bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rates, causes and predictors of all-cause and avoidable mortality in 163 686 children and young people with and without intellectual disabilities: a record linkage national cohort study
Authors: Hughes-McCormack Laura Anne , Rydzewska Ewelina , Cooper Sally-Ann , Fleming Michael , Mackay Daniel , Dunn Kirsty , Ward Laura , Sosenko Filip , Barlow Fiona , Miller Jenny , Symonds Joseph D , Jani Bhautesh D , Truesdale Maria , Cairns Deborah , Pell Jill , Henderson Angela , Melville Craig 
Published: September 2022

ObjectivesTo investigate mortality rates and associated factors, and avoidable mortality in children/young people with intellectual disabilities.DesignRetrospective cohort; individual record-linked data between Scotland’s 2011 Census and 9.5 years of National Records for Scotland death certification data.SettingGeneral community.ParticipantsChildren and young people with intellectual disabilities living in Scotland aged 5–24 years, and an age-matched comparison group.Main outcome measuresDeaths up to 2020: age of death, age-standardised mortality ratios (age-SMRs); causes of death including cause-specific age-SMRs/sex-SMRs; and avoidable deaths.ResultsDeath occurred in 260/7247 (3.6%) children/young people with intellectual disabilities (crude mortality rate=388/100 000 person-years) and 528/156 439 (0.3%) children/young people without intellectual disabilities (crude mortality rate=36/100 000 person-years). SMRs for children/young people with versus those without intellectual disabilities were 10.7 for all causes (95% CI 9.47 to 12.1), 5.17 for avoidable death (95% CI 4.19 to 6.37), 2.3 for preventable death (95% CI 1.6 to 3.2) and 16.1 for treatable death (95% CI 12.5 to 20.8). SMRs were highest for children (27.4, 95% CI 20.6 to 36.3) aged 5–9 years, and lowest for young people (6.6, 95% CI 5.1 to 8.6) aged 20–24 years. SMRs were higher in more affluent neighbourhoods. Crude mortality incidences were higher for the children/young people with intellectual disabilities for most International Statistical Classification of Diseases and Related Health Problems, 10th Revision chapters. The most common underlying avoidable causes of mortality for children/young people with intellectual disabilities were epilepsy, aspiration/reflux/choking and respiratory infection, and for children/young people without intellectual disabilities were suicide, accidental drug-related deaths and car accidents.ConclusionChildren with intellectual disabilities had significantly higher rates of all-cause, avoidable, treatable and preventable mortality than their peers. The largest differences were for treatable mortality, particularly at ages 5–9 years. Interventions to improve healthcare to reduce treatable mortality should be a priority for children/young people with intellectual disabilities. Examples include improved epilepsy management and risk assessments, and coordinated multidisciplinary actions to reduce aspiration/reflux/choking and respiratory infection. This is necessary across all neighbourhoods.
Economic burden of excess weight among older adults in Singapore: a cross-sectional study
Authors: Junxing Chay , Huynh Vinh Anh , Lamoureux Ecosse , Tham Kwang Wei , Finkelstein Eric Andrew 
Published: September 2022

ObjectivesTo estimate the incremental per capita and aggregate direct and indirect costs of excess weight among older adults (aged 40–80) in Singapore.DesignSecondary data analysis of an existing cross-sectional surveySettingResidential districts in South-West SingaporeParticipants5848 older adults (aged 40–80) from Singapore’s three dominant ethnic groupsPrimary and secondary outcome measuresWe used regression models to estimate per capita medical expenditures and absenteeism costs attributable to overweight and obesity based on WHO’s body-mass index (BMI) classification. Per capita estimates were multiplied by prevalence to obtain aggregate costs.ResultsThe sample included 2467 Chinese, 2128 Indians and 1253 Malays. Indians and Malays are three to four times more likely to be obese (BMI≥30 kg/m2) than Chinese. Among Chinese, compared with those who are normal weight, individuals who are overweight missed one additional workday per year more (p<0.05). Individuals in the obese category had S$720 per year greater medical expenditures (p<0.05) but missed workdays were not statistically different from those in the normal weight category. Among Indians, differences were not significant between normal and overweight categories. Indians in the obese category incurred an additional S$310 per year (p<0.10) more than those of normal weight. For Malays, no significant differences by BMI category were identified. Aggregate burden is estimated at S$261M (million) (95% CI: 57M to 465M) with 68% from medical expenditures. Chinese, Malays and Indians make up 79%, 12% and 9% of the population, respectively, but account for 76%, 19% and 4% of the costs of excess weight respectively.ConclusionExcess weight imposes a substantial health and economic burden among older Singaporeans. Successful efforts to prevent and reduce obesity prevalence may generate both health and economic improvements.
Disordered eating behaviours and eating disorders in adults with type 1 diabetes (DEBBI): rational and design of an observational longitudinal online study
Authors: Priesterroth Lilli , Grammes Jennifer , Strohm Edda Anna , Kubiak Thomas 
Published: September 2022

