bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cost-effectiveness analysis of pembrolizumab with or without chemotherapy for the treatment of patients with metastatic, non-squamous non-small cell lung cancer and high PD-L1 expression in Switzerland
Authors: Barbier Michaela Carla , Pardo Esther , Panje Cédric Michael , Gautschi Oliver , Lupatsch Judith Eva ,   for the Swiss Group for Clinical Cancer Research (SAKK)
Published: March 2021

Abstract
Introduction
Pembrolizumab monotherapy or in combination with chemotherapy are two new treatment options for patients with metastatic non-squamous non-small cell lung cancer (NSCLC) and high (≥ 50%) programmed death ligand 1 (PD-L1) expression. We conducted a cost-effectiveness analysis for Switzerland comparing these two options but also pembrolizumab to chemotherapy.

Methods
We constructed a 3-state Markov model with a time horizon of 10 years. Parametric functions were fitted to Kaplan–Meier overall survival (OS) and progression-free survival (PFS) using 2-year follow-up data from the KN-024 and KN-189 registration trials. We included estimated costs for further treatment lines and costs for best supportive care. Costs were assessed from the Swiss healthcare payer perspective. We used published utility values.

Results
Combination therapy resulted in an expected gain of 0.17 quality-adjusted life years (QALYs) per patient and incremental costs of Swiss Francs (CHF) 81,085 as compared to pembrolizumab. These estimates led to an incremental cost-effectiveness ratio (ICER) of CHF 475,299/QALY. Pembrolizumab in comparison to chemotherapy was estimated to generate mean incremental QALYs of 0.83 and incremental costs of CHF 56,585, resulting in an ICER of CHF 68,580/QALY. Results were most sensitive to changes in costs of 1L pembrolizumab and combination therapy, together with changes in PFS. In the probabilistic sensitivity analysis, we estimated combination therapy was cost-effective in 4.9% of the simulations and pembrolizumab monotherapy in 82.9%, assuming a willingness-to-pay threshold of CHF 100,000 per QALY gained.

Conclusions
Pembrolizumab is likely to be cost-effective from the Swiss healthcare payer perspective, whereas pembrolizumab plus chemotherapy is not.
Forest inventory-based assessments of the invasion risk of Pseudotsuga menziesii (Mirb.) Franco and Quercus rubra L. in Germany
Authors: Bindewald A. , Miocic S. , Wedler A. , Bauhus J. 
Published: March 2021

AbstractIn Europe, some non-native tree species (NNT) are classified as invasive because they have spread into semi-natural habitats. Yet, available risk assessment protocols are often based on a few limited case studies with unknown representativeness and uncertain data quality. This is particularly problematic when negative impacts of NNT are confined to particular ecosystems or processes, whilst providing valuable ecosystem services elsewhere. Here, we filled this knowledge gap and assessed invasion risks of two controversially discussed NNT in Germany (Quercus rubra L., Pseudotsuga menziesii (Mirb.) Franco) for broad forest types using large scale inventory data. For this purpose, establishment success of natural regeneration was quantified in terms of cover and height classes. The current extent of spread into protected forest habitats was investigated in south-west Germany using regional data. Establishment was most successful at sites where the NNT are abundant in the canopy and where sufficient light is available in the understory. Natural regeneration of both NNT was observed in 0.3% of the total area of protected habitats. In forest habitats with sufficient light in the understory and competitively inferior tree species, there is a risk that Douglas fir and red oak cause changes in species composition in the absence of management interventions. The installation of buffer zones and regular removal of unwanted regeneration could minimize such risks for protected areas. Our study showed that forest inventories can provide valuable data for comparing the establishment risk of NNT amongst ecosystem types, regions or jurisdictions. This information can be improved by recording the abundance and developmental stage of widespread NNT, particularly in semi-natural ecosystems.
A multidisciplinary investigation of deep-seated landslide reactivation triggered by an extreme rainfall event: a case study of the Monesi di Mendatica landslide, Ligurian Alps
Authors: Notti Davide , Wrzesniak Aleksandra , Dematteis Niccolò , Lollino Piernicola , Fazio Nunzio Luciano , Zucca Francesco , Giordan Daniele 
Published: March 2021

