bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic treatment-level discrepancies in patients with lumbosacral radicular pain and lumbar spine anomalies
Authors: Liebrand Bart , Brakel Koen , Boon Arthur , van der Weegen Walter , Wal Selina van der , Vissers Kris CP 
Published: December 2021

BackgroundLumbosacral transitional vertebra can result in an anomalous number of lumbar vertebrae associated with wrong level treatment. The primary aim of this study was to characterize discrepancies between reported referring levels and levels from MRI reports with treated levels. The secondary aim was to analyze interobserver variability between a pain physician and a radiologist when determining levels and classifying lumbosacral transitional vertebrae.MethodsBetween February 2016 and October 2019, a retrospective case series of prospectively collected data of the affected levels mentioned in referrals, MRI reports and treated levels was performed. The counting process, level determination, classification of lumbosacral transitional vertebrae and a secondary control were carried out by independent researchers using a standard methodology.ResultsOf the 2443 referrals, 143 patients had an anomalous number of lumbar vertebrae; of these, 114 were included for analysis. The vertebral level noted in the patient’s file, in the referral, and the reported level of treatment differed in 40% of these cases. The vertebral level between the MRI reports and treatment differed in 46% of cases. The interobserver reliability (radiologist vs pain physician) for classifying a transitional vertebra was fair ((κ=0.40) and was substantial (κ=0.70) when counting the vertebrae.ConclusionIn the presence of lumbar spine anomalies, we report a high prevalence of discrepancies between referral levels and MRI pathological findings with treatment levels. Further research is needed to better understand clinical implications.
ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth
Authors: Ma Wai Kit , Voss Dillon M. , Scharner Juergen , Costa Ana S.H. , Lin Kuan-Ting , Jeon Hyun Yong , Wilkinson John E. , Jackson Michaela , Rigo Frank , Bennett C. Frank , Krainer Adrian R. 
Published: December 2021

Abstract

The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in regulation of the Warburg effect, which is characterized by the preference for aerobic glycolysis over oxidative phosphorylation for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene and is a potential therapeutic target. Antisense oligonucleotides (ASO) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform have been shown to induce apoptosis in cultured glioblastoma cells when delivered by lipofection. Here, we explore the potential of ASO-based PKM splice switching as a targeted therapy for liver cancer. A more potent lead constrained-ethyl (cEt)/DNA ASO induced PKM splice switching and inhibited the growth of cultured hepatocellular carcinoma (HCC) cells. This PKM isoform switch increased pyruvate-kinase activity and altered glucose metabolism. In an orthotopic HCC xenograft mouse model, the lead ASO and a second ASO targeting a nonoverlapping site inhibited tumor growth. Finally, in a genetic HCC mouse model, a surrogate mouse-specific ASO induced Pkm splice switching and inhibited tumorigenesis, without observable toxicity. These results lay the groundwork for a potential ASO-based splicing therapy for HCC.

Significance:
Antisense oligonucleotides are used to induce a change in PKM isoform usage in hepatocellular carcinoma, reversing the Warburg effect and inhibiting tumorigenesis.
A Randomized Phase II Study Comparing Nivolumab with Carboplatin–Pemetrexed for EGFR-Mutated NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors (WJOG8515L)
Authors: Hayashi Hidetoshi , Sugawara Shunichi , Fukuda Yasushi , Fujimoto Daichi , Miura Satoru , Ota Keiichi , Ozawa Yuichi , Hara Satoshi , Tanizaki Junko , Azuma Koichi , Omori Shota , Tachihara Motoko , Nishino Kazumi , Bessho Akihiro , Chiba Yasutaka , Haratani Koji , Sakai Kazuko , Nishio Kazuto , Yamamoto Nobuyuki , Nakagawa Kazuhiko 
Published: December 2021

Abstract

Purpose:
Although the efficacy of programmed cell death–1 (PD-1) blockade is generally poor for non–small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs.

Patients and Methods:
Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin–pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS).

Results:
Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin–pemetrexed [log-rank P &lt; 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61–2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53–1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin–pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell–inflamed gene expression profile score (0.11 vs. −0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab.