IntroductionDisordered eating behaviours (DEB) and eating disorders (ED) are among the most common mental health comorbidities of type 1 diabetes. However, research on diabetes-specific risk and protective factors is limited. To this end, comprehensive characterisations of DEB and ED in type 1 diabetes, as well as longitudinal research on the course of DEB and ED, are needed to gain more insight. The ‘Disordered eating behaviours and eating disorders in diabetes type I’ (DEBBI) study aims to describe DEB/ED and their correlates in people with type 1 diabetes, to identify key diabetes-specific, psychosocial risk and protective factors, and to describe the course of DEB over time.Methods and analysisThe DEBBI study is a longitudinal online survey with follow-up assessments after 6, 12 and 18 months, targeted at adults who have been diagnosed with type 1 diabetes for at least 12 months. The survey covers data on diabetes diagnosis and self-management (eg, diabetes treatment and complications), lifestyle (eg, eating habits, physical activity), psychosocial well-being (eg, anxiety, depressive symptoms) and demographic and medical information. It includes validated instruments and self-generated items. One key aspect of the data analysis will be latent profile analyses to determine latent subtypes of DEB manifestation in people with type 1 diabetes and their courses over time, including data on the clinical picture and symptoms, behaviours and diabetes-specific complications.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the State Medical Chamber of Rhineland-Palatine, Germany (ID 2021-16040). Participants give informed written consent before starting the survey. The DEBBI study will provide more clarity in the so far inconsistent empirical evidence base and will help to inform research on prevention and intervention strategies that are tailored to diabetes-specific needs.Trial registration numberThe study is registered with DRKS German Clinical Trials Register (DRKS00028833).
Quantitative Spatial Profiling of Immune Populations in Pancreatic Ductal Adenocarcinoma Reveals Tumor Microenvironment Heterogeneity and Prognostic Biomarkers
Authors: Mi Haoyang , Sivagnanam Shamilene , Betts Courtney B. , Liudahl Shannon M. , Jaffee Elizabeth M. , Coussens Lisa M. , Popel Aleksander S. 
Published: September 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor 5-year survival rates, necessitating identification of novel therapeutic targets. Elucidating the biology of the tumor immune microenvironment (TiME) can provide vital insights into mechanisms of tumor progression. In this study, we developed a quantitative image processing platform to analyze sequential multiplexed IHC data from archival PDAC tissue resection specimens. A 27-plex marker panel was employed to simultaneously phenotype cell populations and their functional states, followed by a computational workflow to interrogate the immune contextures of the TiME in search of potential biomarkers. The PDAC TiME reflected a low-immunogenic ecosystem with both high intratumoral and intertumoral heterogeneity. Spatial analysis revealed that the relative distance between IL10+ myelomonocytes, PD-1+ CD4+ T cells, and granzyme B+ CD8+ T cells correlated significantly with survival, from which a spatial proximity signature termed imRS was derived that correlated with PDAC patient survival. Furthermore, spatial enrichment of CD8+ T cells in lymphoid aggregates was also linked to improved survival. Altogether, these findings indicate that thePDAC TiME, generally considered immuno-dormant or immunosuppressive, is a spatially nuanced ecosystem orchestrated by ordered immune hierarchies. This new understanding of spatial complexity may guide novel treatment strategies for PDAC.
Significance: Quantitative image analysis of PDAC specimens reveals intertumoral and intratumoral heterogeneity of immune populations and identifies spatial immune architectures that are significantly associated with disease prognosis.
Space Is the Place: Mapping the Cell–Cell Interactions That Predict Immunotherapy Responses in Melanoma
Authors: Smalley Inna , Smalley Keiran S.M. 
Published: September 2022

