bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis and validation of mathematical models of secondary velocities along vertical and transverse directions in wide open-channel turbulent flows
Authors: Kundu Snehasis , Chattopadhyay Titas
Published: February 2022

Cellular secondary flows are inevitably present in turbulent flows through ducts, natural or artificial channels, and compound channels. Secondary currents significantly modify the characteristics of turbulent quantities, the pattern of primary flow velocity by causing dip-phenomenon. To understand the detailed mechanism and hidden cause, modelling of secondary flow velocities is crucial. In this study, proper mathematical models of secondary flow velocities along vertical and transverse directions are proposed for steady and uniform turbulent flow through wide open channels with equal smooth and rough bed strips. Starting from the continuity and the Reynolds averaged Navier–Stokes equations, governing equation for secondary velocity is derived first and then using appropriate boundary conditions (no-slip boundary conditions at channel bottom and free surface, and maximum vertical velocity in magnitude at the interface of two cellular secondary cells and at mid-depth of the channel. All these conditions are consistent with several experimental observations). A new model of the streamwise Reynolds shear stress is proposed for the entire cross-sectional plane and using it, the analytical solutions are obtained. Proposed models include the effects of viscosity of the fluid and the eddy viscosity model of turbulence. All suggested models are validated with existing experimental data in rectangular open-channel flows, compound open channel flows, and duct flows, and satisfactory results are obtained. Furthermore, models are also compared with existing empirical models from literature to show the effectiveness and superiority of proposed models. Apart from these, the obtained results from this study are used to investigate the effects of vertical and transverse secondary flow velocities on the settling velocity vector in a cross-sectional plane. Effective alternative models for the settling velocity vector are suggested. The model of settling velocity vector is also compared with the existing model. Finally, all results are justified from physical viewpoints.
Inferring longevity from advanced rib remodelling in insular dwarf deer
Authors: Miszkiewicz Justyna J , Van Der Geer Alexandra A E
Published: February 2022

Dwarfed insular mammals are of significant interest to evolutionary biology because of their morphological and physiological adaptations triggered by variables inherent to geographical isolation. One life history trait that is expected to be modified in relation to body size reduction is extended longevity facilitated by ecological parameters such as predator and competitor release and fluctuating resource availability. However, systematic examination of longevity in extreme cases of dwarfism is difficult as such cases are largely represented by fossils of extinct species. We studied seven rib fragments of the extraordinary endemic Pleistocene dwarf deer Candiacervus (size 2) to test whether its bone matrix shows evidence for extensive bone remodelling typically seen in large and long-living mammals. We found that all ribs had well-remodelled Haversian bone, implying several generations of resorption and re-deposition processes. Osteon density was high relative to small bone cross-section size, with examples of porosity similar to that seen in elderly animals. We report the first combined micro-morphological and micro-morphometric record of Candiacervus rib histology, agreeing with previous literature discussing the evolutionary biology of dwarf ruminants. Further experimental validation of osteon density in extant deer will confirm whether dwarfed Candiacervus indeed lived longer than expected for its body mass.
Reassessing pharmacogenomic cell sensitivity with multilevel statistical models
Authors: Ploenzke Matt , Irizarry Rafael
Published: February 2022

Pharmacogenomic experiments allow for the systematic testing of drugs, at varying dosage concentrations, to study how genomic markers correlate with cell sensitivity to treatment. The first step in the analysis is to quantify the response of cell lines to variable dosage concentrations of the drugs being tested. The signal to noise in these measurements can be low due to biological and experimental variability. However, the increasing availability of pharmacogenomic studies provides replicated data sets that can be leveraged to gain power. To do this, we formulate a hierarchical mixture model to estimate the drug-specific mixture distributions for estimating cell sensitivity and for assessing drug effect type as either broad or targeted effect. We use this formulation to propose a unified approach that can yield posterior probability of a cell being susceptible to a drug conditional on being a targeted effect or relative effect sizes conditioned on the cell being broad. We demonstrate the usefulness of our approach via case studies. First, we assess pairwise agreements for cell lines/drugs within the intersection of two data sets and confirm the moderate pairwise agreement between many publicly available pharmacogenomic data sets. We then present an analysis that identifies sensitivity to the drug crizotinib for cells harboring EML4-ALK or NPM1-ALK gene fusions, as well as significantly down-regulated cell-matrix pathways associated with crizotinib sensitivity.
Co-Desistance From Crime: Engaging the Pro-Social Dimensions of Co-Offending
Authors: Halsey Mark , Mizzi Jenna
Published: February 2022

Drawing on primary data from a unique crime prevention initiative in Australia, this article examines how a small group of co-offenders harnessed the pro-social dimensions of their offending to co-desist from crime. We focus particularly on the evolving nature of group dynamics and the roles played by policing (including non-policing), innovative ‘24/7’ casework, and the provision of a culturally safe divergent setting in the emergence of co-desistance scenarios. We show how initial apprehensions around co-offenders associating in the community were unfounded and in fact proved key to the success of such an approach. Building on the supported desistance literature, the article positions co-desistance as a related but distinct concept worthy of further study in its own right.
A case of SOD1 deficiency: implications for clinical trials
Authors: Farrimond Lucy , Talbot Kevin
Published: February 2022

