bluuebunny/crossref_metadata_2025 huggingface dataset:
Human immunodeficiency virus: The potential of medicinal plants as antiretroviral therapy
Authors: Shahzad Muhammad , Chen Huan , Akhtar Tasleem , Rafi Ali , Zafar Muhammad Shoaib , Zheng Yong‐Tang
Published: February 2022

Human immunodeficiency virus (HIV) infection is fast becoming widespread in the world with 37.7 million people living with HIV in 2020. Antiretroviral therapy involving chemical drugs has declined acquired immunodeficiency syndrome (AIDS)‐related mortality and improved the life quality of AIDS/HIV sufferers. However, the emergence of drug resistance and side effects are the main obstacles for the long‐term use of these chemicals as antiretroviral therapy. Recently, a lot of emphasis is being put on finding naturally occurring drug candidates that show activity against HIV and can be potentially used as antiretroviral therapy. In this study, different medicinal plants, Pistacia khinjuk, Teucrium stocksianum, Uncaria tomentosa, Pistacia integerrima, Trigonella gharuensis, and Artocarpus lakoocha, were explored for their anti‐HIV potential. Syncytium and p24 assays were performed to determine antiviral activity, while the MTT assay was used to determine cytotoxicity. Results showed that extracts from all six plants inhibited HIV replication in vitro. Also, extracts from Pistacia khinjuk, Teucrium stocksianum, Uncaria tomentosa, and Pistacia integerrima showed low cytotoxicity with a 50% cytotoxicity concentration value of >200 μM. Results of this study indicate that there is potential in these natural extracts to become candidate drugs to be used as complementary and alternative medicine for HIV infection.
Changes in extreme precipitation events in the Zambezi River basins based on CORDEX‐CORE models, Part II: Future projections under 1.5, 2.0, and 3.0°C global warming levels
Authors: Samuel Sydney , Wiston Modise , Mphale Kgakgamatso , Faka Dieudonne Nsadisa
Published: February 2022

This study examines the potential implications of 1.5, 2.0, and 3.0°C global warming levels (GWLs) on the austral summer (November–March) extreme precipitation indices over the Zambezi River basin (ZRB) relative to the control period (1971–2000). We computed extreme precipitation based on daily data from observations and the Coordinated Regional Downscaling Experiment (CORDEX)‐Coordinated Output for Regional Evaluations (CORE) multi‐model ensemble mean (ENSMean). First, we evaluated the performance of the CORDEX‐CORE ENSMean in simulating extreme precipitation based on six indices; the number of rainy days (RR1), simple daily intensity index (SDII), maximum consecutive wet days (CWD), maximum consecutive dry days (CDD), heavy precipitation days (R10), and very heavy precipitation days (R20). The results indicate that the CORDEX‐CORE ENSMean can simulate the spatial distributions of extreme precipitation over the ZRB. However, CORDEX‐CORE largely overestimates the magnitudes of RR1 and CWD. The projected changes show a decrease in RR1, CWD, and R10 under all GWLs, with a robust and pronounced decrease under 3.0°C GWL. In contrast, CDD and SDII are projected to increase under all GWLs, with a robust and pronounced increase in CDD under 3.0°C GWL. The regionally averaged changes show that the median values of CWD, RR1, and R10 (SDII and CDD) are projected to decrease (increase) under all GWLs over the ZRB and sub‐basins. The probability density function (PDF) shows negative (positive) shifts in the mean of CWD, RR1, and R10 (SDII and CDD) over the ZRB and sub‐basins under all GWLs. In contrast, R20 is projected to increase (decrease) over most of the western (eastern) ZRB under all GWLs. Assessing the implications of an additional 0.5 and 1.5°C (1.0°C) warming to 1.5°C (2.0°C) GWL shows that limiting GWL to 1.5°C would restrict the future exposure of the ZRB to extreme precipitation.
Uniform monotonicity of Orlicz spaces equipped with the Mazur–Orlicz F‐norm and dominated best approximation in F‐normed Köthe spaces
Authors: Cui Yunan , Hudzik Henryk , Kaczmarek Radosław , Kolwicz Paweł
Published: February 2022

We collect several useful equivalent conditions for order continuity in F‐normed Köthe spaces. Next, we study uniform monotonicity of Orlicz function (sequence) spaces equipped with the Mazur–Orlicz F‐norm. We show necessary and sufficient conditions, separately. Moreover, we study the best dominated approximation problems in F‐normed Köthe spaces showing that order continuity and strict monotonicity are crucial tools in these problems. Finally, we apply the general results in Orlicz spaces. We focus mainly on these methods and techniques which are essentially different and more delicate in comparison to the case of normed Köthe spaces.
Comprehensive analysis of PTEN‐related ceRNA network revealing the key pathways WDFY3‐AS2 ‐ miR‐21‐5p/miR‐221‐3p/miR‐222‐3p ‐ TIMP3 as potential biomarker in tumorigenesis and prognosis of kidney renal clear cell carcinoma
Authors: Zhou Xishan , Liu Guofeng , Xu Mo , Ying Xintao , Li Bianfeng , Cao Fengxi , Cheng Shuqiang , Xiao Beibei , Cheng Miao , Liang Liang , Jia Mingxi , Li Wen , Liu Jiheng , Li Zheng
Published: February 2022

