a potential starting point for a differentiated future of EU–Turkey relations.
The European Commission’s Role in EU–Turkey Relations
Authors: Bürgin Alexander
Published: June 2021

Based on a review of the relations between the European Commission (EC) and Turkey across a selection of policy areas, this chapter illustrates two aspects of EC influence in EU–Turkey relations. First, as a defender of the rules of the (enlargement) game, the Commission has rebuffed attempts by some member states to undermine Turkey’s membership prospects. The EC’s influence in the debate on the most appropriate approach to Turkey underlines its autonomous role within the EU system and the relevance of its norm-based argumentation. However, due to Turkey’s current alienation from the EU’s normative standards, norm-based arguments in favor of Turkey’s membership have lost much of their weight even within the Commission. Second, the EC has been an important ‘agent of change’ in Turkish domestic politics, even in times of deteriorating political relations with the EU. Because of its contributions to regular interactions, in particular, in the framework of projects financed by the EU’s Instrument for Pre-Accession Assistance, the EC has continued to increase administrative capacity and policy learning processes within Turkey’s bureaucracy, which, in turn, contributed to Ankara’s continued harmonization with the EUacquisin some sectors, despite the waning relevance of the EU’s conditionality strategy.
Fracture-induced pain-like behaviours in a femoral fracture mouse model
Authors: Magnusdottir R. , Gohin S. , ter Heegde F. , Hopkinson M. , McNally I.F. , Fisher A. , Upton N. , Billinton A. , Chenu C.
Published: June 2021

This study is the first comprehensive characterisation of the pain phenotype after fracture using both evoked and naturalistic behaviours in adult male and ovariectomised female mice. It also shows that an anti-nerve growth factor (NGF) therapy could be considered to reduce pain after fracture surgery.

Introduction

Bone fractures are common due to the ageing population and very painful even after healing. The phenotype of this pain is still poorly understood. We aimed to characterise it in a femoral fracture model in mice.

Methods

We employed both adult male, and female ovariectomised (OVX) mice to mimic osteoporotic fractures. Mice underwent a unilateral femoral fracture maintained by an external fixator or a sham surgery. Pain behaviours, including mechanical and thermal sensitivity, weight bearing and LABORAS, were measured from baseline to 6 weeks after fracture. The effect on pain of an antibody against nerve growth factor (anti-NGF) was assessed. Changes in nerve density at the fracture callus were analysed by immunohistochemistry.

Results

Following surgery, all groups exhibited high levels of invoked nociception. Mechanical and thermal hyperalgesia were observed from 1 week after surgery, with nociceptive sensitization in the fracture group maintained for the 6 weeks, whereas it resolved in the sham group after 3 weeks. OVX induced reduction in pain thresholds, which was maintained after fracture. The frequency of naturalistic behaviours did not change between groups. Anti-NGF administered before and weekly after surgery alleviated fracture-induced mechanical nociception. The density of nerve fibres in the fracture callus was similar in all groups 6 weeks after surgery.

Conclusions

Fractures in rodent models are highly painful in both sexes. This pain-like phenotype is prolonged and should be routinely considered in fracture healing studies as it can affect the study outcome. The anti-NGF alleviates fracture-induced mechanical pain.
Correction to: Optimized hidden target screening for very polar molecules in surface waters including a compound database inquiry
Authors: Minkus Susanne , Grosse Sylvia , Bieber Stefan , Veloutsou Sofia , Letzel Thomas
Published: June 2021

A Correction to this paper has been published: https://doi.org/10.1007/s00216-021-03427-z
Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors
Authors: Pilla Reddy Venkatesh , Fretland Adrian J. , Zhou Diansong , Sharma Shringi , Chen Buyun , Vishwanathan Karthick , McGinnity Dermot F. , Xu Yan , Ware Joseph A.
Published: June 2021

Purpose

Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown.

Methods

A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data.

Results

While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin.

Conclusion

Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.
Free flap for soft palate reconstruction: long-term functional evaluation of a new technique
Authors: Colliard A. , Pincet L. , Simon C. , May L. , Lambercy K.
Published: June 2021

Purpose

The soft palate (SP) has a complex anatomy and physiology. Reconstruction after tumour resection is a challenge, and procedures that only restore bulk don’t give good results. We aim to present a new technique for the in-setting and the functional outcomes.

