bluuebunny/crossref_metadata_2025 huggingface dataset:
Terrestrial Arthropod Diversity in the United Arab Emirates
Authors: Howarth Brigitte
Published: October 2023

Despite harsh climatic conditions and low and erratic rainfall patterns, the United Arab Emirates’ (UAE) terrestrial arthropod fauna is diverse and extremely well adapted to the local environment, with some species occurring in high abundance. Until recently, the UAE’s terrestrial arthropods were poorly studied. The past two decades have seen the knowledge of arthropod diversity increase dramatically, with more than 4000 species now known to occur in the Emirates, including hundreds of species that were previously unknown for the UAE and had never been recorded globally. With so many species recently added to the inventory of the nation, their ecology (i.e., life cycles, interactions, habitat needs) are yet to be studied. This presents a challenge for conservation planning, but also offers many opportunities for further study of these organisms. Where the life-histories of species are known, they demonstrate that arthropods of the UAE are an integral part of local food webs and contribute essential ecosystem services. As is the case globally, the UAE’s arthropods are under threat from habitat loss and destruction. The lack of long-term monitoring programs means that it is currently not possible to assess whether the trend of arthropod biodiversity loss seen worldwide is echoed in the UAE.
Geography and Geology of the United Arab Emirates: A Naturalist’s Introduction
Authors: Feulner Gary R.
Published: October 2023

The main geographical divisions of the UAE include many sub-environments that nurture the country’s diverse plant and animal life. The UAE’s biogeographical position enhances its potential natural biodiversity. The beaches and sabkha of the Coastal Plains are punctuated by lagoons, mangroves, and even rocky headlands. The Sand Deserts grade from quartz sand megadunes inland to white carbonate sands along the Gulf. To the northeast, where they merge with the Alluvial Plain, they are increasingly well-vegetated. The Mountain Regions feature great diversity along many parameters. The Hajar Mountains are composed primarily of a suite of rocks, collectively called ‘ophiolite’, that once formed part of the ocean crust and upper mantle. Ophiolite rocks are associated elsewhere with low botanical diversity and high endemism. Hajar Mountain wadis sustain discrete freshwater habitats with a diverse array of life. The carbonate mountains of the Ru’us Al Jibal range (the Musandam mountains) and Jebel Hafeet differ significantly—physiographically, geochemically, hydrologically and floristically—from the Hajar Mountains. The tectonic collision of Arabia with Eurasia, commencing ca. 30 mya, enabled the extensive exchange of terrestrial and freshwater organisms. The Arabian Gulf is a shallow continental depression that has been emergent repeatedly during glacially lowered sea stands.
Sharks and Rays of the United Arab Emirates
Authors: Henderson Aaron C. , Al Hameli Shamsa
Published: October 2023

The waters of the United Arab Emirates (UAE) are home to a wide variety of shark and ray species, many of which are unique to the region and about which relatively little is known. Research efforts to date have focused primarily on identifying the species that occur locally and their importance to fisheries, but further research is required to understand their inherent biological and ecological traits. Decades of heavy fishing pressure and coastal development have impacted shark and ray populations to the extent that some, once common species, are now considered rare. Encouragingly, the UAE has adopted a National Plan of Action for the Conservation of Sharks to guide researchers and policy makers in their efforts to ensure that the nation’s shark and ray populations are effectively managed and conserved.
Cities as Ecosystems in the Emirates
Authors: Burt John A. , Campbell Oscar , Judas Jacky
Published: October 2023

The United Arab Emirates (UAE) has had dramatic economic and population growth since its 1971 federation, with the built environment, green spaces, water features and other urban amenities growing to support its burgeoning population. These features, in turn, often provide unique habitats and microenvironments for a wide variety of resident and migratory species that benefit from their association with urban ecosystems, both on land and in nearshore coastal environments. While urbanization has undoubtedly caused important environmental challenges that should not be discounted, our growing cities have developed unique and important ecologies, much of which remains underappreciated and understudied in the UAE. Here we summarize the current understanding of urban ecology in the Emirates, providing insights into features that make cities amenable environments for organisms, particularly in the context of the UAE’s extreme environment. We also discuss several representative groups of organisms that benefit from the artificial environments provided by cities in both terrestrial and marine urban settings.
The Emirates at 2050: Balancing Development and Environmental Stewardship
Authors: Burt John A. , Al-Mansoori Noura , Bejarano Ivonne , Brown Gary , Campbell Oscar , Els Johannes , Feulner Gary R. , Friis-Montoya Guillermo , Henderson Aaron , Howarth Brigitte , John David M. , Judas Jacky , Mateos-Molina Daniel , Mitchell Matthew , Natoli Ada , Paparella Francesco , Yaghmour Fadi
Published: October 2023