AbstractAlthough immune checkpoint inhibition (ICI) has revolutionized the treatment of advanced melanoma, reliable predictive biomarkers are still lacking. In this issue of Cancer Research, Antoranz and colleagues used RNA sequencing and multiplexed IHC to study the spatial immune landscape of pretreatment melanoma specimens from patients who either responded or did not respond to antiprogrammed death protein 1 (PD-1) therapy. The authors identified the spatial interaction between cytotoxic T cells and M1-like macrophages expressing PD-L1 at the tumor boundary as predictive of responses to immune checkpoint inhibition. These studies pave the way for the development of new spatial biomarkers to identify patients most likely to benefit from ICI therapy.See related article by Antoranz et al., p. 3275
Development of a Molecular Blood-Based Immune Signature Classifier as Biomarker for Risks Assessment in Lung Cancer Screening
Authors: Fortunato Orazio , Huber Veronica , Segale Miriam , Cova Agata , Vallacchi Viviana , Squarcina Paola , Rivoltini Licia , Suatoni Paola , Sozzi Gabriella , Pastorino Ugo , Boeri Mattia 
Published: September 2022

Abstract

Background:
Low-dose CT (LDCT) screening trials have shown that lung cancer early detection saves lives. However, a better stratification of the screening population is still needed. In this respect, we generated and prospectively validated a plasma miRNA signature classifier (MSC) able to categorize screening participants according to lung cancer risk. Here, we aimed to deeply characterize the peripheral immune profile and develop a diagnostic immune signature classifier to further implement blood testing in lung cancer screening.

Methods:
Peripheral blood mononuclear cell (PBMC) samples collected from 20 patients with LDCT-detected lung cancer and 20 matched cancer-free screening volunteers were analyzed by flow cytometry using multiplex panels characterizing both lymphoid and myeloid immune subsets. Data were validated in PBMC from 40 patients with lung cancer and 40 matched controls and in a lung cancer specificity set including 27 subjects with suspicious lung nodules. A qPCR-based gene expression signature was generated resembling selected immune subsets.

Results:
Monocytic myeloid-derived suppressor cell (MDSC), polymorphonuclear MDSC, intermediate monocytes and CD8+PD-1+ T cells distinguished patients with lung cancer from controls with AUCs values of 0.94/0.72/0.88 in the training, validation, and lung cancer specificity set, respectively. AUCs raised up to 1.00/0.84/0.92 in subgroup analysis considering only MSC-negative subjects. A 14-immune genes expression signature distinguished patients from controls with AUC values of 0.76 in the validation set and 0.83 in MSC-negative subjects.

Conclusions:
An immune-based classifier can enhance the accuracy of blood testing, thus supporting the contribution of systemic immunity to lung carcinogenesis.

Impact:
Implementing LDCT screening trials with minimally invasive blood tests could help reduce unnecessary procedures and optimize cost-effectiveness.
FDA Approval Summary: Mobocertinib for Metastatic Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations
Authors: Duke Elizabeth S. , Stapleford Liza , Drezner Nicole , Amatya Anup K. , Mishra-Kalyani Pallavi S. , Shen Yuan-Li , Maxfield Kimberly , Zirkelbach Jeanne Fourie , Bi Youwei , Liu Jiang , Zhang Xinyuan , Wang Hezhen , Yang Yuching , Zheng Nan , Reece Kelie , Wearne Emily , Glen Jacqueline J. , Ojofeitimi Idara , Scepura Barbara , Nair Abhilasha , Bikkavilli Rama Kamesh , Ghosh Soma , Philip Reena , Pazdur Richard , Beaver Julia A. , Singh Harpreet , Donoghue Martha 
Published: September 2022