This scientific commentary refers to ‘Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity’ by Ezer et al. (https://doi.org/10.1093/brain/awab416).
Altered cortical microstructure in preterm infants at term-equivalent age relative to term-born neonates
Authors: Wang Wenjun , Yu Qiaowen , Liang Wenjia , Xu Feifei , Li Zhuoran , Tang Yuchun , Liu Shuwei
Published: February 2022

Preterm (PT) birth is a potential factor for abnormal brain development. Although various alterations of cortical structure and functional connectivity in preterm infants have been reported, the underlying microstructural foundation is still undetected thoroughly in PT infants relative to full-term (FT) neonates. To detect the very early cortical microstructural alteration noninvasively with advanced neurite orientation dispersion and density imaging (NODDI) on a whole-brain basis, we used multi-shell diffusion MRI of healthy newborns selected from the Developing Human Connectome Project. 73 PT infants and 69 FT neonates scanned at term-equivalent age were included in this study. By extracting the core voxels of gray matter (GM) using GM-based spatial statistics (GBSS), we found that comparing to FT neonates, infants born preterm showed extensive lower neurite density in both primary and higher-order association cortices (FWE corrected, P < 0.025). Higher orientation dispersion was only found in very preterm subgroup in the orbitofrontal cortex, fronto-insular cortex, entorhinal cortex, a portion of posterior cingular gyrus, and medial parieto-occipital cortex. This study provided new insights into exploring structural MR for functional and behavioral variations in preterm population, and these findings may have marked clinical importance, particularly in the guidance of ameliorating the development of premature brain.
Market power, markup volatility and the role of cooperatives in the food value chain: evidence from Italy
Authors: Lee Hyejin , Van Cayseele Patrick
Published: February 2022

Agricultural cooperatives are often promoted as a way to give farmers countervailing market power and greater income stability. This paper investigates to what extent cooperatives in food supply chains achieve these objectives. We estimate firm-level markups and markup volatility in the Italian fruits and vegetable (F&V) and dairy sectors at both the farming and processing stages for the period 2007–2014. We find mixed results: compared to non-cooperatives, F&V processor cooperatives have higher markups, while F&V farmer cooperatives and dairy processor cooperatives have lower markups. We do not find strong evidence of their role on markup volatility.
Comparative insight into the roles of the non active-site residues E169 and N173 in imparting the beta-lactamase activity of CTX-M-15
Authors: Verma Jyoti , Jain Diamond , Mallik Dhriti , Ghosh Anindya S
Published: February 2022

CTX-M-15 is a major extended-spectrum beta-lactamase disseminated throughout the globe. The roles of amino acids present in the active-site are widely studied though little is known about the role of the amino acids lying at the close proximity of the CTX-M-15 active-site. Here, by using site-directed mutagenesis we attempted to decipher the role of individual amino acids lying outside the active-site in imparting the beta-lactamase activity of CTX-M-15. Based on the earlier evidence, three amino acid residues namely, Glu169, Asp173 and Arg277 were substituted with alanine. The antibiotic susceptibility of E. coli cells harboring E169A and N173A substituted CTX-M-15 were enhanced by ∼ >32 fold for penicillins and ∼ 4–32 fold for cephalosporins, in comparison to CTX-M-15. However, cells carrying CTX-M-15_R277A did not show a significant difference in antibiotic susceptibility as compared to the wild-type. Further, the catalytic efficiency of the purified CTX-M-15_E169A and CTX-M-15_N173A were compromised when compared with the efficient beta-lactam hydrolysis of purified CTX-M-15. Moreover, the thermal stability of the mutated proteins CTX-M-15_E169A and CTX-M-15_N173A were reduced as compared to the wild type CTX-M-15. Therefore, we conclude that E169 and N173 are crucial non-active-site amino acids that are able to govern the CTX-M-15 activity.
Visualizing the next frontiers in wine yeast research
Authors: Pretorius I S
Published: February 2022

A range of game-changing biodigital and biodesign technologies are coming of age all around us, transforming our world in complex ways that are hard to predict. Not a day goes by without news of how data-centric engineering, algorithm-driven modelling, and biocyber technologies—including the convergence of artificial intelligence, machine learning, automated robotics, quantum computing, and genome editing—will change our world. If we are to be better at expecting the unexpected in the world of wine, we need to gain deeper insights into the potential and limitations of these technological developments and advances along with their promise and perils. This article anticipates how these fast-expanding bioinformational and biodesign toolkits might lead to the creation of synthetic organisms and model systems, and ultimately new understandings of biological complexities could be achieved. A total of four future frontiers in wine yeast research are discussed in this article: the construction of fully synthetic yeast genomes, including minimal genomes; supernumerary pan-genome neochromosomes; synthetic metagenomes; and synthetic yeast communities. These four concepts are at varying stages of development with plenty of technological pitfalls to overcome before such model chromosomes, genomes, strains, and yeast communities could illuminate some of the ill-understood aspects of yeast resilience, fermentation performance, flavour biosynthesis, and ecological interactions in vineyard and winery settings. From a winemaker's perspective, some of these ideas might be considered as far-fetched and, as such, tempting to ignore. However, synthetic biologists know that by exploring these futuristic concepts in the laboratory could well forge new research frontiers to deepen our understanding of the complexities of consistently producing fine wines with different fermentation processes from distinctive viticultural terroirs. As the saying goes in the disruptive technology industry, it take years to create an overnight success. The purpose of this article is neither to glorify any of these concepts as a panacea to all ills nor to crucify them as a danger to winemaking traditions. Rather, this article suggests that these proposed research endeavours deserve due consideration because they are likely to cast new light on the genetic blind spots of wine yeasts, and how they interact as communities in vineyards and wineries. Future-focussed research is, of course, designed to be subject to revision as new data and technologies become available. Successful dislodging of old paradigms with transformative innovations will require open-mindedness and pragmatism, not dogmatism—and this can make for a catch-22 situation in an archetypal traditional industry, such as the wine industry, with its rich territorial and socio-cultural connotations.
What Is an Aging-Related Disease? An Epidemiological Perspective
Authors: Le Couteur David G , Thillainadesan Janani
Published: February 2022