The United Arab Emirates (UAE) faces the challenge of balancing rapid economic development with environmental preservation and conservation in the Anthropocene era. The nation’s unique ecosystems, characterized by arid desert, rugged mountains, and diverse marine habitats, are vulnerable to disturbances such as urbanization, habitat degradation, groundwater extraction and climate change. To chart a more sustainable course for the Emirates by 2050, the paper proposes policy recommendations such as adopting a national strategy for sustainable development, strengthening environmental policies, investing in urban planning and design, promoting sustainable water management, encouraging use of nature-based solutions, addressing climate change, fostering environmental education, supporting research in environmental sciences, encouraging national and regional cooperation, promoting sustainable business practices in the private sector, and monitoring the progress of environmental policies. By embracing a vision of development that respects the natural environment and safeguards its plant and animal life, the UAE can demonstrate its commitment and serve as a model for other nations to follow, becoming a shining example of responsible development by 2050.
The Marine Environment of the Emirates
Authors: Burt John A. , Paparella Francesco
Published: October 2023

The United Arab Emirates (UAE) is bordered by two very different marine systems, the Arabian Gulf and the Sea of Oman. Both lie within the arid sub-tropical high pressure zone, but they are characterized by markedly different environmental conditions. Today’s Gulf is a shallow, enclosed sea (average depth < 30 m) that has only existed since the last ice age, and the modern Gulf coastline was established only about 6000 years ago. The waters of the UAE’s Gulf coast are characterized by extreme temperatures across seasons, evaporation-driven hyper-salinity, complex tides, high turbidity, and occasional low oxygen, among other stressors. The Sea of Oman, in contrast, is over a kilometer deep and is well mixed with the offshore waters of the Indian Ocean, experiencing essentially normal sub-tropical oceanic conditions as a result. Regional winds such as ‘shamals’ and the Indian Ocean monsoon play important roles in creating and structuring marine environmental conditions. Given the prospect of global climate change, the future of marine systems across the Emirates, including organisms and ecosystems, will largely depend on how regional winds will change in the coming decades.
The Vegetation of the United Arab Emirates and Ecosystem Management Issues
Authors: Brown Gary , Feulner Gary R.
Published: October 2023

This chapter discusses the terrestrial vegetation of the United Arab Emirates, and the main units are described in the context of broad habitat types. Despite the huge increase in human activity over the past decades, natural terrestrial habitat types continue to occupy, by far, the larger part of the country. However, they are often severely degraded. The main issues affecting the flora and vegetation are largely the same as in other arid parts of the world, with overgrazing remaining a serious challenge. With regard to tackling these major issues, the various emirates have begun to create a network of protected areas. Effective management plans are required to ensure that they fulfil their role in protecting the natural heritage of the country. If rigorously implemented, the recently introduced ‘grazing law’ in Abu Dhabi emirate could create a useful blueprint for a sustainable grazing regime outside of the protected areas, leading to an enhancement of ecosystem functioning over the longer term.
The Mountain Regions of the United Arab Emirates: An Ecosystem Perspective
Authors: Feulner Gary R.
Published: October 2023

The mountains of the eastern UAE and northern Oman have long been recognized as a distinct biogeographical province hosting a mix of regional, endemic and relict species. This chapter treats the mountain regions of the UAE for the first time as an ecological unit in their own right, independent of generalizations often primarily rooted in Oman-based studies. They are recognized as a system of interrelated but geologically, physiographically, geochemically, hydrologically, floristically, and sometimes faunistically discrete sub-units: the Hajar Mountains, the Ru′us Al Jibal, the Dibba Zone, Jebel Hafeet and related Foreland Ridges, and the Alluvial Plains. Wide-ranging field investigations have shown that the mix of plant species varies significantly among these ecological sub-units. The Hajar Mountains feature the world’s most extensive exposures of ultrabasic bedrock, which elsewhere have been associated with low botanical diversity and high endemism. Such relationships in the Hajar Mountains have been largely ignored, although recent fieldwork has identified a dozen or so species evidently sensitive to ultrabasic geochemistry. UAE mountain flora and fauna vary significantly with latitude, corresponding to both regional factors and higher elevations in the northerly Ru′us Al Jibal. Temporal change is accelerated by human activity, including the proliferation of dams and other infrastructure.
Mangrove Ecosystems of the United Arab Emirates
Authors: Friis Guillermo , Killilea Mary E.
Published: October 2023

Gray mangroves (Avicennia marina) represent the only evergreen forests of the United Arab Emirates (UAE), where they occur at the northern edge of the species’ range and are subject to extreme environmental conditions. Mangroves occur both throughout the western and eastern coasts of the seven Emirates, either in natural or restored populations. They act as ecosystem engineers, creating a habitat that is exploited by a wide variety of organisms, including species of conservation concern. As the only mangrove species of the Arabian Gulf, the gray mangroves represent a relevant asset for local communities. They provide numerous ecosystem services of cultural and socioeconomic importance, from their aesthetics and recreational uses in urban spaces to their role as carbon sinks or nursery habitats for species targeted for commercial fishing. Thanks to successful afforestation programs, the UAE mangroves are experiencing a steady recovery after severe cover losses resulting from the intense urban development that followed the 1970s oil boom, and nowadays they represent more than half of the total mangrove cover in the Arabian Gulf. However, national mangrove forests still face considerable threats derived from human activities. Active, long-term policies and management will be needed to ensure the survivorship of these critical ecosystems.
Coastal Lagoons (Khors) of the Emirates
Authors: Mateos-Molina Daniel , Pittman Simon J. , Antonopoulou Marina , Carpenter Stephen , Möller Mona , Muzaffar Sabir Bin , Bejarano Ivonne
Published: October 2023