Kidney renal clear cell carcinoma (KIRC) is one of the most common malignancies, and there is still a lack of effective biomarkers for early detection and prognostic prediction. In here, we compared the characteristics of RNA sequencing data sets of KIRC samples based on the tumor suppressor gene phosphatase and tensin homolog (PTEN). The 1016 long noncoding RNAs, 48 microRNAs (miRNAs), and 2104 messenger RNAs associated with PTEN were identified and these genes were differentially expressed between tumor and paracancerous tissues. The most relevant pathway was found to be WDFY3‐AS2 ‐ miR‐21‐5p/miR‐221‐3p/miR‐222‐3p ‐ TIMP3 according to the rules of competing endogenous RNA (ceRNA) regulation. WDFY3‐AS2 and TIMP3 expression were positively correlated and reduced in KIRC samples, while miR‐21‐5p, miR‐221‐3p, and miR‐222‐3p were relatively highly expressed. The relatively low expression of WDFY3‐AS2 and TIMP3 in KIRC were associated with poor prognosis in KIRC patients, while higher expression of miR‐21‐5p, miR‐221‐3p, and miR‐222‐3p predicted reduced survival (p < 0.05). Univariate and multivariate Cox regression analysis showed that lower expression of WDFY3‐AS2 and TIMP3 was significantly related to tumor grade, tumor size, lymph node metastasis, distant metastasis, and TNM stage. The expression of TIMP3 in KIRC tissues was also verified by immunohistochemistry, and the results were consistent with our analytical data. In summary, this study constructed a new model with clinical predictive value and identified the WDFY3‐AS2/TIMP3 pathway that was closely associated with the prognosis of KIRC, which could serve as a promising biomarker for the diagnosis and treatment of KIRC.
New Insight into the human genetic diversity in North African populations by genotyping of SNPs in DRD3, CSMD1 and NRG1 genes
Authors: Mestiri Souhir , Boussetta Sami , Pakstis Andrew J. , El Kamel Sarra , Ben Ammar El Gaaied Amel , Kidd Kenneth K. , Cherni Lotfi
Published: February 2022

Background

The single nucleotide polymorphisms (SNPs) of the dopamine D3 receptor (DRD3), the CUB and sushi multiple domains 1 (CSMD1) and the neuregulin 1 (NRG1) genes were used to study the genetic diversity and affinity among North African populations and to examine their genetic relationships in worldwide populations.

Methods

The rs3773678, rs3732783 and rs6280 SNPs of the DRD3 gene located on chromosome 3, the rs10108270 SNP of the CSMD1 gene and the rs383632, rs385396 and rs1462906 SNPs of the NRG1 gene located on chromosome 8 were analysed in 366 individuals from seven North African populations (Libya, Kairouan, Mehdia, Sousse, Kesra, Smar and Kerkennah).

Results

The low values of FST indicated that only 0.27%–1.65% of the genetic variability was due to the differences between the populations. The Kairouan population has the lowest average heterozygosity among the North African populations. Haplotypes composed of the ancestral alleles ACC and ACAT were more frequent in the Kairouan population than in other North African populations. The PCA and the haplotypic analysis showed that the genetic structure of populations in North Africa was closer to that of Europeans, Admixed Americans, South Asians and East Asians. However, analysis of the rs3732783 and rs6280 SNPs revealed that the CT microhaplotype was specific to the North African population.

Conclusions

The Kairouan population exhibited a relatively low rate of genetic variability. The North African population has undergone significant gene flow but also evolutionary forces that have made it genetically distinct from other populations.
Decreased expression of autophagy‐related genes in the complete remission phase of acute myeloid leukemia
Authors: Tandel Parisa , Ranjbaran Reza , Ebrahimi Eqbal , Rezvani Alireza , Ramzi Mani , Tamaddon Gholamhossein
Published: February 2022

Background

Autophagy is a conserved recycling process in cells. However, the effects of autophagy on the remission and treatment response of acute myeloid leukemia (AML) patients have not been clarified.

Methods

The expression of MAP1LC3B, ATG5, ATG10, RB1CC1, and AMBRA1 genes was assessed in 32 newly diagnosed AML patients, 18 complete remission (CR) patients, and seven relapsed patients, as well as 15 controls, by real‐time polymerase chain reaction (PCR).

Results

The expression of all five genes was significantly higher in the newly diagnosed AML patients as compared to the controls (p < 0.0001). The MAP1LC3B, ATG5, ATG10, RB1CC1, and AMBRA1 gene expression significantly reduced in CR patients compared to newly diagnosed AML patients (p = 0.006, 0.003, 0.0002, 0.006, and 0.004, respectively). The AMBRA1 gene expression was significantly higher in the relapsed cases as compared to both newly diagnosed (p = 0.01) and CR patients (p = 0.03). Moreover, a significant positive correlation was observed between the expression of MAP1LC3B (r = 0.739, p = 0.000001), ATG5 (r = 0.682, p = 0.00001), and ATG10 (r = 0.586, p = 0.0004) genes and white blood cell (WBC) count in patients at diagnosis.

Conclusion

The expression of MAP1LC3B, ATG5, ATG10, RB1CC1, and AMBRA1 genes can be examined to follow‐up the remission of AML and the patient's response to treatment.
Technical note: Evaluation of a V‐Net autosegmentation algorithm for pediatric CT scans: Performance, generalizability, and application to patient‐specific CT dosimetry
Authors: Adamson Philip M. , Bhattbhatt Vrunda , Principi Sara , Beriwal Surabhi , Strain Linda S. , Offe Michael , Wang Adam S. , Vo Nghia‐Jack , Gilat Schmidt Taly , Jordan Petr
Published: February 2022

Purpose

This study developed and evaluated a fully convolutional network (FCN) for pediatric CT organ segmentation and investigated the generalizability of the FCN across image heterogeneities such as CT scanner model protocols and patient age. We also evaluated the autosegmentation models as part of a software tool for patient‐specific CT dose estimation.