AbstractIn November 2016, an extreme rainfall event affected the Ligurian Alps (NW Italy). Consequently, several landslides and debris flows occurred in the upper Tanarello stream basin. In particular, the village of Monesi di Mendatica was severely damaged by two landslide phenomena: the activation of a rotational landslide, which caused the total collapse of two buildings and part of the main road, and the reactivation of a deep-seated planar massive and a complex landslide, which widely fractured most of the buildings in the village. The latter phenomenon was mostly unknown and had never been monitored prior to the 2016 event. Due to the extensive damage, the village of Monesi was completely evacuated, and the road connecting a ski resort area in the upper part of the valley was closed. Furthermore, a potentially dangerous situation related to the eventual progressive evolution of this landslide that could cause a temporary occlusion of the Tanarello stream still remains. For this reason, we defined the landslide behaviour, triggering conditions and chronological evolution leading to the 2016 event using a multidisciplinary approach. This approach consisted of field surveys, satellite DInSAR time series analyses, digital image correlation techniques, rainfall records analyses, postevent monitoring campaigns and subsurface investigation data analyses, and numerical modelling. This multidisciplinary approach enhanced our understanding of this landslide, which is fundamental to better comprehend its behaviour and possible evolution.
Angiodiversity and organotypic functions of sinusoidal endothelial cells
Authors: Koch Philipp-Sebastian , Lee Ki Hong , Goerdt Sergij , Augustin Hellmut G. 
Published: March 2021

Abstract‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.
Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study
Authors: Kuemmel Sherko , Tondini Carlo A. , Abraham Jacinta , Nowecki Zbigniew , Itrych Bartosz , Hitre Erika , Karaszewska Bogusława , Juárez-Ramiro Alejandro , Morales-Vásquez Flavia , Pérez-García Jose Manuel , Cardona-Huerta Servando , Monturus Estefania , Sequi Marco , Restuccia Eleonora , Benyunes Mark , Martín Miguel 
Published: March 2021

Abstract
Purpose
Intravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC.

Methods
In this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy.

Results
At clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%.

Conclusions
Safety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies.

Trial registration
NCT02402712
Breast cancer treatment and survival differences in women in remote and socioeconomically disadvantaged areas, as demonstrated by linked data from New South Wales (NSW), Australia
Authors: Buckley Elizabeth , Elder Elisabeth , McGill Sarah , Kargar Zahra Shahabi , Li Ming , Roder David , Currow David 
Published: March 2021

Abstract
Introduction
Reducing variations in cancer treatment and survival is a key aim of the NSW Cancer Plan. Variations in breast cancer treatment and survival in NSW by remoteness and socioeconomic status of residence were investigated to determine benchmarks. Reducing variations in cancer treatment and survival is a key aim of the NSW Cancer Plan. Variations in breast cancer treatment and survival in NSW by remoteness and socioeconomic status of residence were investigated to determine benchmarks.

Methods
A retrospective cohort study used linked data for invasive breast cancers, diagnosed in May 2002 to December 2015 from the NSW Cancer Registry, with corresponding inpatient, and medical and pharmaceutical insurance data. Associations between treatment modalities, area socioeconomic status and residential remoteness were explored using logistic regression. Predictors of breast cancer survival were investigated using Kaplan–Meier product-limit estimates and multivariate competing risk regression.

Results
Results indicated a high 5-year disease-specific survival in NSW of 90%. Crude survival was equivalent by residential remoteness and marginally lower in lower socioeconomic areas. Competing risk regression showed equivalent outcomes by area socioeconomic status, except for the least disadvantaged quintile, which showed a higher survival. Higher sub-hazard ratios for death occurred for women with breast cancer aged 70 + years, and more advanced stage. Adjusted analyses indicated more advanced stage in lower socioeconomic areas, with less breast reconstruction and radiotherapy, and marginally less hormone therapy for women from these areas. Conversely, among these women who had breast conserving surgery, there was higher use of chemotherapy. Remoteness of residence was associated in adjusted analyses with less radiotherapy and less immediate breast reconstruction. In these short term data, remoteness of residence was not associated with lower survival.

Conclusion
This study provides benchmarks for monitoring future variations in treatment and survival.
Spacing and Interleaving Effects Require Distinct Theoretical Bases: a Systematic Review Testing the Cognitive Load and Discriminative-Contrast Hypotheses
Authors: Chen Ouhao , Paas Fred , Sweller John 
Published: March 2021