Conclusions:
Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.
HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non–Small Cell Lung Cancer
Authors: Yonesaka Kimio , Tanizaki Junko , Maenishi Osamu , Haratani Koji , Kawakami Hisato , Tanaka Kaoru , Hayashi Hidetoshi , Sakai Kazuko , Chiba Yasutaka , Tsuya Asuka , Goto Hiroki , Otsuka Eri , Okida Hiroaki , Kobayashi Maki , Yoshimoto Ryoto , Funabashi Masanori , Hashimoto Yuuri , Hirotani Kenji , Kagari Takashi , Nishio Kazuto , Nakagawa Kazuhiko 
Published: December 2021

Abstract

Purpose:
EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non–small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody–drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC.

Experimental Design:
Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells.

Results:
We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd.

Conclusions:
Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.
Visitors to Leuke Island
Authors: Abramzon Mikhail , Tunkina Irina 
Published: December 2021

Abstract
This article is the publication of the plates compiled by N.N. Murzakevich, secretary of the Odessa Society for History and Antiquities. It contains tracings of 241 Classical coins and lists of coin finds from the island of Fidonisi (known as Leuke in antiquity), which had been excavated in the 1840s and early 1850s. Recent data have led to a doubling of the list of Greek centres (up to 202) and the rulers of a number of states and peoples, whose coins made their way to the island. Details of these finds and the dates of the emissions illustrate clearly the development and chronological framework of the religious and economic ties between the northern coast of Pontus with the various regions of the Classical oikumene. The geographical range of the coin finds (from Magna Graecia, Sicily and the Levant to the Aegean, the Balkans, the Pontic region and Asia and as far away as Mesopotamia) demonstrates that the sanctuary of Achilles on the island of Leuke situated at a meeting point of Black Sea trade routes, enjoyed enormous popularity in the Classical world. The publication of these plates compiled by N.N. Murzakevich makes available new information on the maritime trade in the Pontus area between the 5th century BC and the 5th century AD.
Early Franciscans in England: Sickness, Healing and Salvation
Authors: Jones Peter Murray 
Published: December 2021

Abstract
From their first arrival in England in 1224, the Franciscans were concerned with the treatment of ill-health for both practical and spiritual reasons. Many brothers fell sick, and their illnesses required both interpretation and treatment. Some friars practised healing on their brethren and on lay patients. This article will focus on the question of the relationship between the religious vocation of the friars and the exigencies of sickness. Little evidence survives in England in the form of administrative records. But two early Franciscan writings (Tractatus de adventu fratrum minorum in Angliam, and the letters of Adam Marsh OFM, d. 1259) throw significant light on attitudes to illness and practical responses.
From New Spain to Damascus: Ottoman Religious Authorities and the Making of Medical Knowledge on Tobacco
Authors: Gürbüzel Aslıhan 
Published: December 2021

Abstract
This article examines the translation, circulation, and adaptation of the medical opinion of Spanish physician Nicolas Monardes (d. 1588) on tobacco in the Ottoman Empire. In addition to medical and encyclopedist authors, the spread of new medical knowledge in learned and eventually popular registers was the result of the efforts of religious authorities. These latter authorities, namely jurists, Sufis, and preachers, took an interest in the bodily and mental effects of smoking for its moral implications. In forming their medical-moral discourse, they sought and studied contemporary medical works of both Ottoman and European provenance. Challenging the strict division between learned and popular medicine, this article argues that Ottoman religious authorities, while often excluded from the history of medicine, played significant roles in the circulation, adaptation, and localization of medical knowledge.
Nemesius of Emesa on Desire, Pleasure, and Sex
Authors: de Wet Chris L. 
Published: December 2021

Abstract
This article investigates the views of Nemesius, the bishop of Emesa in Roman Syria at the end of the fourth century CE, on desire, pleasure, and sex, mainly from his work, De natura hominis, asking specifically how Nemesius’s account represents what we might term the “medical making” of an early Christian sexual culture. Nat. hom. was most likely composed at the end of the fourth century CE, and represents the first full and formal Christian anthropology, incorporating views from Christian and non-Christian philosophy (especially Plato and Aristotle) and, of course, extensively utilising (and often even quoting verbatim) ancient medical literature (especially Galen). The study commences by providing a descriptive account of Nemesius’s framework on the dynamics of desire, pleasure, and sex, and then draws some conclusions on how these views of Nemesius translate into a very particular Christian sexual culture in late antique Syria.
Indirect Governance of Transnational Crises
Authors: Zamudio González Laura 
Published: December 2021