There are no established or standardized definitions of aging-related disease. Data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were used to model the relationship between age and incidence of diseases. Clustering analysis identified 4 groups of noncommunicable diseases: Group A diseases with an exponential increase in incidence with age; Group B diseases with an exponential increase in incidence that usually peaked in late life which then declined or plateaued at the oldest ages; and Groups C and D diseases with an onset in earlier life and where incidence was stable or decreased in old age. From an epidemiological perspective, Group A diseases are “aging-related diseases” because there is an exponential association between age and incidence, and the slope of the incidence curves remains positive throughout old age. These included the major noncommunicable diseases dementia, stroke, and ischemic heart disease. Whether any of the other diseases are aging-related is uncertain because their incidence either does not change or more often decreases in old age. Only biological studies can determine how the aging process contributes to any of these diseases and this may lead to a reclassification of disease on the basis of whether they are directly caused by or are in continuity with the biological changes of aging. In the absence of this mechanistic data, we propose the term “aging-related disease” should be used with precision based on epidemiological evidence.
Development of a quantitative evaluation tool for Seoul’s community-based participatory health program ‘building healthy communities’
Authors: Song Sunmi , Kim Hae-Young , Heo Hyun-Hee
Published: February 2022

Community-based participatory health (CBPH) programs are important for addressing health disparities; however, the limited development of validated scales to measure outcomes may hinder the utilization and upscaling of such programs. Thus, this study aimed to develop a culturally appropriate and valid tool for the quantitative evaluation of a CBPH program and to test theory-driven pathways of associations among participation, social capital, empowerment and health outcomes. This study used a participatory and mixed methods approach. Formative research, including a literature review, survey results over the past 2 years, focus group interviews and participatory evaluation committee meetings, was conducted. Four program components—participation, social capital, empowerment and quality of life (QoL)—were identified and used to construct a validated evaluation tool. A total of 317 participants (89.9% women, mean age = 57.7 ± 11.5 years) responded to the survey. The data were analyzed for internal consistency and factor structure. Structural equation modeling (SEM) was used to test the theoretical pathways of health promotion through the CBPH program. The SEM results showed two significant mediation pathways such that participation in interventions was associated with higher QoL via social capital accumulation and improved empowerment. Our results exemplify a validated scale that can be used to evaluate the intermediate- and long-term outcomes of a CBPH program.
Tinker, Tailor, Twitter, Lie: Government Disinformation and Freedom of Expression in a Post-Truth Era
Authors: Pentney Katie
Published: February 2022

The spread of disinformation has received significant attention in recent years, yet little has been paid to government disinformation, and whether governments may violate freedom of expression not only in how they regulate disinformation, but also in how they facilitate, sow and spread it. This article analyses whether and to what extent Article 10 of the ECHR is engaged by government disinformation. It extends the analysis from well-established violations of freedom of expression—overt censorship and withholding information—into novel forms of government interference in the ‘post-truth’ age: false claims of ‘fake news’ levelled at the press and intentional lies about matters of public importance. These latter categories warrant further attention, as governments can cause just as much harm to public discourse and debate by intentionally injecting falsehoods as by censoring truth. A purposive approach to freedom of expression is needed to protect not only the means of expression, but also the ends—vibrant democratic discourse and meaningful public debate.
The Relationship between Body Appreciation and Health Behaviors among Women and Adolescent Girls: A Scoping Review
Authors: Nolen Erin , Panisch Lisa S
Published: February 2022

Literature on body image and health behaviors has largely been pathology-based, investigating body dissatisfaction and disordered eating. Body appreciation is a useful construct of positive body image and has been used to understand its relationship with health behaviors beyond eating. This scoping review explores the literature on the relationship between body appreciation and physical health-promoting behaviors and health-compromising behaviors. A comprehensive search of databases was conducted to gather correlational studies written in English between January 2005 and November 2019. Behaviors related to eating and exercise were excluded. Nine quantitative studies met inclusion criteria. Evidence suggests an overall positive relationship between body appreciation and health-promoting behaviors, including preventive sexual health behaviors, preventive cancer behaviors, and seeking medical attention. Alternatively, body appreciation is negatively associated with health-compromising behaviors including risky sexual activity and alcohol and tobacco use. Promoting positive body image, above and beyond the reduction of body dissatisfaction, may play a crucial role in the health and well-being of women and girls. Research that examines positive body image in groups that are racially diverse and include sexual and gender minorities and people without healthcare access is urgently needed.
Combining scientific survey and commercial catch data to map fish distribution
Authors: Alglave Baptiste , Rivot Etienne , Etienne Marie-Pierre , Woillez Mathieu , Thorson James T , Vermard Youen
Published: February 2022