Methods

We retrospectively included in a monocentric retrospective cohort study every patient with a first diagnosis of a soft palate squamous cell carcinoma (SPSCC), who underwent a tumoral resection with a free flap reconstruction, from February 2013 to July 2017. For the in-setting, a special care is given for the flap in-setting: we suture the flap more caudally than usual under the tongue base, creating a neo-posterior pilar. The primary outcome was the deglutition function, assessed by the M. D Anderson Dysphagia Inventory (MDADI). We also analyzed the patient’s quality of life with the FOSS score and the occurrence of nasal regurgitation or larynx aspiration.

Results

We included twenty patients, with a median follow-up of 26.5 months. The median MDADI score was 89, and the mode was 93. A Fisher test shows a significant improvement of MDADI scores for unilateral vs bilateral reconstructions (p = 0.03). The median FOSS score was 2, and the mode was 2. Seven (35%) patients complained of nasal regurgitation, three (15%) reported episodic laryngeal aspiration.
The effects of health shocks on family status: do financial incentives encourage marriage?
Authors: Ehlert Andree
Published: June 2021

This paper asks whether marriage decisions of unmarried mature couples are driven by the prospect of financial advantages for the later widowed after one partner has suffered a serious health shock. We hypothesize that, in contrast to traditional marriage models, such health shocks may induce unmarried couples to obtain economic benefits, such as survivors’ pensions in particular, through marriage in advance of one partner’s death. This question has not yet been studied empirically. Hazard models capturing unobserved effects are applied to longitudinal data of the German Socioeconomic Panel. It turns out that the probability of marriage after male partners’ health shocks can increase significantly depending on the amount of expected survivors’ pensions for the (likely) surviving female partners. In contrast, an increased probability of marriage after health shocks to women (depending on the expected financial benefits to men) was not found. These findings are supported by various robustness checks. Economic and political implications are discussed and the results are placed in an international context.
Combining 4D Flow MRI and Complex Networks Theory to Characterize the Hemodynamic Heterogeneity in Dilated and Non-dilated Human Ascending Aortas
Authors: Calò Karol , Gallo Diego , Guala Andrea , Rodriguez Palomares Jose , Scarsoglio Stefania , Ridolfi Luca , Morbiducci Umberto
Published: June 2021

Motivated by the evidence that the onset and progression of the aneurysm of the ascending aorta (AAo) is intertwined with an adverse hemodynamic environment, the present study characterized in vivo the hemodynamic spatiotemporal complexity and organization in human aortas, with and without dilated AAo, exploring the relations with clinically relevant hemodynamic and geometric parameters. The Complex Networks (CNs) theory was applied for the first time to 4D flow magnetic resonance imaging (MRI) velocity data of ten patients, five of them presenting with AAo dilation. The time-histories along the cardiac cycle of velocity-based quantities were used to build correlation-based CNs. The CNs approach succeeded in capturing large-scale coherent flow features, delimiting flow separation and recirculation regions. CNs metrics highlighted that an increasing AAo dilation (expressed in terms of the ratio between the maximum AAo and aortic root diameter) disrupts the correlation in forward flow reducing the correlation persistence length, while preserving the spatiotemporal homogeneity of secondary flows. The application of CNs to in vivo 4D MRI data holds promise for a mechanistic understanding of the spatiotemporal complexity and organization of aortic flows, opening possibilities for the integration of in vivo quantitative hemodynamic information into risk stratification and classification criteria.
Die Differenz Haushalt vs. Markt als latentes Beobachtungsschema
Authors: Wobbe Theresa
Published: June 2021