AbstractSpaced and interleaved practices have been identified as effective learning strategies which sometimes are conflated as a single strategy and at other times treated as distinct. Learning sessions in which studying information or practicing problems are spaced in time with rest-from-deliberate-learning periods between sessions generally result in better learning outcomes than massed practice without rest-from-deliberate-learning periods. Interleaved practice also consists of spaced sessions, but by interleaving topics rather than having rest-from-deliberate-learning periods. Interleaving is usually contrasted with blocking in which each learning topic is taught in a single block that provides an example of massed practice. The general finding that interleaved practice is more effective for learning than blocked practice is sometimes attributed to spacing. In the current paper, the presence of rest-from-deliberate-learning periods is used to distinguish between spaced and interleaved practice. We suggest that spaced practice is a cognitive load effect that can be explained by working memory resource depletion during cognitive effort with recovery during rest-from-deliberate-learning, while interleaved practice can be explained by the discriminative-contrast hypothesis positing that interleaving assists learners to discriminate between topic areas. A systematic review of the literature provides evidence for this suggestion.
On the Ontological Status of Mechanisms and Processes in the Social World
Authors: Delgado Henrique Estides 
Published: March 2021

AbstractThis paper gives a philosophical outline of the importance of plausible ontologies in the social sciences and argues how mechanisms and processes should be placed as the foundation in the social world. The argumentation is mainly based on a critical appraisal of the use of mechanisms and processes in the works of Norbert Elias, Charles Tilly, and Jon Elster. I start by elaborating on how inquiries of scientific interest evolve to shed light on cases, facts and the things that constitute such facts, whilst the actual explanation demands the description of mechanisms and processes. Basically, focusing on(co)variationanddifference makingis not sufficient to sustain claims of ontological plausibility and reasonableness. It is thus pointed out how the practices and proceedings of the social sciences can be ontologically enhanced by embracing the complementary roles ofmechanismsplusprocessestogether withdifference making,as is performed in a special science such as biology, as well as is informally but promisingly pursued in the works of the discussed social scientists. While discussing their work, it is also argued that we should differentiate between processes and mechanisms in order to formalize this approach, which highlights the role of technologies and institutions as prime building blocks for social explanation. I conclude by presenting a claim that in taking seriously that the purported relations between beings and entities need to make discursive sense and historical sense, the social sciences will increase our cognitive success about the things of the world.
The morphology of choroidal neovascularization in chronic central serous chorioretinopathy presenting with flat, irregular pigment epithelium detachment
Authors: Azzolini Claudio , Cattaneo Jennifer , Premoli Laura , Metrangolo Cristian , Chiaravalli Maurizio , Donati Simone 
Published: March 2021

Abstract
Purpose
To evaluate morphological characteristics of choroidal neovascularization in chronic central serous chorioretinopathy (CSC) presenting with flat and irregular pigment epithelium detachment (FIPED) by means of innovative multimodal imaging.

Methods
In this observational cross-sectional study, we examined 10 consecutive patients affected by chronic CSC and FIPED using fluorescein angiography (FA), indocyanine-green angiography (ICGA) and optical coherence tomography angiography (OCTA). A qualitative analysis of the nature and characteristics of neovascular membrane was performed, combining available multimodal imaging and literature data.

Results
Multiple areas of retinal pigment epithelium alterations, macular hypo- and hyperpigmentation and atrophic areas were identified. Spectral domain OCT (SD-OCT) showed subretinal fluid in 80% of eyes and the ‘double layer sign’ in all patients. Late FA phases showed staining areas without leakage in all eyes; ICGA showed a hyperfluorescent plaque with surrounding hypofluorescence in 80% of patients. OCTA detected characteristic neovascular networks in the outer retina within the FIPEDs, classified as filamentous vessels with a pruned tree-like pattern in five eyes and a tangled pattern in three eyes. The choriocapillaris network showed dark areas in 80% of eyes and diffuse dark spots in all eyes.

Conclusion
Multimodal imaging completes clinical characterization of FIPEDs in chronic CSC. This study using OCTA technology describes the phenotype of hidden neovascular lesions in shape and morphology.
Transforming variables to central normality
Authors: Raymaekers Jakob , Rousseeuw Peter J. 
Published: March 2021

AbstractMany real data sets contain numerical features (variables) whose distribution is far from normal (Gaussian). Instead, their distribution is often skewed. In order to handle such data it is customary to preprocess the variables to make them more normal. The Box–Cox and Yeo–Johnson transformations are well-known tools for this. However, the standard maximum likelihood estimator of their transformation parameter is highly sensitive to outliers, and will often try to move outliers inward at the expense of the normality of the central part of the data. We propose a modification of these transformations as well as an estimator of the transformation parameter that is robust to outliers, so the transformed data can be approximately normal in the center and a few outliers may deviate from it. It compares favorably to existing techniques in an extensive simulation study and on real data.
Mycochemicals in wild and cultivated mushrooms: nutrition and health
Authors: Cateni Francesca , Gargano Maria Letizia , Procida Giuseppe , Venturella Giuseppe , Cirlincione Fortunato , Ferraro Valeria 
Published: March 2021