Methods

A collection of 359 pediatric CT datasets with expert organ contours were used for model development and evaluation. Autosegmentation models were trained for each organ using a modified FCN 3D V‐Net. An independent test set of 60 patients was withheld for testing. To evaluate the impact of CT scanner model protocol and patient age heterogeneities, separate models were trained using a subset of scanner model protocols and pediatric age groups. Train and test sets were split to answer questions about the generalizability of pediatric FCN autosegmentation models to unseen age groups and scanner model protocols, as well as the merit of scanner model protocol or age‐group‐specific models. Finally, the organ contours resulting from the autosegmentation models were applied to patient‐specific dose maps to evaluate the impact of segmentation errors on organ dose estimation.

Results

Results demonstrate that the autosegmentation models generalize to CT scanner acquisition and reconstruction methods which were not present in the training dataset. While models are not equally generalizable across age groups, age‐group‐specific models do not hold any advantage over combining heterogeneous age groups into a single training set. Dice similarity coefficient (DSC) and mean surface distance results are presented for 19 organ structures, for example, median DSC of 0.52 (duodenum), 0.74 (pancreas), 0.92 (stomach), and 0.96 (heart). The FCN models achieve a mean dose error within 5% of expert segmentations for all 19 organs except for the spinal canal, where the mean error was 6.31%.

Conclusions

Overall, these results are promising for the adoption of FCN autosegmentation models for pediatric CT, including applications for patient‐specific CT dose estimation.
Constant light exposure alters gut microbiota and short‐/medium‐chain fatty acids and aggravates PCOS‐like traits in HFD‐fed rats
Authors: Yue Fangzhi , Xing Lin , Wu Shanyu , Wei Lin , Zhou Zhijun , Shi Ying , Lam Sin Man , Shui Guanghou , Xiang Xingwei , Russell Ryan , Zhang Dongmei
Published: February 2022

Objective

This study investigated the effects of constant light exposure on polycystic ovary syndrome (PCOS)‐like endocrine and metabolic changes in high‐fat diet (HFD)‐fed rats and to elucidate the related microbiotic mechanisms.

Methods

A total of 32 female Sprague‐Dawley rats were divided into four groups (n = 8 each): rats on a normal chow diet with standard light‐dark cycle, rats on a normal chow diet with constant light exposure, rats on an HFD with standard light‐dark cycle, and rats on an HFD with constant light exposure. After 16 weeks of treatment, changes in anthropometric parameters, estrous cycle, hormone profiles, ovarian pathology, and gut microbiota and short‐/medium‐chain fatty acids in colon contents were assessed.

Results

Constant light exposure aggravated PCOS‐like phenotypes in HFD‐fed rats, such as hyperandrogenism, disrupted estrous cycle, and polycystic ovaries. Additionally, constant light exposure and an HFD synergized to decrease α‐diversity of gut microbiota, create a reduced abundance of Ruminococcus genus, and create an increased abundance of Firmicutes and the Firmicutes/Bacteroidetes ratio. In HFD‐fed rats, the group with constant light exposure had an increase in propionate acid and a decrease in total medium‐chain fatty acids in colon contents compared with the standard light‐dark cycle group.

Conclusions

Constant light exposure causes gut dysbiosis, alters production of short‐ and medium‐chain fatty acids, and aggravates PCOS‐like traits in HFD‐fed rats.
Prepare randomized clinical trial: Acceptability, engagement, and lifestyle effects of a weight loss intervention beginning in pre‐pregnancy
Authors: LeBlanc Erin S. , Boisvert Cassie , Catlin Chris , Lee Mi H. , Smith Ning , Vesco Kimberly K. , Savage Jennifer , Mitchell Diane C. , Gruß Inga , Stevens Victor J.
Published: February 2022

Background

Healthier lifestyles in early pregnancy are associated with lower rates of pregnancy complications, childhood adiposity, and maternal and child cardiovascular risks. However, it is not known whether lifestyle coaching initiated prior to pregnancy can affect behavior and attitudes during pregnancy.

Methods

Three hundred and twenty six women planning pregnancy within 2 years with BMI ≥27 kg/m2 were randomized to a behavioral weight loss intervention or to usual care. Analyses reported here examined the intervention’s impact on mid‐pregnancy diet quality and activity levels; program acceptability; and effects of pregnancy on intervention engagement.

Results

One hundred and sixty eight participants experienced pregnancy during the study (intervention: 91; usual care: 77). From randomization to mid‐pregnancy, participants who received the intervention had larger increases in fruit intake than usual care participants (+0.67 vs. +0.06 cups; p = 0.02) and engaged in more vigorous‐intensity activity (3.9 [5.5] vs. 1.2 [3.0] Met‐hr/week p = 0.002) and sports/exercise (17.0 [14.1] vs. 11.0 [9.5] Met‐hr/week; p = 0.03); the groups also differed in changes in sedentary time (−4.9 [15.0] vs. +0.5 [7.6] Met‐hr/week; p = 0.02). Intervention satisfaction was high (>80%), and experiencing pregnancy during the intervention was associated with higher engagement.

Conclusion

A coaching‐based intervention beginning in pre‐pregnancy successfully helped women attain healthier diet and exercise habits in mid‐pregnancy.

Clinical trials registration

Registered with ClinicalTrials.gov, NCT02346162, first registered on January 26, 2015, before date of initial participant enrollment (May 2015), https://clinicaltrials.gov/ct2/show/NCT02346162.
Psychosocial impact of testing human papillomavirus positive in Australia's human papillomavirus‐based cervical screening program: A cross‐sectional survey
Authors: Chadwick Verity , Bennett Kirsty F. , McCaffery Kirsten J. , Brotherton Julia M. L. , Dodd Rachael H.
Published: February 2022

Objective

To examine the impact of self‐reported human papillomavirus (HPV) test result (HPV negative, HPV positive, HPV result unknown) on a range of psychosocial outcomes.