Developing Species Distribution Models (SDM) for marine exploited species is a major challenge in fisheries ecology. Classical modelling approaches typically rely on fish research survey data. They benefit from a standardized sampling design and a controlled catchability, but they usually occur once or twice a year and they may sample a relatively small number of spatial locations. Spatial monitoring of commercial data (based on logbooks crossed with Vessel Monitoring Systems) can provide an additional extensive data source to inform fish spatial distribution. We propose a spatial hierarchical framework integrating both data sources while accounting for preferential sampling (PS) of commercial data. From simulations, we demonstrate that PS should be accounted for in estimation when PS is actually strong. When commercial data far exceed scientific data, the later bring little information to spatial predictions in the areas sampled by commercial data, but bring information in areas with low fishing intensity and provide a validation dataset to assess the integrated model consistency. We applied the framework to three demersal species (hake, sole, and squids) in the Bay of Biscay that emphasize contrasted PS intensity and we demonstrate that the framework can account for several fleets with varying catchabilities and PS behaviours.
The global burden of peptic ulcer disease in 204 countries and territories from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019
Authors: Ren Jiajia , Jin Xuting , Li Jiamei , Li Ruohan , Gao Ya , Zhang Jingjing , Wang Xiaochuang , Wang Gang
Published: February 2022

Background

Peptic ulcer disease is one of the most common diseases in gastroenterology clinics. However, reported data about the global burden of peptic ulcer disease are still scarce.

Methods

This was a secondary data analysis on the prevalence, mortality and disability-adjusted life years (DALYs) due to peptic ulcer disease by sex, age group and socio-demographic index (SDI) at the global level in 21 regions and 204 countries and territories between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019.

Results

Globally, the prevalence cases of peptic ulcer disease increased from 6 434 103 (95% uncertainty interval 5 405 963 to 7 627 971) in 1990 to 8 090 476 (6 794 576 to 9 584 000) in 2019. However, the age-standardized prevalence rate decreased from 143.4 (120.5 to 170.2) per 100 000 population in 1990 to 99.4 (83.9 to 117.5) per 100 000 population in 2019. Moreover, the age-standardized mortality rate decreased by 59.4% (55.3 to 63.1) and the DALYs rate fell by 60.6% (56.8 to 63.9) from 1990 to 2019. Across SDI quintiles, low-middle and low SDI quintiles had the highest age-standardized prevalence, mortality and DALYs rates from 1990 to 2019.

Conclusion

The age-standardized prevalence, mortality and DALYs estimates of peptic ulcer disease decreased from 1990 to 2019 globally, but more efforts are needed for the prevention, early diagnosis and treatment of peptic ulcer disease in low SDI and low-middle SDI groups of countries.
Impact of Latent Tuberculosis on Diabetes
Authors: Tepekule Burcu , Kusejko Katharina , Zeeb Marius , Tarr Philip E , Calmy Alexandra , Battegay Manuel , Furrer Hansjakob , Cavassini Matthias , Bernasconi Enos , Notter Julia , Günthard Huldrych F , Nemeth Johannes , Kouyos Roger D ,   Swiss HIV Cohort Study, Abela I , Aebi-Popp K , Anagnostopoulos A , Battegay M , Bernasconi E , Braun D L , Bucher H C , Calmy A , Cavassini M , Ciuffi A , Dollenmaier G , Egger M , Elzi L , Fehr J , Fellay J , Furrer H , Fux C A , Günthard H F , Hachfeld A , Haerry D , Hasse B , Hirsch H H , Hoffmann M , Hösli I , Huber M , Kahlert C R , Kaiser L , Keiser O , Klimkait T , Kouyos R D , Kovari H , Kusejko K , Martinetti G , Martinez de Tejada B , Marzolini C , Metzner K J , Müller N , Nemeth J , Nicca D , Paioni P , Pantaleo G , Perreau M , Rauch A , Schmid P , Speck R , Stöckle M , Tarr P , Trkola A , Wandeler G , Yerly S
Published: February 2022

While an increased risk of active and latent tuberculosis infection (LTBI) in people with type-2 diabetes (DM) has been demonstrated, it is less well characterized whether LTBI is associated with an increased risk of developing DM. We investigated the link between LTBI and DM in people living with HIV in the Swiss HIV Cohort Study via time-dependent Cox proportional hazards models. We found that LTBI significantly increased the risk of developing DM (HR = 1.47), which was robust across different adjustment and censoring techniques. Our results thus suggest that LTBI may be associated with an increased risk of developing DM.
One Health compartmental analysis of ESBL-producing Escherichia coli on Reunion Island reveals partitioning between humans and livestock
Authors: Miltgen Guillaume , Martak Daniel , Valot Benoit , Kamus Laure , Garrigos Thomas , Verchere Guillaume , Gbaguidi-Haore Houssein , Ben Cimon Céline , Ramiandrisoa Mahery , Picot Sandrine , Lignereux Anne , Masson Geoffrey , Jaffar-Bandjee Marie-Christine , Belmonte Olivier , Cardinale Eric , Hocquet Didier , Mavingui Patrick , Bertrand Xavier
Published: February 2022

Background

Extended-spectrum β-lactamase-producing Escherichia coli (ESBL-Ec) is a major cause of infections worldwide. An understanding of the reservoirs and modes of transmission of these pathogens is essential, to tackle their increasing frequency.