Abstract
Intergovernmental, regional, and international organizations play an active role in the governance of transnational crises. In the context of the COVID-19 pandemic in Latin America, the World Health Organization and the Pan-American Health Organization have been linked with multiple actors and levels of decision-making, putting into practice what the literature on global governance refers to as indirect governance by orchestration. This article shows that, in practice, the mechanisms of orchestration have established heterogeneous models of coordination and action that, in situations of transnational crisis, allow these organizations to bring together resources, capacities, and authority.
Discretionary Governance
Authors: Garsten Christina , Sörbom Adrienne 
Published: December 2021

Abstract
Built on the exclusive funding of 1,000 large transnational corporations, the World Economic Forum is a not-for-profit Swiss foundation, aiming to shape the direction of globalization. Its events are characterized by low degrees of formality and transparency. Research on what this organization does is scarce. This article suggests the term discretionary governance to capture the precarious, yet existing, social order that the organization shapes. By discretionary governance, we mean a set of discreet practices based on the organization’s judgement in ways that escape established democratic controls. Drawing on ethnographic data the paper demonstrates how selection, secrecy, and status form key components of this tenuous ordering. Selection processes and secrecy contribute to status elevation of the individuals and organizations chosen to participate. Upon them and the organization itself is bestowed a symbolic capital that is practical and possibly profitable in the world of global governance.
The ‘Infodemic’: Is International Law Ready to Combat Fake News in the Age of Information Disorder?
Authors: Nasu Hitoshi 
Published: December 2021

Abstract
This article considers the readiness of international law to protect States from information operations that are launched as the means of disrupting government response to the spread of infectious diseases, such as COVID-19. It examines both the external- and internal-facing dynamics for international regulation of misinformation, with the focus on the principle of non-intervention as an external regulation of misinformation under general international law and freedom of expression guaranteed under human rights treaties for internal regulation.
International Law of State Responsibility and COVID-19: An Ideology Critique
Authors: Knox Robert , Tzouvala Ntina 
Published: December 2021

Abstract
Despite minimal prospects of success, international lawyers spent the first few months of the global pandemic discussing whether the rules of state responsibility could be invoked against states, especially China, for their acts and omissions regarding COVID-19. In this piece, we take these debates seriously, if not necessarily literally. We argue that the unrealistic nature of these debates does not make them irrelevant. Rather, we propose an ideology critique of state responsibility as a legal field. Our approach is two-fold. First, we argue these debates need to be situated within the rise of geopolitical competition between the US and its allies on the one hand and China on the other. In this context, state responsibility is always laid at the feet of one’s opponents. Secondly, we posit that my emphasising the role of states, recourse to state responsibility renders invisible the role of transnational processes of capitalist production and exchange that have profound effects on nature and set the stage for the emergence and spread of infectious diseases. Drawing from the work of the geographer Neil Smith, we argue against the ‘naturalisation’ of disasters performed much of the international legal discourse about COVID-19.
The Boundary Layer Air Quality-Analysis Using Network of Instruments (BAQUNIN) Supersite for Atmospheric Research and Satellite Validation over Rome Area
Authors: Iannarelli Anna Maria , Di Bernardino Annalisa , Casadio Stefano , Bassani Cristiana , Cacciani Marco , Campanelli Monica , Casasanta Giampietro , Cadau Enrico , Diémoz Henri , Mevi Gabriele , Siani Anna Maria , Cardaci Massimo , Dehn Angelika , Goryl Philippe 
Published: December 2021

Abstract
The Boundary layer Air Quality-analysis Using Network of Instruments (BAQUNIN) supersite is presented. The site has been collecting pollutant concentrations and meteorological parameters since 2017. Currently, BAQUNIN consists of three observation sites located in the city center of Rome (Italy), and in the neighboring semirural and rural areas. To the best of our knowledge, BAQUNIN is one of the first observatories in the world to involve several passive and active ground-based instruments installed in multiple locations, managed by different research institutions, in a highly polluted megacity affected by coastal weather regimes. BAQUNIN has been promoted by the European Space Agency to establish an experimental research infrastructure for the validation of present and future satellite atmospheric products and the in-depth investigation of the planetary and urban boundary layers. Here, the main characteristics of the three sites are described, providing information about the complex instrumental suite and the produced data. The supersite adopts a policy of free sharing of its validated dataset with the community. Finally, the BAQUNIN potential is demonstrated with a case study involving a major fire that occurred in a waste treatment plant near the urban center of Rome, and the consequent investigation of the plume properties revealed by different instruments.
Potential Predictability of Southwest U.S. Rainfall: Role of Tropical and High-Latitude Variability
Authors: Peings Y. , Lim Y. , Magnusdottir G. 
Published: December 2021