Methods

Women and other people with a cervix in Australia aged 25–74 years who reported having participated in cervical screening since December 2017 were recruited through Facebook and Instagram to complete an online survey. The primary outcome measures were anxiety, emotional distress, and general distress.

Results

Nine hundred fifteen participants completed the online survey; 73.2% reported testing HPV negative (‘HPV−’), 15% reported testing HPV positive (‘HPV+’) and 11.8% reported that they did not know/remember their test result (‘HPV unknown’). Compared to participants testing HPV−, participants testing HPV+ had higher mean anxiety (41.67 vs. 37.08, p < 0.001) and emotional distress scores (11.88 vs. 7.71, p < 0.001). Concern about test result (34.3% vs. 1.3%, p < 0.001), perceived risk compared to average women (55.4% vs. 14.1%, p < 0.001), and cancer worry (27.8% vs. 5.9%, p < 0.001) were also greater among HPV+ participants than participants testing HPV−. Participants testing HPV+ felt less reassured about their screening result than participants testing HPV− (16% vs. 75.1%, p < 0.001). Participants testing HPV+ had greater knowledge of HPV (11.96 vs. 10.36 out of 16, p < 0.001) and HPV testing (3.94 vs 3.28 out of 5, p < 0.001) than participants who reported testing HPV−.

Conclusions

Elevated levels of anxiety and emotional distress were found in those testing HPV+ compared with those testing HPV−. Future research should examine what strategies should be used to deliver test results and what additional information is provided, in order to alleviate anxiety among individuals testing HPV+.
Electronic Structure Investigation of GaN Nanowire Doped with Transition Metals Particles via First Principle
Authors: Lu Feifei , Liu Lei , Tian Jian
Published: February 2022

In order to make GaN nanowires better used in the field of spin‐polarized electron sources, the structure and properties of transition metal (Cr, Mn, Fe, Co, and Ni) particles doped nanowires are studied through first principles. The research results show that transition metal (TM) particles are more likely to be doped on the outermost surface of GaN nanowires. The work function of Cr‐doped GaN nanowires has the largest decrease, which is 2.06 eV. For TM‐doped nanowires, magnetic moments are induced, which are mainly derived from the polarization of 3d electrons of TM atoms and 2p electrons of N atoms. Mn‐doped GaN nanowires with 100% spin polarization characteristics seem to be good candidates for spin‐polarized electron source photocathode applications.
Efficiently list‐edge coloring multigraphs asymptotically optimally
Authors: Iliopoulos Fotis , Sinclair Alistair
Published: February 2022

We give polynomial time algorithms for the seminal results of Kahn, who showed that the Goldberg–Seymour and list‐coloring conjectures for (list‐)edge coloring multigraphs hold asymptotically. Kahn's arguments are based on the probabilistic method and are non‐constructive. Our key insight is that we can combine sophisticated techniques due to Achlioptas, Iliopoulos, and Kolmogorov for the analysis of local search algorithms with correlation decay properties of the probability spaces on matchings used by Kahn in order to construct efficient edge‐coloring algorithms.
Superior Unidirectional Water Transport and Mechanically Stable 3D Orthogonal Woven Fabric for Human Body Moisture and Thermal Management
Authors: Fan Wei , Zhang Ge , Zhang Xiaolin , Dong Kai , Liang Xiaoping , Chen Weichun , Yu Lingjie , Zhang Yingying
Published: February 2022

Unidirectional water transport performance is vital for maintaining human thermal and wet comfort in the field of garment materials. In this work, a 3D orthogonal woven fabric (3DOWF) with excellent one‐way transport capacity and mechanical properties is developed via 3D weaving and plasma treatment. The 3DOWF consists of polyester yarns (first layer), cotton yarns (second layer), and viscose yarns (third layer) with successively enhanced water absorption capacity. This allows droplets to penetrate spontaneously from the hydrophobic layer to the hydrophilic layer but not vice versa. Moreover, the Coolmax yarn with the core suction effect in the Z‐direction and the plasma‐treated polyester of the 3DOWF are shown to efficiently speed up the water transport process. In particular, the water penetration rate of the 3DOWF reaches 25 µl s‐1. In turn, the surface temperature after water absorption is increased by 2.6 °C compared with the cotton fabric, while the tensile strengths in the weft and warp directions of the 3DOWF are 49.62 and 18 MPa, respectively. These values represent the best insulation and mechanical characteristics thus far reported among unidirectional water transport fabrics. Therefore, the 3DOWF has great potential for use in watchbands, backpack belts, insoles, and other functional textiles.
Rheological, Textural, and Digestibility Characteristics of Low Fat Mayonnaise as Affected by the Addition of Sorghum‐Xanthan Gum and Corn‐Xanthan Gum Extrudates (RS3)
Authors: Shaikh Faiza , Ali Tahira Mohsin , Hasnain Abid
Published: February 2022