Coastal lagoons represent one of the most productive and diverse ecosystems in the United Arab Emirates (UAE) due to their position at the dynamic transition zone between land and sea. UAE’s coastal lagoons, also known as khors, are home to a diverse assemblage of organisms, including many resident and endangered species that rely on the interconnected mosaics of habitat types (mangroves, seagrass, saltmarshes, mudflats) that also provide a wealth of benefits to society. These ecosystem characteristics, and the need to ensure their sustainable development, have made lagoons a high priority for conservation in the Emirates. Primarily located along the UAE’s Arabian Gulf coast, coastal lagoons have been highly impacted by urbanization that modifies or removes habitats and disturbs wildlife due to increased pollution from artificial light, noise and chemicals. Coastal lagoons in the UAE are in urgent need of protection to ensure that current and future generations continue to enjoy healthy coastal ecosystems. Integrated ecosystem-based management that is supported by local institutions and includes participatory monitoring through citizen science programmes will increase public engagement and advance progress towards the goal of living in harmony with nature.
Currency (Layering)
Authors: Mooij Annelieke
Published: October 2023

This chapter discusses the second phase of MLFT, namely layering. Layering is the process of concealing the origins of the funds before integrating them into the legal economy. As stated in the introduction it is not possible to draw clear lines between the phases. Layering is conducted through a combination of anonymous wallets and unregulated currencies. The previous chapter has focused on virtual wallets, this chapter will therefore focus on the currencies themselves. Currencies used in the Metaverse form an alternative to the regulated banking industry. There is therefore the risk that these currencies are not or underregulated. This chapter therefore starts in Sect. 6.2 by discussing cryptocurrencies. This section also includes a discussion on mixing services and decentralized cryptoexchanges (DEX). Section 6.3 continues by discussing the centralized currencies without the status of legal tender. These currencies include gaming currencies and currencies provided by platforms. Section 6.4 then continues by analyzing the currencies with the status of legal tender. These include the central bank digital currencies and cryptocurrencies that are recognized as legal tender such as Bitcoin. The chapter finishes in Sect. 6.5 with the conclusions and recommendations.
Non-fungible Tokens and Stateless Firms
Authors: Mooij Annelieke
Published: October 2023

This chapter discusses the additional risks on MLFT that are created by the Metaverse. These two risks as discussed in the introduction are the Non-Fungible Tokens and the anonymity created by the Metaverse. Section 8.1 starts by discussing Non-Fungible Tokens (NFTs) and the specific risk for MLFT. It considers both the risks from a financial aspect as well as the risk it poses for transferring information. Section 8.2 discusses the concept of stateless firms. The construction of the Metaverse makes it possible for firms to remain fully anonymous. Section 8.2 discusses how the risks of these stateless firms can be limited.
Influence of the mating design on the additive genetic variance in plant breeding populations
Authors: Lanzl Tobias , Melchinger Albrecht E. , Schön Chris-Carolin
Published: October 2023

Key message

Mating designs determine the realized additive genetic variance in a population sample. Deflated or inflated variances can lead to reduced or overly optimistic assessment of future selection gains.

The additive genetic variance $${V}_{A}$$

V
A

inherent to a breeding population is a major determinant of short- and long-term genetic gain. When estimated from experimental data, it is not only the additive variances at individual loci (QTL) but also covariances between QTL pairs that contribute to estimates of $${V}_{A}$$

V
A

. Thus, estimates of $${V}_{A}$$

V
A

depend on the genetic structure of the data source and vary between population samples. Here, we provide a theoretical framework for calculating the expectation and variance of $${V}_{A}$$

V
A

from genotypic data of a given population sample. In addition, we simulated breeding populations derived from different numbers of parents (P = 2, 4, 8, 16) and crossed according to three different mating designs (disjoint, factorial and half-diallel crosses). We calculated the variance of $${V}_{A}$$

V
A

and of the parameter b reflecting the covariance component in $${V}_{A},$$

V
A

,

standardized by the genic variance. Our results show that mating designs resulting in large biparental families derived from few disjoint crosses carry a high risk of generating progenies exhibiting strong covariances between QTL pairs on different chromosomes. We discuss the consequences of the resulting deflated or inflated $${V}_{A}$$

V
A

estimates for phenotypic and genome-based selection as well as for applying the usefulness criterion in selection. We show that already one round of recombination can effectively break negative and positive covariances between QTL pairs induced by the mating design. We suggest to obtain reliable estimates of $${V}_{A}$$