AbstractThe mushrooms have contributed to the development of active ingredients of fundamental importance in the field of pharmaceutical chemistry as well as of important tools in human and animal health, nutrition, and functional food. This review considers studies on the beneficial effects of medicinal mushrooms on the nutrition and health of humans and farm animals. An overview of the chemical structure and composition of mycochemicals is presented in this review with particular reference to phenolic compounds, triterpenoids and sterols, fatty acids and lipids, polysaccharides, proteins, peptides, and lectins. The nutritional value and chemical composition of wild and cultivated mushrooms in Italy is also the subject of this review which also deals with mushrooms as nutraceuticals and the use of mushrooms in functional foods. The nutraceutical benefits of UV irradiation of cultivated species of basidiomycetes to generate high amounts of vitamin D2 is also highlighted and the ability of the muhsrooms to inhibit glycation is analyzed. Finally, attention is paid to studies on bioactivities of some Italian wild and cultivated mushrooms with particular reference to species belonging to the genus Pleurotus. The review highlights the potential of medicinal mushrooms in the production of mycochemicals that represent a source of drugs, nutraceutical, and functional food.
Graphic abstract
Shrub expansion in the Arctic may induce large‐scale carbon losses due to changes in plant‐soil interactions
Authors: Parker Thomas C. , Thurston Alana M. , Raundrup Katrine , Subke Jens-Arne , Wookey Philip A. , Hartley Iain P. 
Published: March 2021

Abstract
Background
Tall deciduous shrubs are increasing in range, size and cover across much of the Arctic, a process commonly assumed to increase carbon (C) storage. Major advances in remote sensing have increased our ability to monitor changes aboveground, improving quantification and understanding of arctic greening. However, the vast majority of C in the Arctic is stored in soils, where changes are more uncertain.

Scope
We present pilot data to argue that shrub expansion will cause changes in rhizosphere processes, including the development of new mycorrhizal associations that have the potential to promote soil C losses that substantially exceed C gains in plant biomass. However, current observations are limited in their spatial extent, and mechanistic understanding is still developing. Extending measurements across different regions and tundra types would greatly increase our ability to predict the biogeochemical consequences of arctic vegetation change, and we present a simple method that would allow such data to be collected.

Conclusions
Shrub expansion in the Arctic could promote substantial soil C losses that are unlikely to be offset by increases in plant biomass. However, confidence in this prediction is limited by a lack of information on how soil C stocks vary between contrasting Arctic vegetation communities; this needs to be addressed urgently.
Monty Hall three door ’anomaly’ revisited: a note on deferment in an extensive form game
Authors: Otto Philipp E. 
Published: March 2021

AbstractThe Monty Hall game is one of the most discussed decision problems, but where a convincing behavioral explanation of the systematic deviations from probability theory is still lacking. Most people not changing their initial choice, when this is beneficial under information updating, demands further explanation. Not only trust and the incentive of interestingly prolonging the game for the audience can explain this kind of behavior, but the strategic setting can be modeled more sophisticatedly. When aiming to increase the odds of winning, while Monty’s incentives are unknown, then not to switch doors can be considered as the most secure strategy and avoids a sure loss when Monty’s guiding aim is not to give away the prize. Understanding and modeling the Monty Hall game can be regarded as an ideal teaching example for fundamental statistic understandings.
A Note on the Three Dimensional Dirac Operator with Zigzag Type Boundary Conditions
Authors: Holzmann Markus 
Published: March 2021

AbstractIn this note the three dimensional Dirac operator$$A_m$$Amwith boundary conditions, which are the analogue of the two dimensional zigzag boundary conditions, is investigated. It is shown that$$A_m$$Amis self-adjoint in$$L^2(\Omega ;{\mathbb {C}}^4)$$L2(Ω;C4)for any open set$$\Omega \subset {\mathbb {R}}^3$$Ω⊂R3and its spectrum is described explicitly in terms of the spectrum of the Dirichlet Laplacian in$$\Omega $$Ω. In particular, whenever the spectrum of the Dirichlet Laplacian is purely discrete, then also the spectrum of$$A_m$$Amconsists of discrete eigenvalues that accumulate at$$\pm \infty $$±∞and one additional eigenvalue of infinite multiplicity.