Low‐fat mayonnaise samples are produced using corn (EC) and sorghum (ES) starch extrudates. The resistant starch rich (RS3 ) extrudates are produced by extruding corn and sorghum starch in the presence of xanthan gum at 1% w/w level, i.e., ECX and ESX, respectively. These extrudates are incorporated in low fat mayonnaise at 10% w/w. The EC and ES based mayonnaise, i.e., MC and MS, respectively are treated as control mayonnaise while the ECX and ESX incorporated mayonnaise MCX and MSX, respectively are low‐fat mayonnaises prepared with RS3 starches and hence are compared to control. Rheological characterization of the samples is done using frequency sweep tests, flow curves, and oscillatory tests. The tan θ values obtained through frequency sweep measurements classify mayonnaise samples into weak gels. All the mayonnaise samples best‐fitted the power law model and exhibit thixotropic (time‐dependent), shear‐thinning behavior with thixotropy being higher in MS and MSX. The % recovery and % strain of corn based mayonnaise are found to be higher. The incorporation of ESX extrudates increases the viscosity, improves the firmness and decreases the predicted glycemic index of MSX as compared to MS and MCX while providing a stable emulsion with appropriate rheological, textural, and sensory attributes.
Microalgal‐based remediation of wastewater: A step towards environment protection and management
Authors: Goswami Rahul Kumar , Agrawal Komal , Verma Pradeep
Published: February 2022

The widespread problem of water pollution is jeopardizing the ecosystem and our health. The contamination of freshwater through anthropogenic activities and its discharge into the ecosystems leads to the generation of wastewater. Wastewater mainly contains nutrient loads and the recent emerging contaminants such as pharmaceutical wastes, drugs, micropollutants, heavy metals, pesticides, phenolic compounds, and dyes have increased and contaminated the aquatic bodies. The existence of these emerging pollutants can cause serious threats to ecosystems and humans. Thus, conventional wastewater treatment was focused on the removal of solid compounds or nutrient loads. However, it could not remove the emerging contaminants and later microalgae that are photosynthetic eukaryotic microorganisms were found to be an efficient and eco‐friendly source for the remediation of diverse kinds of wastewater. Apart from nutrient removal, the algal biomass acts as the efficient feedstock for the generation of bioenergy products. However, limited data have been published regarding the remediation of emerging pollutants through microalgae. Thus, focusing on the recent gaps, the current review provides an overview of the potential of microalgae for the remediation of nutrient loads. Critically deliberate the recent advances and detailed summary of microalgae potential for the remediation of wastewaters containing high nutrient loads especially focused on the remediation of different emerging contaminants. It highlights the advanced approaches used in the microalgae remediation process and provides comprehensive information about the different bioenergy products such as liquid, gaseous, and bioelectricity generated through the utilization of wastewater‐grown microalgae.
Idiopathic hypereosinophilic syndrome in a cheetah (Acinonyx jubatus)
Authors: Clayton Ashley , Petite Audrey , Feltrer Rambaud Yedra , Holding Ellen , Hopper Jane
Published: February 2022

A 10‐year‐old male cheetah (Acinonyx jubatus) presented with weight loss, inappetence and weakness. Clinical examination revealed muscle loss, splenomegaly and dehydration. Haematology and biochemistry showed hyperglobulinaemia and marked leukocytosis with eosinophilia and neutrophilia. Urinalysis revealed proteinuria. Following an empirical 7‐day course of clavulanate potentiated amoxicillin, normal appetite and demeanour were observed. One month later, it re‐represented with the same clinical signs. Clinical examination was repeated. Radiographs showed ileocaecocolic junction dilation. Ultrasound examination revealed enlarged mesenteric lymph nodes, splenic nodules and colonic thickening. Fine‐needle aspirates of these organs and bone marrow aspirates showed marked atypical eosinophilic infiltration with haematology showing peripheral eosinophilia. Idiopathic hypereosinophilic syndrome was diagnosed. Treatment with prednisolone was initiated with good compliance, but there was a marked clinical deterioration 2 days later, and euthanasia was elected on welfare grounds.
Structure and magnetic properties of RE4Ni2Mg3 with RE=Y, Tb−Tm and Lu – New representatives of the Ru4B2Al3 type
Authors: Reimann Maximilian Kai , Pöttgen Rainer
Published: February 2022

The intermetallic compounds RE4Ni2Mg3 with RE=Y, Tb−Tm and Lu were synthesized from the elements in sealed tantalum ampules in a high‐frequency furnace and characterized by powder X‐ray diffraction. The RE4Ni2Mg3 phases crystallize with a site occupancy variant of the tetragonal Ru4B2Al3 type structure, space group P4/mmm. The structures of Tm4.21(1)Ni2Mg2.79(1), Lu4.28(1)Ni2Mg2.72(1) and Lu4.41(1)Ni2Mg2.59(1) were refined from single crystal X‐ray diffractometer data. Refinements of the occupancy parameters indicated different degrees of RE/Mg mixing on several Wyckoff positions. The RE4Ni2Mg3 structures are simple intergrowth variants of CsCl and AlB2 related slabs with distorted Ni@RE6 trigonal prisms and Mg@RE8 distorted cubes. Temperature dependent magnetic susceptibility studies reveal Pauli paramagnetism for Y4Ni2Mg3 and Lu4Ni2Mg3. The compounds with RE=Dy, Ho, Er and Tm are Curie‐Weiss paramagnets that order antiferromagnetically between 17.1(1) (RE=Dy) and 6.0(1) K (RE=Tm). The antiferromagnetic ground states are substantiated by metamagnetic transitions.
Dimensions of Circularity for Healthy Metabolisms and Spaces
Authors: Russo Michelangelo , van Timmeren Arjan
Published: February 2022