V
A

and its components in a population sample by applying statistical methods differing in their treatment of QTL covariances.
Experimental verification of the internal ballistics numerical simulations of classical weapons in Lagrangian coordinates
Authors: Kagankiewicz Filip , Magier Mariusz
Published: October 2023

Using the possibilities of modern science and technology, it can be said that the presented mathematical model has been formulated without significant simplifications, and its (numerical) solution itself will be performed with high accuracy. The main purpose of the work was to create a tool supporting the calculation of the main problem of internal ballistics for barrel propellant systems in order to achieve digital solutions as close as possible to the results obtained using experimental ballistics methods. The scientific hypothesis of the work postulates that the physical model of internal ballistics formulated in Lagrange coordinates will allow to solve the main problem of internal ballistics of barrel systems in a digital way, obtaining such solution results that will satisfactorily reflect the solution results obtained using experimental ballistics methods. The results of digital simulations of physical phenomena of solutions to the main problem of internal ballistics of barrel weapons were compared with the results of experimental tests and the degree of agreement was determined.
Combined analytical approach empowers precise spectroscopic interpretation of subcellular components of pancreatic cancer cells
Authors: Szymoński Krzysztof , Skirlińska-Nosek Katarzyna , Lipiec Ewelina , Sofińska Kamila , Czaja Michał , Wilkosz Natalia , Krupa Matylda , Wanat Filip , Ulatowska-Białas Magdalena , Adamek Dariusz
Published: October 2023

The lack of specific and sensitive early diagnostic options for pancreatic cancer (PC) results in patients being largely diagnosed with late-stage disease, thus inoperable and burdened with high mortality. Molecular spectroscopic methodologies, such as Raman or infrared spectroscopies, show promise in becoming a leader in screening for early-stage cancer diseases, including PC. However, should such technology be introduced, the identification of differentiating spectral features between various cancer types is required. This would not be possible without the precise extraction of spectra without the contamination by necrosis, inflammation, desmoplasia, or extracellular fluids such as mucous that surround tumor cells. Moreover, an efficient methodology for their interpretation has not been well defined. In this study, we compared different methods of spectral analysis to find the best for investigating the biomolecular composition of PC cells cytoplasm and nuclei separately. Sixteen PC tissue samples of main PC subtypes (ductal adenocarcinoma, intraductal papillary mucinous carcinoma, and ampulla of Vater carcinoma) were collected with Raman hyperspectral mapping, resulting in 191,355 Raman spectra and analyzed with comparative methodologies, specifically, hierarchical cluster analysis, non-negative matrix factorization, T-distributed stochastic neighbor embedding, principal components analysis (PCA), and convolutional neural networks (CNN). As a result, we propose an innovative approach to spectra classification by CNN, combined with PCA for molecular characterization. The CNN-based spectra classification achieved over 98% successful validation rate. Subsequent analyses of spectral features revealed differences among PC subtypes and between the cytoplasm and nuclei of their cells. Our study establishes an optimal methodology for cancer tissue spectral data classification and interpretation that allows precise and cognitive studies of cancer cells and their subcellular components, without mixing the results with cancer-surrounding tissue. As a proof of concept, we describe findings that add to the spectroscopic understanding of PC.

Graphical Abstract
MRI characteristics and oncological follow-up of patients with ISUP grade group 4 or 5 prostate cancer
Authors: Boschheidgen M. , Schimmöller L. , Kastl R. , Drewes L. R. , Jannusch K. , Radke K. L. , Kirchner J. , Ullrich T. , Niegisch G. , Albers P. , Antoch G. , Radtke J. P.
Published: October 2023

Objectives

To analyze multiparametric MRI (mpMRI) characteristics of patients with International Society of Urological Pathology (ISUP) grade group (GG) 4 or 5 prostate cancer (PC) and to correlate MRI parameters with the occurrence of biochemical recurrence (BCR) after radical prostatectomy (RPE).

Methods

In this single-center cohort study consecutive patients with mpMRI and ISUP GG 4 or 5 PC were retrospectively analyzed. Clinical, MR-guided biopsy, and diagnostic mpMRI parameter were assessed. A subcohort of patients with RPE and follow-up was analyzed separately. A univariate and multivariate analyses were performed to determine parameters that are associated to patients with BCR after RPE.

Results

145 patients (mean age 70y, median PSA 10.9 ng/ml) were analyzed. 99% had a PI-RADS classification of 4 or 5, 48% revealed MRI T3 stage, and median diameter of the MRI index lesion (IL) was 15 mm. IL showed a median ADC value of 668 ×10−6 mm2/s and exhibited contrast enhancement in 94% of the cases. For patients with follow-up after RPE (n = 82; mean follow-up time 68 ± 27 m), MRI parameters were significantly different for contact length of the IL to the pseudocapsule (LCC), MRI T3 stage, and IL localization (p < 0.05). Higher PSAD and MRI T3 stage were independent parameters for the risk of BCR when incorporating clinical, biopsy, and MRI parameters.