Abstract
On September 15, 2021, the FDA granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788–15–101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial that included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% [95% confidence interval (CI), 20%–37%] with a median duration of response of 17.5 months (95% CI, 7.4–20.3). The most common adverse reactions (&gt;20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and torsades de pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation–positive NSCLC.
A Neural Model for Insect Steering Applied to Olfaction and Path Integration
Authors: Adden Andrea , Stewart Terrence C. , Webb Barbara , Heinze Stanley 
Published: September 2022

Abstract
Many animal behaviors require orientation and steering with respect to the environment. For insects, a key brain area involved in spatial orientation and navigation is the central complex. Activity in this neural circuit has been shown to track the insect's current heading relative to its environment and has also been proposed to be the substrate of path integration. However, it remains unclear how the output of the central complex is integrated into motor commands. Central complex output neurons project to the lateral accessory lobes (LAL), from which descending neurons project to thoracic motor centers. Here, we present a computational model of a simple neural network that has been described anatomically and physiologically in the LALs of male silkworm moths, in the context of odor-mediated steering. We present and analyze two versions of this network, one rate based and one based on spiking neurons. The modeled network consists of an inhibitory local interneuron and a bistable descending neuron (flip-flop) that both receive input in the LAL. The flip-flop neuron projects onto neck motor neurons to induce steering. We show that this simple computational model not only replicates the basic parameters of male silkworm moth behavior in a simulated odor plume but can also take input from a computational model of path integration in the central complex and use it to steer back to a point of origin. Furthermore, we find that increasing the level of detail within the model improves the realism of the model's behavior, leading to the emergence of looping behavior as an orientation strategy. Our results suggest that descending neurons originating in the LALs, such as flip-flop neurons, are sufficient to mediate multiple steering behaviors. This study is therefore a first step to close the gap between orientation circuits in the central complex and downstream motor centers.
Protecting the Borders from the Outside
Authors: Letourneux Laura 
Published: September 2022

Abstract
Regulation (EU) 2016/1624 enables Frontex to launch operations in the territory of third countries. Accordingly, status agreements between the EU and the Western Balkan countries as well as Moldova have been concluded. This article provides an in-depth analysis of these instruments. As this article will demonstrate, the conclusion of the status agreements constitutes an improvement, in comparison with the instruments of cooperation already in place. Yet, their implementation could lead to human rights violations. The status agreements provide that the team members sent by Frontex act under the instructions of the host state. Consequently, the third state would incur the prime responsibility for human rights violations committed by these border guards. This transfer of authority has not been stemmed from a transfer of jurisdiction over acts committed by the members of the team: rather they are entitled to immunity for all acts committed during their official functions.
The Transregional Illustrated Magazine Al-Arabi
Authors: Gräf Bettina , Hindelang Laura 
Published: September 2022

Abstract
This article investigates the transregional cultural magazine Al-Arabi (al-‘Arabi) during the late 1950s and 1960s under its first editor, the Egyptian scientist Ahmad Zaki. Founded in Kuwait, the magazine’s establishment and sociocultural-political agenda are reconstructed within the context of Kuwait’s cultural diplomacy and pan-Arabism during decolonization and early Cold War politics. Al-Arabi offered timely discussions on Arab cities, gender, literature, politics and science, and readily embraced color photography for illustrations as a way of stimulating transnational understanding during times of substantial change in the region. Consequently, an analysis of Al-Arabi provides insights into historical strategies for re-imagining the region from within. Overall, the magazine can be situated in a long-standing tradition of Arab printing and publishing, while also forming part of a global illustrated magazine culture. Using a transdisciplinary approach, the article combines archival research and interviews with the media-historical and art-historical analyses of text, image and graphic design.
Wedding Crashers: an Epistemological Model for When Refusal to Provide Service to Protected Groups Is Not Wrongful Discrimination
Authors: Avraham Ronen , Statman Daniel 
Published: September 2022