In this first chapter of the Book “Regenerative Territories. Dimensions of Circularity for Healthy Metabolisms”, the relation between circularity and space is explored. The main focus is the development over time, and in particular the way how spatial planning and strategies respond to new unpredictable urgencies and opportunities related with territorial metabolisms. In relation to space and time, 5 grand rules are explored as necessary to implement the transition towards Circularity: (1) The Circular Economy paradigm shift requires a socio-ecological perspective and looking beyond boundaries; (2) Circular Economy is based on systems thinking and territorial metabolism; (3) a Circular Economy calls for a renewed approach to the public domain and stakeholder involvement; (4) amplifying the definition of Circular Economy with the inclusion of wastescapes; and (5) Planning the Circular Economy as an open collaborative system. The paradigm shift of contemporary planning towards circularity is aimed to facilitate the capacity of cities to be adaptive and flexible to the speeding up of the biggest changes in the present-day society. Therefore, the relation between the various spatial scales is strictly interlinked to the time scales, as well as to the metabolic processes and Life Cycles of Territories. In this perspective, the “existing city” is a non-negotiable common heritage, the result of a “selective accumulation” of material and immaterial traces produced by the slow and progressive anthropic work in the territory. Contemporary spatial planning looks beyond boundaries. This concerns both the physical boundaries between areas or countries, both the boundaries of the various scale levels of solutions, of the interrelated networks, of the public space and, particularly, of their reciprocity. It induces the scrutinization of the underlying social needs and the finding of instruments that allow the spatial planning and renewed infrastructure to fit the changing social objectives such as sustainability and liveability. The territory of the Circular Economy is the city, as a complex and multidimensional organism. However, the most problematic field for experimenting with “circular planning” is the peri-urban territory consisting of urbanized areas, crossed by differentiated phenomena of settlement expansion beyond the limits of the countryside, which identifies rural and open space, traditionally coinciding with the limits of the city. A circular planning for the regeneration of the peri-urban identifies the waste spaces, the decay of the territory, the obsolescence and end of life of buildings, functions and urban parts now inadequate, namely wasted landscapes (wastescapes). The latter are both the result of metabolic transformations of the territory and generator of prospects and potential for rebalancing the material welfare of the city.
Adult Acute Lymphoblastic Leukaemia
Authors: Jacoby Elad , Gökbuget Nicola , Nagler Arnon
Published: February 2022

ALL is a malignancy of lymphoid progenitor cells, with a bimodal incidence, peaking in early childhood and in older age. In children, ALL tends to have an excellent prognosis, with more than 85% of patients achieving long-term survival. The outcome of younger adults has improved considerably as well. However, overall survival decreases with age (Dores et al. 2012), partially due to the different genetic background of adult ALL, with a higher proportion of Philadelphia chromosome-positive (Ph+) ALL and Ph-like and KMT2A rearrangements in comparison to childhood ALL (Iacobucci and Mullighan 2017). The introduction of paediatric-inspired regimens has improved outcomes in adults, but these regimens are less tolerated in older patients (Curran and Stock 2015).
Mantle Cell Lymphoma
Authors: Milpied Noel , Dreyling Martin
Published: February 2022

Mantle cell lymphoma is a distinct lymphoma subtype with a widely varying clinical course. Established high-risk biological factors include blastoid cytomorphology, high cell proliferation (Ki-67 > 67%), and p53 mutations (Aukema et al. 2018). While current first-line approaches are still chemotherapy-based, BTK inhibitors are the preferred targeted approach, especially in early relapse cases (POD24) (Dreyling et al. 2017; Visco et al. 2021). However, cases of relapse/progression under BTK inhibitors display extremely aggressive features with a dismal outcome after conventional regimens (Martin et al. 2016).
Multiple Myeloma
Authors: Yakoub-Agha Ibrahim , Einsele Hermann
Published: February 2022

To date, over 100 clinical trials investigating the use of CAR-T cells in MM have been registered at clinicaltrials.gov. Although several CD19-directed CAR-T cell products have been approved (Ghobadi 2018; Yassine et al. 2020), CD19 surface expression on plasma cells is limited or absent, leading to uncertain efficacy in clinical trials that used anti-CD19 alone in patients with MM (Garfall et al. 2015, 2019). Using superresolution microscopy, CD19 can be detected on a large proportion of myeloma cells, which could explain the successful targeting and lysis of myeloma cells by CD19-detecting CAR-T cells (Nerreter et al. 2019). Of note, some ongoing studies in which CD19 is targeted in combination with other antigens, especially BCMA, are being conducted (Beauvais et al. 2020).
Developments in Other Haematological Malignancies: Other Lymphoid Malignancies
Authors: Corradini Paolo , Trümper Lorenz
Published: February 2022

Peripheral T cell lymphomas comprise a heterogeneous group of rare diseases, representing 10–15% of all non-Hodgkin lymphomas (NHLs). Upfront treatment for peripheral T cell lymphoma (pTNHL) includes CHOP-like (cyclophosphamide, adriamycin, vincristine, prednisone) multiagent chemotherapy with or without etoposide, followed by stem cell transplantation as consolidation in responsive fit patients. This approach induces durable long-term remission in approximately 40% of cases; early refractoriness during induction occurs in approximately 25% of patients, with the remaining patients typically relapsing within 24 months. With the exception of patients with anaplastic large cell lymphomas who are eligible to receive brentuximab vedotin, there is no standard of care in the relapse setting. In patients not eligible to receive high-dose chemotherapy followed by allogeneic stem cell transplantation, the prognosis is dismal.
Myeloid Malignancies
Authors: Ferrand Christophe , Rambaldi Alessandro
Published: February 2022