Conclusion

ISUP GG 4 or 5 PC has distinctive characteristics on mpMRI and were detected on MRI in all cases. In addition, higher PSAD and MRI T3 stage were significant predictors for BCR after RPE.
Are novel oral oncolytics underdosed in obese patients?
Authors: Lin Lishi , van der Meer Ellen K. O. , Steeghs Neeltje , Beijnen Jos H. , Huitema Alwin D. R.
Published: October 2023

Purpose

Data on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight and body mass index (BMI) on trough levels of oral oncolytics with an exposure–response relationship. The oral oncolytics of interest were abiraterone, alectinib, cabozantinib, crizotinib, imatinib, pazopanib, sunitinib and trametinib.

Methods

This retrospective cohort study included patients treated with the selected oral oncolytics at the standard dose, with a measured trough level at steady state and with available body weight. The Spearman’s correlation test was used to determine the correlation between body weight and trough levels. The Fisher’s exact text was used to compare the frequency of inadequate trough levels between BMI categories.

Results

1265 patients were included across the different oral oncolytics. A negative correlation coefficient was observed between weight and trough levels for crizotinib (n = 75), imatinib (n = 201) and trametinib (n = 310), respectively, ρ = − 0.41, ρ = − 0.24 and ρ = − 0.23, all with a p-value < 0.001. For crizotinib, a higher percentage of patients with a body weight > 100 kg had inadequate trough levels. No statistically significant differences were observed in the frequency of inadequate trough levels between BMI categories.

Conclusion

Higher body weight was only correlated with lower plasma trough levels for crizotinib, imatinib, and trametinib. Therefore, patients with a high body weight may require dose escalation to obtain adequate target levels when treated with these oral oncolytics.
Predicting estimated glomerular filtration rate after partial and radical nephrectomy based on split renal function measured by radionuclide: a large-scale retrospective study
Authors: Zheng Wanxiang , Hou Guangdong , Ju Dongen , Yan Fei , Liu Kepu , Niu Zhiping , Huang Luguang , Xing Zibao , Kong Lingchen , Liu Pengfei , Zhang Geng , Wei Di , Yuan Jianlin
Published: October 2023

Purpose

The purpose of this study was to develop predictive models for postoperative estimated glomerular filtration rate (eGFR) based on the split glomerular filtration rate measured by radionuclide (rGFR), as choosing radical nephrectomy (RN) or partial nephrectomy (PN) for complex renal masses requires accurate prediction of postoperative eGFR.

Methods

Patients who underwent RN or PN for a single renal mass at Xijing Hospital between 2008 and 2022 were retrospectively included. Preoperative split rGFR was evaluated using technetium-99 m-diethylenetriaminepentaacetic acid (Tc-99 m DTPA) renal dynamic imaging, and the postoperative short-term (< 7 days) and long-term (3 months to 5 years) eGFRs were assessed. Linear mixed-effect models were used to predict eGFRs, with marginal R2 reflecting predictive ability.

Results

After excluding patients with missing follow-up eGFRs, the data of 2251 (RN: 1286, PN: 965) and 2447 (RN: 1417, PN: 1030) patients were respectively included in the long-term and short-term models. Two models were established to predict long-term eGFRs after RN (marginal R2 = 0.554) and PN (marginal R2 = 0.630), respectively. Two other models were established to predict short-term eGFRs after RN (marginal R2 = 0.692) and PN (marginal R2 = 0.656), respectively. In terms of long-term eGFRs, laparoscopic and robotic surgery were superior to open surgery in both PN and RN.

Conclusions

We developed novel tools for predicting short-term and long-term eGFRs after RN and PN based on split rGFR that can help in preoperative decision-making.
Prognostic factors in patients with high-risk stage II colon cancer after curative resection: a post hoc analysis of the JFMC46-1201 trial
Authors: Sugimoto Kiichi , Sakamoto Kazuhiro , Tsuchiya Takashi , Takahashi Takao , Ohge Hiroki , Sato Toshihiko , Taguri Masataka , Morita Satoshi , Sadahiro Sotaro
Published: October 2023

Purpose

The goal of the current study was to identify prognostic factors for disease-free survival (DFS) and overall survival (OS) in high-risk stage II colon cancer.

Methods

The subjects were patients with histologically confirmed stage II colon cancer undergoing R0 resection who met at least one of the following criteria: T4, perforation/penetration, poorly differentiated adenocarcinoma, mucinous carcinoma, and < 12 examined lymph nodes. Patients self-selected surgery alone or a 6-month oral uracil and tegafur plus leucovorin (UFT/LV) regimen. Serum CEA mRNA at ≥ 24 h after surgery and < 2 weeks after registration was also examined as a potential prognostic factor for stage II colon cancer. This study is registered with UMIN-CTR (protocol ID: UMIN000007783).

Results

1880 were included in the analysis to identify prognostic factors for DFS and OS in patients with high-risk stage II colon cancer. In multivariate analyses, gender, depth of tumor invasion, extent of lymph node dissection, number of examined lymph nodes, and postoperative adjuvant chemotherapy (POAC) emerged as significant independent prognostic factors for DFS. Similarly, multivariate analysis showed that age, gender, depth of tumor invasion, perforation/penetration, extent of lymph node dissection, number of examined lymph nodes, and POAC were significant independent prognostic factors for OS. Univariate analyses showed no significant difference in DFS or OS for CEA mRNA-positive and mRNA-negative cases.