Objectives

We investigated the contributions of various compartments (humans, animals, environment), to human colonization or infection with ESBL-Ec over a 3 year period, on an island.

Methods

The study was performed on Reunion Island (Southwest Indian Ocean). We collected ESBL-Ec isolates prospectively from humans, wastewater and livestock between April 2015 and December 2018. Human specimens were recovered from a regional surveillance system representative of the island’s health facilities. These isolates were compared with those from livestock and urban/rural wastewater, by whole-genome sequencing.

Results

We collected 410 ESBL-Ec isolates: 161 from humans, 161 from wastewater and 88 from animals. Phylogenomic analysis demonstrated high diversity (100 STs), with different STs predominating among isolates from humans (ST131, ST38, ST10) and animals (ST57, ST156). The large majority (90%) of the STs, including ST131, were principally associated with a single compartment. The CTX-M-15, CTX-M-27 and CTX-M-14 enzymes were most common in humans/human wastewater, whereas CTX-M-1 predominated in animals. Isolates of human and animal origin had different plasmids carrying blaCTX-M genes, with the exception of a conserved IncI1-ST3 blaCTX-M-1 plasmid.

Conclusions

These molecular data suggest that, despite their high level of contamination, animals are not a major source of the ESBL-Ec found in humans living on this densely populated high-income island. Public health policies should therefore focus primarily on human-to-human transmission, to prevent human infections with ESBL-Ec.
Management of elderly patients with early gastric cancer in Japan
Authors: Sekiguchi Masau , Oda Ichiro , Morita Shinji , Katai Hitoshi , Yano Tomonori , Terashima Masanori , Kataoka Tomoko , Muto Manabu
Published: February 2022

Management of elderly patients with early gastric cancer is an important issue in an aging society such as Japan. While endoscopic resection is recommended as the standard treatment for early gastric cancers with extremely low risk of lymph node metastasis (<1%), gastrectomy with lymphadenectomy is recommended for the other early gastric cancers as the standard treatment even in elderly patients. Endoscopic submucosal dissection is the most recommended endoscopic resection procedure because of its high ability for ‘en bloc’ resection. Endoscopic submucosal dissection can reportedly provide favorable short-term outcomes in elderly patients. In terms of patient prognosis, the importance of considering patients’ physical and nutritional conditions before endoscopic submucosal dissection has recently attracted attention. With respect to gastrectomy, the nationwide data in Japan have demonstrated relatively low 5-year overall survival and non-negligible post-operative 90-day mortality in men aged ≥75 years and women aged ≥80 years compared with those in younger patients. Among these elderly patients, 20% or more reportedly died within 5 years after gastrectomy mostly due to other diseases. These facts suggested the necessity of a less invasive management option for the elderly patients. Efforts are being made to provide a non-invasive follow-up option without gastrectomy following endoscopic resection in elderly patients. To avoid the increase in gastric cancer-related deaths, the selection of patients with relatively low lymph node metastasis risk is essential, and several tools to estimate the lymph node metastasis risk from early gastric cancers have been developed. To avoid overtreatment with gastrectomy in more elderly early gastric cancer patients, new endoscopic submucosal dissection indications for them are also warranted.
Management of elderly patients with bone and soft tissue sarcomas: JCOG Bone and Soft Tissue Tumor Study Group
Authors: Tanaka Kazuhiro , Ozaki Toshifumi
Published: February 2022

Approximately, 40% of bone sarcomas and 60% of soft tissue sarcoma arise in patients aged ≥65 years. However, because sarcoma is very rare, there is little evidence regarding the management of elderly patients with sarcoma. Age has been reported as a prognostic factor in patients with sarcomas. The standard therapy for all localized bone and soft tissue sarcomas is surgical resection, even in elderly patients. Radiation or ion-beam therapy can be considered for unresectable sarcomas. Although adjuvant chemotherapy is standard for osteosarcoma, the usefulness of adjuvant chemotherapy for elderly patients has not been verified; therefore, it may not be recommended for elderly patients with osteosarcoma. For elderly patients with advanced osteosarcoma, if general conditions permit, doxorubicin- and/or ifosfamide-based regimens as well as molecular-targeted therapies, including sorafenib, regorafenib and everolimus, may be considered, although these drugs have not been approved for sarcoma in Japan. Adjuvant chemotherapy with doxorubicin plus ifosfamide is recommended for patients with high-risk localized soft tissue sarcoma if they are aged ≤70 years. For first-line treatment of advanced soft tissue sarcoma in elderly patients, doxorubicin monotherapy is considered to be the standard regimen, and pazopanib can be an alternative. For second-line treatment, gemcitabine-based regimens, pazopanib, trabectedin and eribulin may be options for elderly patients with advanced soft tissue sarcoma.
Cellular Telephone Use and the Risk of Brain Tumors: Update of the UK Million Women Study
Authors: Schüz Joachim , Pirie Kirstin , Reeves Gillian K , Floud Sarah , Beral Valerie ,   for the Million Women Study Collaborators
Published: February 2022