Abstract
This study explores the potential predictability of Southwest U.S. (SWUS) precipitation for the November–March season in a set of numerical experiments performed with the Whole Atmospheric Community Climate Model. In addition to the prescription of observed sea surface temperature and sea ice concentration, observed variability from the MERRA-2 reanalysis is prescribed in the tropics and/or the Arctic through nudging of wind and temperature. These experiments reveal how a perfect prediction of tropical and/or Arctic variability in the model would impact the prediction of seasonal rainfall over the SWUS, at various time scales. Imposing tropical variability improves the representation of the observed North Pacific atmospheric circulation, and the associated SWUS seasonal precipitation. This is also the case at the subseasonal time scale due to the inclusion of the Madden–Julian oscillation (MJO) in the model. When additional nudging is applied in the Arctic, the model skill improves even further, suggesting that improving seasonal predictions in high latitudes may also benefit prediction of SWUS precipitation. An interesting finding of our study is that subseasonal variability represents a source of noise (i.e., limited predictability) for the seasonal time scale. This is because when prescribed in the model, subseasonal variability, mostly the MJO, weakens the El Niño–Southern Oscillation (ENSO) teleconnection with SWUS precipitation. Such knowledge may benefit S2S and seasonal prediction as it shows that depending on the amount of subseasonal activity in the tropics on a given year, better skill may be achieved in predicting subseasonal rather than seasonal rainfall anomalies, and conversely.

Significance Statement
Subseasonal and seasonal predictability of precipitation over the Southwest United States (SWUS) during the wet season is challenging, and long-range forecasts from climate models still exhibit poor skill over this region. In this study we use numerical experiments with constrained tropical and/or Arctic atmospheric variability to explore how climate processes in these two regions impact the SWUS precipitation. Our results highlight how much forecast skill in SWUS precipitation may be gained from better predictions in tropical and high latitudes, from subseasonal to multiyear time scales.
Reinforcement learning assisted oxygen therapy for COVID-19 patients under intensive care
Authors: Zheng Hua , Zhu Jiahao , Xie Wei , Zhong Judy 
Published: December 2021

Abstract
Background
Patients with severe Coronavirus disease 19 (COVID-19) typically require supplemental oxygen as an essential treatment. We developed a machine learning algorithm, based on deep Reinforcement Learning (RL), for continuous management of oxygen flow rate for critically ill patients under intensive care, which can identify the optimal personalized oxygen flow rate with strong potentials to reduce mortality rate relative to the current clinical practice.

Methods
We modeled the oxygen flow trajectory of COVID-19 patients and their health outcomes as a Markov decision process. Based on individual patient characteristics and health status, an optimal oxygen control policy is learned by using deep deterministic policy gradient (DDPG) and real-time recommends the oxygen flow rate to reduce the mortality rate. We assessed the performance of proposed methods through cross validation by using a retrospective cohort of 1372 critically ill patients with COVID-19 from New York University Langone Health ambulatory care with electronic health records from April 2020 to January 2021.

Results
The mean mortality rate under the RL algorithm is lower than the standard of care by 2.57% (95% CI: 2.08–3.06) reduction (P < 0.001) from 7.94% under the standard of care to 5.37% under our proposed algorithm. The averaged recommended oxygen flow rate is 1.28 L/min (95% CI: 1.14–1.42) lower than the rate delivered to patients. Thus, the RL algorithm could potentially lead to better intensive care treatment that can reduce the mortality rate, while saving the oxygen scarce resources. It can reduce the oxygen shortage issue and improve public health during the COVID-19 pandemic.

Conclusions
A personalized reinforcement learning oxygen flow control algorithm for COVID-19 patients under intensive care showed a substantial reduction in 7-day mortality rate as compared to the standard of care. In the overall cross validation cohort independent of the training data, mortality was lowest in patients for whom intensivists’ actual flow rate matched the RL decisions.