Conclusion

This study showed that gender, depth of tumor invasion, extent of lymph node dissection, number of examined lymph nodes, and lack of use of POAC were significant independent prognostic factors in stage II colon cancer.
Ocrelizumab exposure in relapsing–remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension
Authors: Kappos Ludwig , Traboulsee Anthony , Li David K. B. , Bar-Or Amit , Barkhof Frederik , Montalban Xavier , Leppert David , Baldinotti Anna , Schneble Hans-Martin , Koendgen Harold , Sauter Annette , Wang Qing , Hauser Stephen L.
Published: October 2023

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing–remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.
Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment
Authors: Delgado Silvia R. , Faissner Simon , Linker Ralf A. , Rammohan Kottil
Published: October 2023

The recent success of anti-CD20 monoclonal antibody therapies in the treatment of multiple sclerosis (MS) has highlighted the role of B cells in the pathogenesis of MS. In people with MS, the inflammatory characteristics of B-cell activity are elevated, leading to increased pro-inflammatory cytokine release, diminished anti-inflammatory cytokine production and an accumulation of pathogenic B cells in the cerebrospinal fluid. Rituximab, ocrelizumab, ofatumumab, ublituximab and BCD-132 are anti-CD20 therapies that are either undergoing clinical development, or have been approved, for the treatment of MS. Despite CD20 being a common target for these therapies, differences have been reported in their mechanistic, pharmacological and clinical characteristics, which may have substantial clinical implications. This narrative review explores key characteristics of these therapies. By using clinical trial data and real-world evidence, we discuss their mechanisms of action, routes of administration, efficacy (in relation to B-cell kinetics), safety, tolerability and convenience of use. Clinicians, alongside patients and their families, should consider the aspects discussed in this review as part of shared decision-making discussions to improve outcomes and health-related quality of life for people living with MS.
Composition and dynamics of intestinal fungi during the postnatal 2 months of very low birth weight infants
Authors: Wang Ting , Lu Yanbo , Wu Junhua , Yu Beirong
Published: October 2023

It has been found that intestinal fungi play a role in the composition of the intestinal microecology and in the formation and development of the immunity during childhood. We investigated the gut fungi composition of preterm infants to analysis composition and dynamics of intestinal fungi during the postnatal 2 months of very low birth weight infants. We collected feces from 34 very low birth weight infants (VLBWI) and 28 preterm infants with birth weight >1500 g. We extracted total fungal DNA from feces and analyzed the composition of gut fungus through ITS sequencing. The fungal detectable rate in the experimental group peaked on day 3 (85.19%), then gradually decreased and started to show an increasing trend again by day 28. There were significant differences in the alpha diversity of intestinal fungus between VLBWI and controls, and the VLBWI had its own characteristics at different time points in richness and diversity. A total of 10 phylums and 342 genera were identified in all VLBWI samples. The dominant fungal phylum of the VLBWI group is Ascomycota (50.3%)and Basidiomycota (48.8%). The functional metabolic activity of the experimental group was lower than that of the control group.

Conclusion: The composition and abundance of VLBWI intestinal fungal showed several alterations during the first 2 months of life. The prediction of gut microbiota function suggests that intestinal metabolic function may be altered in VLBWI.

What is Known:• A limited number of studies has been found that symbiont fungi may be able to calibrate host immunological responses, promote development of peripheral lymphoid organs, promote T cell responses, and even may be associated with the development of certain diseases, such as inflammatory bowel disease (IBD), NEC, and allergic diseases. However, previous studies on intestinal microecology have mainly focused on adults while neglecting the role of fungi in the gut of children due to the much lower abundance of intestinal fungi than bacteria, limitations of techniques for detecting fungi, the difficulty of obtaining samples, and the absence of largescale reference databases.

What is New:• In recent years, the discovery and development of fungal detection technologies such as 18s rDNA sequencing technology, Internal Transcribed Spacer(ITS), and DNA fingerprinting technology have further broadened the perspective on the impact of intestinal fungal exposure in early life.
Shared decision-making between paediatric haematologists, children with sickle cell disease and their parents: an exploratory study
Authors: Wijngaarde Ricardo , Koning Mijra , Fijnvandraat Karin , Ubbink Dirk
Published: October 2023