Ausgehend von der Teilung in nichtaktive (Haushalt) und aktive Bevölkerung (Markt) fragt der Beitrag nach der Rolle, die statistische Vergleichsverfahren bei dieser Grenzziehung in der Welt der Arbeit spielen. Dies geschieht vor dem Hintergrund der Verzweigung von zwei strukturellen Entwicklungen, nämlich dem Wandel der (Arbeits‑)Welten und der statistischen Vergleichsverfahren. Der Beitrag gehört zu den ersten, der diese Nahtstelle systematisch und empirisch an der nationalen und internationalen (Beschäftigungs‑)Statistik untersucht. In diesem Beitrag schlage ich vor, die beiden Beobachtungsebenen als ein Feld der inter/nationalen Statistik zu verstehen. Ihre Ähnlichkeiten, Unterschiede und Verzweigungen werden soziologisch bislang noch nicht wahrgenommen. Im Unterschied dazu behandele ich sie aus einer wissensgeschichtlichen und wissenssoziologischen Perspektive gemeinsam hinsichtlich ihrer Selektionsleistungen, Beobachtungsinstrumente und Beschreibungsebenen. Die Ergebnisse zeigen die zunehmende Spezifizierung und Ausdehnung der ökonomischen Dimension von Arbeitstätigkeiten, die durch die Ordnungstechniken der inter/nationalen Statistik, verstärkt nach 1945, forciert werden. Diese Verschiebungen, so das Argument, sind eng mit dem Aufstieg des technischen Wissens im „technical internationalism“ verbunden, die nach 1945 das statistische und das Alltagsverständnis von der wirtschaftlich nichtaktiven Haushaltsarbeit bekräftigen.
Leveraging inner sustainability through cross-cultural learning: evidence from a Quichua field school in Ecuador
Authors: Gray Konrad , Manuel-Navarrete David
Published: June 2021

Inner worlds and subjectivity are increasingly recognized as key dimensions of sustainability transformations. This paper explores the potential of cross-cultural learning and Indigenous knowledge as deep leverage points—hard to pull but truly transformative—for inner world sustainability transformations. In this exploratory study we propose a theoretical model of the inner transformation–sustainability nexus based on three distinctive inside-out pathways of transformation. Each pathway is activated at the inner world of individuals and cascades through the outer levels (individual and collective) of the iceberg model, ultimately resulting in transformations of the individual’s relationship with others, non-humans, or oneself. Our main purpose is to empirically investigate the activation of inner leverage points among graduate students who are alumni of an Indigenous language field school in the Ecuadorian Amazon. Semi-structured interviews designed around three core aspects—(1) human–nature relationships; (2) subjective change; and (3) acknowledgment for Indigenous culture—yielded expressions of becoming aware of new forms of relationships and empirically illustrate the roles of deep leverage points in triggering the three inside-out pathways of our model. A strategic focus on activating inner levers could increase the effectiveness of cross-cultural learning in fostering transformations in relationships with non-humans, oneself and others that may yield sustainability outcomes.
Aluminum Recovery from White Aluminum Dross by a Mechanically Activated Phase Separation and Remelting Process
Authors: Kudyba Artur , Akhtar Shahid , Johansen Inge , Safarian Jafar
Published: June 2021

The aluminum recovery from white aluminum dross by a mechanical treatment and sizing followed by remelting process was investigated. The dross was subjected to a ball mill, and the obtained particles were sized in different ranges. They were studied by advanced materials characterization techniques. It was found that the larger particles contain high metallic portions, and most non-metallic components of the dross are in the fine fraction < 1 mm. The Al-rich particles (> 1 mm) were remelted at 900°C to recover aluminum. It was found that the metal structure after remelting is homogeneous and consisted of a dominant metallic aluminum matrix, containing an average of > 96% Al with around 99% total metallic components. The results show that the applied method is a good economic alternative for the aluminum recovery from white dross, which is important for the valorization/recycling of industrial waste and circular economy.
A new framework for teaching scientific reasoning to students from application-oriented sciences
Authors: Vaesen Krist , Houkes Wybo
Published: June 2021

About three decades ago, the late Ronald Giere introduced a new framework for teaching scientific reasoning to science students. Giere’s framework presents a model-based alternative to the traditional statement approach—in which scientific inferences are reconstructed as explicit arguments, composed of (single-sentence) premises and a conclusion. Subsequent research in science education has shown that model-based approaches are particularly effective in teaching science students how to understand and evaluate scientific reasoning. One limitation of Giere’s framework, however, is that it covers only one type of scientific reasoning, namely the reasoning deployed in hypothesis-driven research practices. In this paper, we describe an extension of the framework. More specifically, we develop an additional model-based scheme that captures reasoning in application-oriented practices (which are very well represented in contemporary science). Our own teaching experience suggests that this extended framework is able to engage a wider audience than Giere’s original. With an eye on going beyond such anecdotal evidence, we invite our readers to test out the framework in their own teaching.
Adsorption isotherm modeling for methylene blue removal onto magnetic kaolinite clay: a comparison of two-parameter isotherms
Authors: Shikuku Victor O. , Mishra Trilochan
Published: June 2021