In addition to chemotherapy, which remains the basic treatment, the treatment panel for acute myeloid leukaemia (AML) has expanded considerably in recent years. Clinicians now have a large choice of therapies: targeted therapies (anti-IDH1/2, anti-FLT3, and anti-BCL2 therapies, among others), drugs targeting epigenetic mechanisms, kinase inhibitors (FLT3, MAPK, and JAK2, etc.), immunotherapies (monoclonal antibodies linked or not to a toxin, dual/bispecific), and cellular immunotherapies. Moreover, despite its toxicities, allogeneic transplantation often remains an effective final therapeutic alternative. However, most patients are refractory or relapsed (R/R) after several lines of therapy. Thus, there is a clinical need in AML R/R patients, and CAR-T cells may be an option and can find a place in the treatment to reduce tumour burden and clinical evolution of the disease (Fig. 18.1, modified from Roussel et al. (2020)).
Genetic Engineering of Autologous or Allogeneic Immune Effector Cells
Authors: Benabdellah Karim , Thomas Simone , Abken Hinrich
Published: February 2022

Manufacturing immune effector cells (T or NK cells) with CAR-encoding DNA sequences requires efficient and safe genetic engineering procedures. For this purpose, an appropriate genetic vector is chosen according to numerous factors, including the vector genome packaging capacity, cellular tropism, genomic integration, immune toxicity, and other factors. In clinical trials, genomes integrating viral vectors, in particular vectors based on members of the Retroviridae family, such as retroviruses and lentiviruses, have been successfully used for more than 20 years. These vectors contain an RNA genome that when transcribed into double-stranded DNA by reverse transcriptase integrates into the genome of the transduced cell.
Bridging Chemotherapy: Relapsed/Refractory Aggressive B-Cell Lymphoma
Authors: Thieblemont Catherine , Borchmann Peter
Published: February 2022

The time interval between leukapheresis and CAR-T cell infusion is critical for many patients with R/R B-cell lymphoma and symptomatic disease that could be fatal if left untreated during the cell manufacturing period. Often, oncologists address this dilemma with bridging therapy (BT), which may include steroids, chemotherapy, targeted therapy, or radiation therapy.
Management of Cytokine Release Syndrome (CRS) and HLH
Authors: Ayuketang Francis Ayuk , Jäger Ulrich
Published: February 2022

Cytokine release syndrome (CRS) is caused by a rapid and mild to massive release of cytokines from immune cells involved in immune reactions, particularly after immunotherapy. The frequency and severity of CRS after CAR-T cell therapy varies between products (any grade: 37–93%, G3/4: 1–23%) (Neelapu et al. 2017; Schuster et al. 2019; Abramson et al. 2020).
Management of Myelotoxicity (Aplasia) and Infectious Complications
Authors: Subklewe Marion , Benjamin Reuben
Published: February 2022

Haematologic toxicity is the most common adverse event after CAR-T cell therapy, with a cumulative 1-year incidence of 58% (CTCAE grade ≥ 3) in the real-world setting (Wudhikarn et al., Blood Advances 2020). It is characterized by a biphasic temporal course and is often prolonged (Fried et al., Bone Marrow Transplant 2019, Rejeski et al., Blood et al. 2021a, b, Fig. 29.1). In a report of Axi-Cel-treated patients, only 30% demonstrated a neutrophil count >1 × 109/L and 50% showed a platelet count >50 × 109/L at 30 days following CAR-T cell treatment (Jain et al., Blood Advances 2020). In a long-term follow-up study of patients with ongoing CR and an absence of MDS, 16% of patients experienced prolonged significant cytopenias that lasted up to 22 months after CAR-T cell treatment (Cordeiro et al., Biol Blood Marrow Transplant 2020). These findings highlight that cytopenia can present long after lymphodepletion and the resolution of acute CRS. Risk factors include severe CRS/ICANS, cytopenia prior to initiation of lymphodepleting chemotherapy, and prior allogeneic stem cell transplantation (Jain et al., Blood Advances 2020, Fried et al., BMT, 2019). Importantly, cytopenia predisposes patients to severe infectious complications, which are the most frequent cause of non-relapse mortality (Nastoupil et al., JCO 2020).
What Defines a Good Tumour Antigen?
Authors: Morris Emma C. , Falkenburg J. H. F.
Published: February 2022

Compared to standard anticancer therapies, such as chemotherapy, small molecule inhibitors and radiation, T cell immunotherapies have the advantages of a high degree of specificity and durability of response typically associated with cellular therapies. The functional specificity of a T cell is determined by its antigen recognition receptor and the target antigen (Bjorkman et al. 1987; Garcia et al. 1996).
Immune Monitoring
Authors: Berger Susanna Carolina , Fehse Boris , Rubio Marie-Thérèse
Published: February 2022

CAR-T cell expansion and persistence are critical parameters for therapeutic efficacy and toxicity (Locke et al. 2020). However, CAR-T cells are patient-specific ‘living drugs’ with an unpredictable ability to expand in vivo. Thus, close postinfusion monitoring should be a major prerequisite to better manage this therapy. Critical parameters include CAR-T cell expansion kinetics and phenotype immune reconstitution and serum biomarkers (Fig. 35.1; Kalos et al. 2011; Hu and Huang 2020). Additionally, prospective collection and storage of patient specimens should be planned for future hypothesis-driven studies at specialized research centres. To date, despite the rapid expansion of CAR-T cell therapy, no standard recommendations exist for CAR monitoring, and harmonization of efforts across multiple centres is urgently needed.
Role of Pharmacists
Authors: Galassi Margherita , Moreno-Martínez Maria Estela
Published: February 2022

The pharmacist has a key role in the management of CAR-T therapies. Selection, ordering, reception, storage, preparation of the product for infusion, and dispensing of CAR-T therapies are some of the pharmacy service responsibilities (Black 2018; Moreno-Martínez et al. 2020; Booth et al. 2020). The pharmacist requires specific training, ensuring coordination with all the professionals in the multidisciplinary team who are involved in the management of these therapies, as summarized in Table 41.1.
GoCART
Authors: Terwel Sofie R. , Kuball Jürgen , Dreyling Martin , Cerisoli Francesco
Published: February 2022