Background

The ongoing debate of whether use of cellular telephones increases the risk of developing a brain tumor was recently fueled by the launch of the fifth generation of wireless technologies. Here, we update follow-up of a large-scale prospective study on the association between cellular telephone use and brain tumors.

Methods

During 1996-2001, 1.3 million women born in 1935-1950 were recruited into the study. Questions on cellular telephone use were first asked in median year 2001 and again in median year 2011. All study participants were followed via record linkage to National Health Services databases on deaths and cancer registrations (including nonmalignant brain tumors).

Results

During 14 years follow-up of 776 156 women who completed the 2001 questionnaire, a total of 3268 incident brain tumors were registered. Adjusted relative risks for ever vs never cellular telephone use were 0.97 (95% confidence interval = 0.90 to 1.04) for all brain tumors, 0.89 (95% confidence interval = 0.80 to 0.99) for glioma, and not statistically significantly different to 1.0 for meningioma, pituitary tumors, and acoustic neuroma. Compared with never-users, no statistically significant associations were found, overall or by tumor subtype, for daily cellular telephone use or for having used cellular telephones for at least 10 years. Taking use in 2011 as baseline, there were no statistically significant associations with talking for at least 20 minutes per week or with at least 10 years use. For gliomas occurring in the temporal and parietal lobes, the parts of the brain most likely to be exposed to radiofrequency electromagnetic fields from cellular telephones, relative risks were slightly below 1.0.

Conclusion

Our findings support the accumulating evidence that cellular telephone use under usual conditions does not increase brain tumor incidence.
Phenotyping methods to assess heat stress resilience in grapevine
Authors: Pettenuzzo Silvia , Cappellin Luca , Grando Maria Stella , Costantini Laura
Published: February 2022

Global warming has become an issue in recent years in viticulture, as increasing temperatures have a negative impact on grapevine (Vitis vinifera) production and on wine quality. Phenotyping for grapevine response to heat stress is, therefore, important to understand thermotolerance mechanisms, with the aim of improving field management strategies or developing more resilient varieties. Nonetheless, the choice of the phenotypic traits to be investigated is not trivial and depends mainly on the objectives of the study, but also on the number of samples and on the availability of instrumentation. Moreover, the grapevine literature reports few studies related to thermotolerance, generally assessing physiological responses, which highlights the need for more holistic approaches. In this context, the present review offers an overview of target traits that are commonly investigated in plant thermotolerance studies, with a special focus on grapevine, and of methods that can be employed to evaluate those traits. With the final goal of providing useful tools and references for future studies on grapevine heat stress resilience, advantages and limitations of each method are highlighted, and the available or possible implementations are described. In this way, the reader is guided in the choice of the best approaches in terms of speed, complexity, range of application, sensitivity, and specificity.
The effects of self-interacting dark matter on the stripping of galaxies that fall into clusters
Authors: Sirks Ellen L , Oman Kyle A , Robertson Andrew , Massey Richard , Frenk Carlos
Published: February 2022

We use the Cluster-EAGLE (c-eagle) hydrodynamical simulations to investigate the effects of self-interacting dark matter (SIDM) on galaxies as they fall into clusters. We find that SIDM galaxies follow similar orbits to their cold dark matter (CDM) counterparts, but end up with ∼25 per cent less mass by the present day. One in three SIDM galaxies is entirely disrupted, compared to one in five CDM galaxies. However, the excess stripping will be harder to observe than suggested by previous DM-only simulations because the most stripped galaxies form cores and also lose stars: The most discriminating objects become unobservable. The best test will be to measure the stellar-to-halo mass relation (SHMR) for galaxies with stellar mass $10^{10}\!-\!10^{11}\, \mathrm{M}_{\odot }$. This is 8 times higher in a cluster than in the field for a CDM universe, but 13 times higher for an SIDM universe. Given intrinsic scatter in the SHMR, these models could be distinguished with noise-free galaxy–galaxy strong lensing of ∼32 cluster galaxies.
The intracluster light on Frontier Fields clusters Abell 370 and Abell S1063
Authors: de Oliveira Nícolas O L , Jiménez-Teja Yolanda , Dupke Renato
Published: February 2022