In this work, kaolinite clay was modified with magnetic magnetite nanoparticles (Fe3O4@MC) by co-precipitation with ferrous and ferric ions as iron precursors to ameliorate its textural and adsorption capacity for methylene blue (MB) dye uptake from synthetic wastewater at low concentrations. The adsorbents were characterized using XRD, BET surface area analysis, VSM, SEM and HRTEM. The BET surface area after chemical treatment increased from 14.616 to 26.913 m2 g−1. The saturation magnetization of Fe3O4@MC was 6.22 emu g−1 and the exhausted adsorbent recoverable by a simple magnet. Adsorption data were modeled using six nonlinear two-parameter isotherm equations, namely Freundlich, Temkin, Fowler–Guggenheim, Elovich, Flory–Huggins and Langmuir model, and the best-fitting model arrived at using three mathematical error functions. MB adsorption onto unmodified clay was best described by the Fowler–Guggenheim isotherm, whereas MB adsorption onto Fe3O4@MC was best described by the Freundlich model. Increase in BET surface area increased the theoretical and experimental maximum adsorption capacity
Effect of immigration time and beetle density on development of the cabbage stem flea beetle, (Psylliodes chrysocephala L.) and damage potential in winter oilseed rape
Authors: Conrad Nils , Brandes Meike , Ulber Bernd , Heimbach Udo
Published: June 2021

In a semi-field net cage experiment set up in three growing seasons (2015–2018) at Julius-Kühn Institute Braunschweig, Germany, the influence of different release times of adult cabbage stem flea beetles, Psylliodes chrysocephala (early September, mid-September, early October) and different beetle densities (6.7, 13.3 and 20 beetles/m2) on reproduction and damage potential in winter oil seed rape was investigated. In parallel to the cage trials, the number of deposited eggs was assessed in small boxes exposed in the field. Beetles released in early September laid significantly more eggs compared to beetles released early October, with a maximum of 270 eggs per female. The early release of beetles resulted in significantly higher numbers of larvae in autumn, but this differed significantly between the years. Warm autumn or winter conditions led to continued egg laying and development, whereas cold conditions stopped the reproduction. Significant yield losses (25%) and significant plant losses during winter were only found in 2016/17 in treatments with an early release of high numbers of beetles (20 beetles /m2). The German damage threshold of 3–5 larvae per plant was reached when 13 beetles/m2 were released before 20th September and 20 beetles per m2 after 20th September. Data of this study can be used for a better damage prediction and a more targeted beetle control.
Process system analysis on oil processing facility and economic viability from oil well-to-tank
Authors: kazmi Bilal , Taqvi Syed Ali Ammar , Naqvi Muhammad , Ilyas Suhaib Umer , Moshin Ali , Inamullah Farah , Naqvi Salman R.
Published: June 2021

Hydrocarbon processing from extraction to the final product is an important aspect that needs an optimised technology for consumption-led market growth. This study investigated real data from the oil processing facility and analysed the simulation model for the entire crude oil processing unit based on the process system engineering aspect using Aspen HYSYS. The study mainly emphasises the process optimisation in processing the hydrocarbon for the maximum yield of the product with less energy consumption. The investigation also includes a thorough economic analysis of the processing facility. The datasets for oil properties are obtained from a modern petroleum refinery. The investigation comprises of varying transient conditions, such as well shutdowns using three oil reservoirs (low, intermediate, and heavy oil). The impact of various conditions, including process heating, well shutdown, oil combinations, presence of water on the production, is analysed. The results indicate that the factors involving crude oil processing are significantly affected by the process conditions, such as pressure, volume, and temperature. The vapour recovery unit is integrated with the oil processing model to recover the separator's gas. The optimisation analysis is performed to maximise the liquid recovery with Reid vapour pressure of 7 and minimum water content in oil around 0.5%. Economic analysis provided an overall capital cost of $ 9.7 × 106 and an operating cost of $2.1 × 106 for the process configuration. The model results further investigate the constraints that maximise the overall energy consumption of the process and reduce the operational cost.