Cellular therapies manufactured from cells of haematopoietic origin, such as CAR-T–cell therapies, provide a revolutionary treatment for patients suffering from haematological diseases. Nonetheless, there are considerable challenges in the implementation of these therapies in this rapidly evolving field. These challenges include but are not limited to the complexity of the supply chains for these living drugs and the management of side effects, requiring centre qualification as well as additional and ongoing education of health care professionals; the long-term follow-up of patients treated with therapies with curative intent; the myriad regulatory requirements at the European Union and local level; and reimbursement of the treatments by budget-constrained authorities.
The Value of CAR-T-cell Immunotherapy in Cancer
Authors: Abou-el-Enein Mohamed , Gauthier Jordan
Published: February 2022

The development of genetically modified chimeric antigen receptor (CAR) T-cells to target cancer by conferring tumour antigen recognition has tremendously improved the fight against the disease and broadened treatment options for haematological malignancies (Elsallab et al. 2020b). However, in contrast to conventional drugs that patients can easily access, the implementation of CAR-T-cell therapy in routine clinical practice poses significant challenges. Access to CAR-T-cell products is currently limited to specific certified centres meeting the requirements set up by manufacturers and regulatory agencies. There are also issues regarding insurance coverage, reimbursement, affordability, and pricing, which have critical impacts on broadening patient access to these novel therapies (Abou-El-Enein et al. 2016a, b). Current list pricing ranges between $373,000 and $475,000 per one-time infusion for the four CAR-T-cell therapies currently approved by the FDA (tisagenlecleucel, Kymriah®; axicabtagene ciloleucel, Yescarta®; brexucabtagene autoleucel, Tecartus®; lisocabtagene maraleucel, Breyanzi®). In addition to the cost of the CAR-T-cell product, patient preparation (leukapheresis and/or lymphodepletion), product infusion, pre- and post-infusion patient management, and monitoring for side effects (Wagner et al. 2021) significantly add to the final price tag. There are calls for restructuring the current payment and reimbursement models to allow better access to CAR-T-cell therapies (Abou-El-Enein et al. 2014). However, this would only be possible after examining the strength of clinical evidence generated during product development (Abou-El-Enein and Hey 2019; Elsallab et al. 2020a) and, most importantly, by determining the value of CAR-T-cell therapy.
What do Patients Want? The Importance of Patient-reported Outcomes
Authors: Schoemans Hélène , Bolaños Natacha , Warwick Lorna
Published: February 2022

Understanding of what it means for patients to receive CAR-T therapy remains insufficient due to the small number of studies with a quality of life (QOL) focus, selection bias of respondents, high risk of attrition due to disease relapse, and limited length of follow-up. CAR-T therapy is often presented as a last option for patients with advanced disease. The primary aim of the treatment is patient survival and hopefully disease elimination. However, understanding other aspects of health, such as functional status, cognitive function, psychosocial concerns, and other health-related (QOL) issues, is key to appreciating the full impact of such therapies at both the individual and societal levels.
Why IT Security Needs Therapy
Authors: Menges Uta , Hielscher Jonas , Buckmann Annalina , Kluge Annette , Sasse M. Angela , Verret Imogen
Published: February 2022

Over the past decade, researchers investigating IT security from a socio-technical perspective have identified the importance of trust and collaboration between different stakeholders in an organisation as the basis for successful defence. Yet, when employees do not follow security rules, many security practitioners attribute this to them being “weak” or “careless”; many employees in turn hide current practices or planned development because they see security as “killjoys” who “come and kill our baby”. Negative language and blaming others for problems are indicators of dysfunctional relationships. We collected a small set of statements from security experts’ about employees to gauge how widespread this blaming is. To understand how employees view IT security staff, we performed a prolific survey with 100 employees (n = 92) from the US & UK, asking them about their perceptions of, and emotions towards, IT security staff. Our findings indicate that security relationships are indeed often dysfunctional. Psychology offers frameworks for identifying relationship and communication flows that are dysfunctional, and a range of interventions for transforming them into functional ones. We present common examples of dysfunctionality, show how organisations can apply those interventions to rebuild trust and collaboration, and establish a positive approach to security in organisations that seizes human potential instead of blaming the human element. We propose Transactional Analysis (TA) and the OLaF questionnaire as measurement tools to assess how organisations deal with error, blame and guilt. We continue to consider possible interventions inspired by therapy such as conditions from individual and group therapy which can be implemented, for example, in security dialogues or the use of humour and clowns.
Transferring Update Behavior from Smartphones to Smart Consumer Devices
Authors: Fassl Matthias , Neumayr Michaela , Schedler Oliver , Krombholz Katharina
Published: February 2022

Automatic updates are becoming increasingly common, which minimizes the amount of update decisions that users have to make. Rapidly deployed important updates have a major impact on security. However, automatic updates also reduce the users’ opportunities to build useful mental models which makes decision-making harder on other consumer devices without automatic updates. Users generally transfer their understanding from domains that they know well (i.e. smartphones) to others. We investigate how well this transfer process works with respect to updates and if users with automatic updates fare worse than those with manual updates.

We conducted a formative field study ($$N = 52$$

N
=
52

) to observe users’ update settings on smartphones and examine reasons for their (de-)activation. Based on the results, we conducted an online survey ($$N = 91$$

N
=
91

) to compare how users perceive update notifications for smartphones and smart consumer devices. One of our main findings is that update decisions based on expected changes do not apply well to these devices since participants do not expect meaningful and visual changes. We suggest naming updates for such devices ‘maintenance’ to move users’ expectations from ‘new features’ to ‘ensuring future functionality’.