We analysed the contribution of the intracluster light (ICL) to the total luminosity of two massive galaxy clusters observed by the Hubble Space Telescope within the Frontier Fields program, Abell 370 (z ∼ 0.375) and Abell S1063 (z ∼ 0.348), in order to correlate it with the dynamical stage of these systems. We applied an algorithm based on the Chebyshev–Fourier functions called CICLE, specially developed to disentangle the ICL from the light of galaxies and measure the ICL fraction. We measured the ICL fraction in three broad-band optical filters, F435W, F606W, and F814W, without assuming any prior hypothesis about the ICL physical properties or morphology. The results obtained from the ICL fraction vary between $\sim 7\!-\!25{{\ \rm per\ cent}}$, and $\sim 3\!-\!22{{\ \rm per\ cent}}$ for both A370 and AS1063, respectively, which are consistent with theoretical predictions for the total amount of ICL obtained by ICL formation and evolution simulations. We found enhanced ICL fractions in the intermediate filter F606W for both clusters and we suggest that this is due to the presence of an excess of younger/lower metallicity stars in the ICL compared to the cluster galaxies. We conclude that both Abell 370 and Abell S1063 are merging systems since they exhibit a similar feature as merging CLASH and Frontier Fields clusters sub-sample previously analysed. We compare these results to the dynamical indicators obtained through different methods and we reinforce the use of ICL as a new and independent method to determine the dynamical state of clusters of galaxies.
Seasonal exacerbation of rheumatoid arthritis detected by big claims data analysis: A retrospective population study
Authors: Ando Fumihiko , Takabayashi Katsuhiko , Fujita Shinsuke , Nakajima Hiroshi , Hanaoka Hideki , Suzuki Takahiro
Published: February 2022

Objectives

The objective of the study was to determine the seasonal changes in the initiation of biological disease-modifying antirheumatic drugs (bDMARDs) and methotrexate (MTX) using big claims data.

Methods

We counted the monthly number of initial administrations of each bDMARD and MTX in patients with rheumatoid arthritis (RA) between April 2010 and March 2017. Data were collected from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. This database covers more than 95% of Japanese citizens. Seasonal changes in the number of initiations were determined. Patient claims were also classified according to drugs, districts, gender, and ages.

Results

The initiation of bDMARDs and MTX administration varied according to the season in a sine curve shape, with the highest numbers in May to July and the lowest numbers in November to January. The same changing pattern was observed among each bDMARD, district, gender, and age groups particularly when the number was on the higher side.

Conclusion

We noted an apparent seasonal change in the number of bDMARDs initiated, with a peak during spring, suggesting an exacerbation of RA in the spring in Japan. These changes are overlooked in daily practice and are only visible using big data.
Rituximab in the real-world treatment of lupus nephritis: A retrospective cohort study in Japan
Authors: Tanaka Yoshiya , Nakayamada Shingo , Yamaoka Kunihiro , Ohmura Koichiro , Yasuda Shinsuke
Published: February 2022

Objectives

Although recommended in established international guidelines for lupus nephritis (LN), rituximab is not officially approved for LN treatment, making all such use off-label. The Japan College of Rheumatology (JCR) conducted a retrospective observational study on real-world efficacy and safety of rituximab treatment for LN in Japan.

Methods

Clinical data were collected from 47 hospitals for LN patients treated with rituximab to retrospectively investigate dosing schedule, efficacy, and safety.

Results

This retrospective analysis included 115 patients: 84 (73%) received 375 mg/m2 weekly up to four doses, and 31 (27%) received 1000 mg/body in one or two doses 2 weeks apart. Rituximab significantly improved findings for urinalysis, systemic lupus erythematosus serology, and systemic lupus erythematosus disease activity and was assessed as ‘extremely effective’ in 24.8% of patients and ‘effective’ in 60.2%. The renal response by the JCR-I criteria was 52.5% for overall response rate (ORR) (complete renal response rate 20.8% and partial renal response rate 31.7%) and that by the JCR-II criteria was 49.5% (21.8% and 27.7%, respectively). Corticosteroid dose was significantly reduced. Rituximab was well tolerated, with frequent but manageable adverse events of infusion reaction and infection.

Conclusions

Rituximab is effective for the treatment of Japanese patients with LN refractory to conventional therapy.
Spacer2PAM: A computational framework to guide experimental determination of functional CRISPR-Cas system PAM sequences
Authors: Rybnicky Grant A , Fackler Nicholas A , Karim Ashty S , Köpke Michael , Jewett Michael C
Published: February 2022

RNA-guided nucleases from CRISPR-Cas systems expand opportunities for precise, targeted genome modification. Endogenous CRISPR-Cas systems in many prokaryotes are attractive to circumvent expression, functionality, and unintended activity hurdles posed by heterologous CRISPR-Cas effectors. However, each CRISPR-Cas system recognizes a unique set of protospacer adjacent motifs (PAMs), which requires identification by extensive screening of randomized DNA libraries. This challenge hinders development of endogenous CRISPR-Cas systems, especially those based on multi-protein effectors and in organisms that are slow-growing or have transformation idiosyncrasies. To address this challenge, we present Spacer2PAM, an easy-to-use, easy-to-interpret R package built to predict and guide experimental determination of functional PAM sequences for any CRISPR-Cas system given its corresponding CRISPR array as input. Spacer2PAM can be used in a ‘Quick’ method to generate a single PAM prediction or in a ‘Comprehensive’ method to inform targeted PAM libraries small enough to screen in difficult to transform organisms. We demonstrate Spacer2PAM by predicting PAM sequences for industrially relevant organisms and experimentally identifying seven PAM sequences that mediate interference from the Spacer2PAM-informed PAM library for the type I-B CRISPR-Cas system from Clostridium autoethanogenum. We anticipate that Spacer2PAM will facilitate the use of endogenous CRISPR-Cas systems for industrial biotechnology and synthetic biology.
8-oxodG accumulation within super-enhancers marks fragile CTCF-mediated chromatin loops
Authors: Scala Giovanni , Gorini Francesca , Ambrosio Susanna , Chiariello Andrea M , Nicodemi Mario , Lania Luigi , Majello Barbara , Amente Stefano
Published: February 2022