Abstract
The question of the relation between wrongful discrimination and the freedom of conscience and religion has been the subject of many debates over the past decade and has occupied both courts and the public. The most well-known legal case in that regard is likely Masterpiece Cakeshop, in which a Colorado bakery owner refused to bake a wedding cake for a homosexual couple and was sued for violating the State’s Anti-Discrimination law. Recently, the Supreme Court of the U.S has agreed to hear yet another Colorado case, 303 Creative llc v. Elenis, in which a website designer wanted to post a message saying she will not design websites for same-sex weddings.
The purpose of our article is to point to a significant distinction between a refusal to serve clients on the basis of their race, gender, sexual orientation, etc., and a refusal to serve them because such service requires the providers to engage in activities or projects to which they deeply oppose. We think the latter case, sometimes, might not at all be discrimination. Importantly, we distinguish between a deep objection to the content of the service or product requested and a rejection of the client because of her characteristics.
How can a supplier prove that his or her refusal to serve a client belonging to a “protected class” is based on the content of the product or service requested and not on the client’s characteristics? We formulate a two-prong test that courts in the US and UK have implicitly adopted. We ask, first, whether the supplier would refuse the same service to a client not belonging to the protected class, and second, whether the supplier would serve the same client (belonging to a protected class) with other products and services. If the answer to both questions is positive, then the supplier’s refusal is not wrongful discrimination because it shows an objection to the product or service requested and not a rejection of the client. In practice, this test is not always easy to apply. We therefore developed an epistemological model to substantiate the conditions that may help providers persuade the courts that their refusal to serve a client stems from the content of the request, not from the client’s identity.
Stories of Resurrection in the Qin Manuscripts and the Transformation of Burial Customs in the Qin Dynasty
Authors: Chen (陳侃理) Kanli 
Published: September 2022

Abstract
The stories *Dan 丹 from the Fangmatan 放馬灘 Qin manuscripts, and Taiyuan you sizhe 泰原有死者 from the Peking University Qin manuscript collection, tell of the afterlife and the proper burial and sacrificial practices for the dead through the words of two men who died and returned to life. The proper burial and sacrificial practices proposed in the texts include the replacement of money and silk with symbolic objects, the abandonment of burying a body in the bent position and the breaking of burial goods, the restriction on joint burial of husband and wife, and advocating moderation and cleanliness in sacrificial rituals at the grave. The two texts reflect how the literate class endeavored to make the old burial and sacrificial customs in Qin culture closer to the collective customs of the six eastern states.
Persistent Mode of February-to-March Precipitation over Southern China: Variation, Mechanism, and Prediction
Authors: Yu Shui , Sun Jianqi 
Published: September 2022

Abstract
Precipitation variations over southern China in February and March have profound influences on local agricultural activities. Therefore, the leading intermonthly variation mode of February-to-March precipitation over southern China is investigated in this study using the extended empirical orthogonal function (EEOF) method. The first leading EEOF (EEOF1) pattern shows a persistent precipitation anomaly from February to March over southern China. Mechanistic analysis indicates that EEOF1’s different phases are related to different factors. A dipole sea surface temperature (SST) pattern with warm anomalies in the South China Sea (SCS) and cold anomalies in the western tropical Pacific (WTP) can lead to negative EEOF1 by exciting an anomalous Philippine Sea cyclone. In contrast, positive EEOF1 is influenced jointly by dipole patterns of SST in the southeast Indian Ocean (SEIO)–WTP area and atmospheric circulation over Europe and West Asia. The individual influence of the SST and atmospheric dipole patterns cannot induce persistent precipitation anomalies over southern China from February to March. Furthermore, we check the prediction skill of the National Center for Atmospheric Research (NCEP) Climate Forecast System (CFSv2) for positive and negative EEOF1. The evaluation results show that CFSv2 can predict the relationship between negative EEOF1 and the SCS–WTP dipole SST pattern, consequently showing skillful prediction for negative EEOF1 at the 1-month lead, with a correct rate of approximately 60%. However, CFSv2 cannot reproduce the combined effect of the aforementioned atmospheric dipole pattern and the SEIO–WTP dipole SST pattern and is therefore unskillful for predicting positive EEOF1, with a correct rate of only approximately 36%.