Children with sickle cell disease (SCD) face various healthcare choices to be made during the disease process that may impact their lives. Shared decision-making (SDM) could improve their health outcomes. We assessed if, and to what extent, paediatricians engage children with SCD and/or their parents in the decision-making process. In this observational cross-sectional study, paediatric SCD patients and their parents visiting the outpatient paediatrics clinic of a university hospital participated in a SDM baseline measurement. Two evaluators independently and objectively analysed the level of patient involvement in decision-making from the audio-recordings of the consultations using the OPTION-5 instrument, a 0–20-point scale from which scores are usually expressed as a percentage of ideal SDM. The level of SDM, as perceived by patients, parents and paediatricians, was appreciated using the SDM-Q-9 and SDM-Q-Doc questionnaires, respectively. Scores could range from 0% (no SDM) to 100% (exemplary SDM). Twenty-four consultations in which a decision needed to be made about SCD treatment were audiotaped and analysed; six were from each paediatrician. The group consisted of 17 male and 7 female patients from various cultural backgrounds between 2 and 17 years old, with a mean age of 9.4 years (SD 4.2). Median OPTION-5 scores were 25.0% [IQR] 20.0–40.0%; range 0–55%). Median SDM-Q-9 and SDM-Q-Doc scores were 56.7% (IQR 39.4–88.9%) and 68.9% (IQR 57.8–77.8%), respectively.

Conclusion: Although subjective scores of SDM were fair, the objectively scored level of SDM among children suffering from SCD leaves room for improvement. This may be realized by increasing knowledge about the benefits of SDM, child-centred SDM interventions and SDM-training for paediatricians that takes into account the complexity of intercultural challenges and risk communication between stakeholders.

What is Known:• Children that suffer from sickle cell disease (SCD) are more vulnerable to factors that negatively impact the care that they receive as well as suboptimal health outcomes.• Shared decision-making (SDM) can help children participate in a collaborative decision-making process about their preferred treatment options and improve their health outcomes.

What is New:• The level of participation in the decision-making process for patients suffering from SCD and the families that they belong to leaves room for improvement. The impact of intercultural challenges and the quality and consistency of risk-communication between stakeholders in paediatric SDM needs further exploration.• Paediatricians are more confident about their ability to involve the child and parents compared to how children and their parents experience their level of involvement in a shared decision-making process.
Validation of the maximal cardiopulmonary exercise test in adolescents with major depressive disorder and comparison of cardiorespiratory fitness with sex- and age-related control values
Authors: Wenzel Charlotte , Bongers Bart Chateau , Schlagheck Marit Lea , Reis Daniela , Reinhard Franziska , Schmidt Peter , Bernitzki Stefan , Oberste Max , Wunram Heidrun Lioba , Zimmer Philipp , Fricke Oliver
Published: October 2023

Endurance training has been shown to be effective in treating adolescents with major depressive disorder (MDD). To integrate endurance training into the therapeutic setting and the adolescents' daily lives, the current performance status of the adolescents should be accurately assessed. This study aims to examine adolescents with MDD concerning exhaustion criteria during a cardiopulmonary exercise test (CPET), as well as to compare the values obtained thereon with sex- and age-related control values. The study included a retrospective examination of exhaustion criteria ((i) oxygen consumption (V̇O2) plateau, (ii) peak respiratory exchange ratio (RERpeak) > 1.0, (iii) peak heart rate (HRpeak) ≥ 95% of the age-predicted maximal HR, and (iv) peak blood lactate concentration (BLCpeak) > 8.0 mmol⋅L−1) during a graded CPET on a cycle ergometer in adolescents with MDD (n = 57). Subsequently, maximal V̇O2, peak minute ventilation, V̇O2 at the first ventilatory threshold, and peak work rate of participants who met at least two of four criteria were compared with published control values using an independent-sample t-test. Thirty-three percent of the total population achieved a V̇O2 plateau and 75% a RERpeak > 1.0. The HR and BLC criteria were met by 19% and 22%, respectively. T-test results revealed significant differences between adolescents with MDD and control values for all outcomes. Adolescents with MDD achieved between 56% and 83% of control values.

   Conclusions: The study shows that compared with control values, fewer adolescents with MDD achieve the exhaustion criteria on a CPET and adolescents with MDD have significantly lower cardiorespiratory fitness.

   Clinical trial registration: No. U1111-1145–1854.

What is Known:• It is already known that endurance training has a positive effect on depressive symptoms.

What is New:• A relevant proportion of adolescents with major depressive disorder do not achieve their V̇O2max during a graded cardiopulmonary exercise test.• Adolescents with major depressive disorder have significantly lower cardiorespiratory fitness compared to sex- and age-related control values.
Emerging markers of cancer cachexia and their relationship to sarcopenia
Authors: Lipshitz Melanie , Visser J. , Anderson R. , Nel D. G. , Smit T. , Steel H. C. , Rapoport B.
Published: October 2023

Purpose

Emerging biomarkers of cancer cachexia and their roles in sarcopenia and prognosis are poorly understood. Baseline assessments of anthropometrics, sarcopenia, cachexia status and biomarkers of cachexia were measured in patients with advanced cancer and healthy controls. Thereafter, relationships of the biomarkers with cachexia and sarcopenia were explored.

Methods

A prospective case–control design was used, including 40 patients with advanced cancer and 40 gender, age-matched controls. Bioelectrical impedance [skeletal muscle index (SMI)] and hand dynamometry [hand grip strength (HGS)] assessed sarcopenia and a validated tool classified cancer cachexia. Albumin, lymphocyte and platelet counts, haemoglobin, C-reactive protein (CRP), pro-inflammatory cytokines/chemokines and citrullinated histone H3 (H3Cit) were measured.