8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a major product of the DNA oxidization process, has been proposed to have an epigenetic function in gene regulation and has been associated with genome instability. NGS-based methodologies are contributing to the characterization of the 8-oxodG function in the genome. However, the 8-oxodG epigenetic role at a genomic level and the mechanisms controlling the genomic 8-oxodG accumulation/maintenance have not yet been fully characterized. In this study, we report the identification and characterization of a set of enhancer regions accumulating 8-oxodG in human epithelial cells. We found that these oxidized enhancers are mainly super-enhancers and are associated with bidirectional-transcribed enhancer RNAs and DNA Damage Response activation. Moreover, using ChIA-PET and HiC data, we identified specific CTCF-mediated chromatin loops in which the oxidized enhancer and promoter regions physically associate. Oxidized enhancers and their associated chromatin loops accumulate endogenous double-strand breaks which are in turn repaired by NHEJ pathway through a transcription-dependent mechanism. Our work suggests that 8-oxodG accumulation in enhancers–promoters pairs occurs in a transcription-dependent manner and provides novel mechanistic insights on the intrinsic fragility of chromatin loops containing oxidized enhancers-promoters interactions.
Responsibility for Acts and Omissions
Authors: Clarke Randolph
Published: February 2022

Accounts of moral responsibility commonly focus on responsibility for actions and their consequences. But we can be responsible as well for omitting to act or refraining from acting, and for consequences of these. And since omitting and refraining are not in every case performing an action, an account of responsibility for actions will not apply straightforwardly to these cases. This paper advances proposals concerning responsibility for omitting, refraining, and their consequences. Providing such an account is complicated by the fact that cases of omitting or refraining are quite varied.
Instrumentalist Theories of Moral Responsibility
Authors: Vargas Manuel
Published: February 2022

In both the historical and contemporary literature on moral responsibility, there are accounts of responsibility that appeal to instrumentalist considerations in accounting for, variously, the nature, structure, and justification of moral responsibility. On the face of it, instrumentalist approaches can seem ill-suited for delivering an adequate theory of responsibility. For example, if one thinks that the hallmark of moral responsibility is its retrospective or “backward-looking” focus, that it involves some notion of desert, or that it somehow invokes or justifies retributive attitudes, instrumentalist theories of responsibility can seem to be nonstarters. Even so, instrumentalist (or “consequentialist”) approaches to responsibility have a storied pedigree within analytic philosophy. In recent years, the approach has enjoyed renewed attention and rehabilitation. This chapter provides an overview of instrumentalist theories of responsibility, including their history, recent developments, and ongoing disputes.
Ethics Is Hard! What Follows? On Moral Ignorance and Blame
Authors: Harman Elizabeth
Published: February 2022

When someone acts morally wrongly because they are caught in the grip of a false moral view, although they have thought a reasonable amount about morality, are they thereby blameless for so acting? Recently, a number of philosophers have embraced the view that moral ignorance does exculpate in such cases. This chapter outlines an attractive line of thought according to which moral ignorance exculpates. This line of thought is mistaken: Being caught in the grip of a false moral view is not exculpatory. Ethics is hard, that’s true. But this doesn’t have the implications for blameworthiness that some people think it does.
Group Responsibility
Authors: List Christian
Published: February 2022

Are groups ever capable of bearing responsibility, over and above their individual members? This chapter discusses and defends the view that certain organized collectives—namely, those that qualify as group moral agents—can be held responsible for their actions, and that group responsibility is not reducible to individual responsibility. The view has important implications. It supports the recognition of corporate civil and even criminal liability in our legal systems, and it suggests that, by recognizing group agents as loci of responsibility, we may be able to avoid “responsibility gaps” in some cases of collectively caused harms for which there is a shortfall of individual responsibility. The chapter also asks whether the view that certain groups are responsible agents commits us to the view that those groups should also be given rights of their own and gives a qualified negative answer.
Forgiveness
Authors: Milam Per-Erik
Published: February 2022

The responsibility and forgiveness literatures have only recently begun to influence one another in a significant way. The aim of this chapter is to introduce a common model of forgiveness and some recent challenges to it, each of which highlights potential connections between forgiveness and responsibility. According to the Standard View, to forgive is to overcome one’s blame toward a culpable wrongdoer. One of the most compelling alternatives to this view is the Norm Changing View, which understands forgiving as the exercise of a normative power that changes what the offender owes the victim. Which of these views one prefers has implications for how one understands the various features of forgiveness, including who can forgive, the difficulty of forgiving, and the possibility of withdrawing forgiveness.