Results

Patients had significantly lower SMI (6.67 kg/m2 versus 7.67 kg/m2, p =  < 0.01) and HGS (24.42 kg versus 29.62 kg) compared to controls, with 43% being sarcopenic. Significant differences were found for albumin, lymphocyte and platelet counts, haemoglobin, CRP, and tumour necrosis factor α (TNFα), (p < 0.01). Interleukin (IL)-6 (p < 0.04), IL-8 (p = 0.02), neutrophil/lymphocyte ratio (NLR), p = 0.02, platelet/lymphocyte (PLR) ratio, p < 0.01 and systemic immune inflammatory index (SII), p < 0.01 differed significantly. No difference was observed for CXC motif chemokine ligand 5 [CXCL5 or epithelial neutrophil-activating peptide 78 (ENA78)] or H3Cit. Albumin and haemoglobin correlated negatively with total protein, skeletal muscle mass and SMI (all p < 0.01). The presence of sarcopenia associated significantly with albumin, haemoglobin and CRP.

Conclusion

Significant relationships and differences of haemoglobin, CRP and albumin supports future use of these biomarkers in cancer cachexia. CXCL5 and H3Cit as valuable biomarkers in cancer cachexia remains to be defined.
Quantifying uncertainty in probabilistic volcanic ash hazard forecasts, with an application to weather pattern based wind field sampling
Authors: Phillips Jeremy , Williams Shannon , Lee Anthony , Jenkins Susanna
Published: October 2023

Probabilistic forecasting of volcanic ash dispersion involves simulating an ensemble of realistic event scenarios to estimate the probability of a particular hazard threshold being exceeded. Although the number of samples that make up the ensemble, how they are chosen, and the desired threshold all set the uncertainty of (or confidence in) the estimated exceedance probability, current practice does not quantify and communicate the uncertainty in ensemble predictions. In this study, we use standard statistical methods to estimate the variance in probabilistic ensembles and use this measure of uncertainty to assess different sampling strategies for the wind field, using the example of volcanic ash transport from a representative explosive eruption in Iceland. For stochastic (random) sampling of the wind field, we show how the variance is reduced with increasing ensemble size and how the variance depends on the desired hazard threshold and the proximity of a target site to the volcanic source. We demonstrate how estimated variances can be used to compare different ensemble designs, by comparing stochastic forecasts with forecasts obtained from a stratified sampling approach using a set of 29 Northern European weather regimes, known as Grosswetterlagen (GWL). Sampling wind fields from within the GWL regimes reduces the number of samples needed to achieve the same variance as compared to conventional stochastic sampling. Our results show that uncertainty in volcanic ash dispersion forecasts can be straightforwardly calculated and communicated, and highlight the need for the volcanic ash forecasting community and operational end-users to jointly choose acceptable levels of variance for ash forecasts in the future.
Tree-ring isotopic composition reveals intraspecific variation in water use efficiency of Pinus pinaster Ait. provenances grown in common gardens
Authors: Antonucci Serena , Marshall John , Santopuoli Giovanni , Marchetti Marco , Tognetti Roberto
Published: October 2023

Key message

The physiological responses expressed by variation in carbon and oxygen stable isotopes and iWUE in five provenances of maritime pine grown in four common gardens were primarily determined by genotype differences in phenotypic plasticity and secondarily by genotype.

Given the impacts of climate change on forest resources and considering the slowness of evolutionary processes in trees, a need arises to understand the interplay between tree species adaptation to climate, genetic variation, and their impact on tree growth and productivity. Broadening knowledge of the capacity of tree populations to respond to climate-related disturbances is a prerequisite for the development of resilience strategies, including assisted migration and climate-smart forestry. This study tests the physiological ability of different maritime pine provenances, comparing Mediterranean (Corsica, Sardinia, and Tuscany) and Atlantic (Portugal) provenances, to adapt to progressively drier conditions that have occurred in the last thirty years. Four provenance trials with randomized blocks of the five maritime pine provenances were used as test sites in Sardinia (Italy). Wood cores were collected from the 40-year-old plants. Cores were split into five-year segments to determine provenance-related variations in carbon and oxygen stable isotopes and provide information on long-term patterns in intrinsic water use efficiency (iWUE). The provenance × site interaction was the most important source of variation, meaning that the genotypes responded differently to the planting sites. Considering the main effects, both genotype and environmental conditions at the planting sites influenced stable isotope composition in tree rings. This suggests that iWUE was determined by phenotypic plasticity that differed among genotypes. In contrast, provenance responses were stable with time, and the provenance × site interaction was stable across time periods. These findings suggest that provenance selection to improve iWUE in maritime pine may need to consider site conditions but point more to soil conditions than to climate. In any case, they limit our ability to recommend maritime pine provenances based on iWUE until the missing site factors can be identified.