bluuebunny/crossref_metadata_2025_split huggingface dataset:
Facts and Hopes in Prediction, Diagnosis, and Treatment of Immune-Related Adverse Events
Authors: Smithy James W. , Faleck David M. , Postow Michael A. 
Published: December 2021

Abstract
Over the past decade, the use of immune checkpoint inhibitors (ICI) has expanded across a wide spectrum of oncology indications. Immune-related adverse events (irAE) from ICIs represent a significant source of morbidity, and in rare instances, can lead to treatment-related mortality. There are significant opportunities to better identify patients at increased risk for immune-related toxicity, diagnose irAEs more accurately and earlier in their course, and develop more individualized therapeutic strategies once complications arise. Clinical characteristics, germline and somatic genetic features, microbiome composition, and circulating biomarkers have all been associated with higher risk of developing irAEs in retrospective series. Many of these data suggest that both antitumor and anti-host ICI-associated immune reactions may be driven by common features of either the tumor or the patient's preexisting immune milieu. While irAE diagnosis is currently based on clinical history, exclusion of alternative etiologies, and sometimes pathologic confirmation, novel blood-based and radiographic assays are in development to identify these complications more precisely. Anecdotal reports and small case series have highlighted the potential role of targeted immunomodulatory agents to treat irAEs, though further prospective investigation is needed to evaluate more rigorously their use in these settings. In this review, we highlight the current state of knowledge about predicting, diagnosing, and treating irAEs with a translational focus and discuss emerging strategies which aim to improve each of these domains.
Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study
Authors: Abdul Razak Albiruni R. , Bauer Sebastian , Suarez Cristina , Lin Chia-Chi , Quek Richard , Hütter-Krönke Marie Luise , Cubedo Ricardo , Ferretti Stephane , Guerreiro Nelson , Jullion Astrid , Orlando Elena J. , Clementi Giorgia , Sand Dejmek Janna , Halilovic Ensar , Fabre Claire , Blay Jean-Yves , Italiano Antoine 
Published: December 2021

AbstractPurpose:Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53–MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.Patients and Methods:In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.Results:As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1–174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.Conclusions:Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle
Authors: Wu Tongbin , Liang Zhengyu , Zhang Zengming , Liu Canzhao , Zhang Lunfeng , Gu Yusu , Peterson Kirk L. , Evans Sylvia M. , Fu Xiang-Dong , Chen Ju 
Published: December 2021

Background:

Left ventricular noncompaction cardiomyopathy (LVNC) was discovered half a century ago as a cardiomyopathy with excessive trabeculation and a thin ventricular wall. In the decades since, numerous studies have demonstrated that LVNC primarily has an effect on left ventricles (LVs) and is often associated with LV dilation and dysfunction. However, in part because of the lack of suitable mouse models that faithfully mirror the selective LV vulnerability in patients, mechanisms underlying the susceptibility of LVs to dilation and dysfunction in LVNC remain unknown. Genetic studies have revealed that deletions and mutations in
PRDM16
(PR domain-containing 16) cause LVNC, but previous conditional
Prdm16
knockout mouse models do not mirror the LVNC phenotype in patients, and the underlying molecular mechanisms by which PRDM16 deficiency causes LVNC are still unclear.

Methods:

Prdm16
cardiomyocyte–specific knockout (
Prdm16

cKO

) mice were generated and analyzed for cardiac phenotypes. RNA sequencing and chromatin immunoprecipitation deep sequencing were performed to identify direct transcriptional targets of PRDM16 in cardiomyocytes. Single-cell RNA sequencing in combination with spatial transcriptomics was used to determine cardiomyocyte identity at the single-cell level.

Results:

Cardiomyocyte-specific ablation of
Prdm16
in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients. PRDM16 functioned mechanistically as a compact myocardium-enriched transcription factor that activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium. Consequently,
Prdm16

cKO

LV compact myocardial cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes or neurons. Chamber-specific transcriptional regulation by PRDM16 was attributable in part to its cooperation with LV-enriched transcription factors Tbx5 and Hand1.

Conclusions:
These results demonstrate that disruption of proper specification of compact cardiomyocytes may play a key role in the pathogenesis of LVNC. They also shed light on underlying mechanisms of the LV-restricted transcriptional program governing LV chamber growth and maturation, providing a tangible explanation for the susceptibility of LV in a subset of LVNC cardiomyopathies.
Faith in Drugs: The Material and Immaterial Effects of Medication in the Early Modern French Catholic World
Authors: Rivest Justin 
Published: December 2021

Abstract
This article explores a set of medications, called les remèdes des pauvres, that were distributed from the late seventeenth century onward to the sick poor of rural France and to French missions abroad. Although it was eventually absorbed into the French state as a form of royally sponsored poor relief, this drug distribution network began in 1670 as a distinctly ecclesiastical endeavour, aimed at allowing parish priests, missionaries, and charitable laywomen to imitate the healing ministry of Christ and his apostles. While critics saw them as peddling a dangerous chemical drug in poor villages, their promoters argued that the active charity involved in distributing the remedies, and even the faith placed in their effectiveness by the sick, played an important role in effecting their cures. As such they offer a useful perspective on the shifting boundaries between medical charity and medical commerce, as well as between natural and supernatural healing.
“The Bush Burned with Fire and the Bush Was Not Consumed”
Authors: Feldmann Kaye Miriam 
Published: December 2021

Abstract
This paper explores the post-metaphysical theology of Richard Kearney (1954–) from a Jewish theological perspective. It seeks to provide an original analysis of his project “anatheism,” considering the prominence of Jewish texts in the development of the concept of anatheism. Rooted in deconstructionist and Continental philosophical discourses, Jewish hermeneutics also plays a central role in anatheism. This discursive intersection has received scarce scholarly attention to date. Biblical and other texts which he interprets, include the rabbinic exegesis of Rashi and of modern Jewish hermeneutical philosophy notably of Martin Buber, Franz Rosenzweig, and Emmanuel Levinas. I analyse elements of Kearney’s interpretation primarily of the “Burning Bush” biblical narrative as a test case for anatheistic reading of Jewish texts as they appear in one particular text “I Am Who May Be” in The God Who May Be: A Hermeneutics of Religion (2001). Kearney’s textual reading of the Burning Bush offers an unusual example of a Christian engagement with Jewish interpretations of the biblical parable as well as of Levinas, Derrida, and others. Kearney’s effort highlights an approach of a mutual search for ways of interpreting texts not “of” the other, but “with” the other, in a mutual engagement of post-metaphysical theology. More broadly, this examination offers an important contribution to the developing field of post-metaphysical theology in the Jewish and Christian traditions, ultimately posing questions as to how and whether elements of Jewish scriptural interpretative techniques might or can imbue contemporary Christian post-metaphysical theologies. Conversely, the question can be asked as to what a Jewish version of anatheism might look like. This examination presents a test case for possibilities of reading and learning from discourses across different religions.
Allied but Deviating NATO in the Multipolar World
Authors: Ozkaleli Ferit Murat , Gunes Ali 
Published: December 2021

Abstract
“How long can NATO last in a post-US hegemonic, multipolar world?” has become an important question in contemporary world politics. By statistically analyzing NATO alliance cohesion since its inception, this analysis contributes to the literature by developing an original set of indicators that rely on the ideal point estimates from a recent UN General Assembly voting dataset. It empirically verifies that NATO members have higher cohesion than other UN members, although the United States has been the most significant deviating member since 1980. The findings support some earlier proposals such as the external threat hypothesis. They also contradict some others, notably the literature on the Donald Trump administration’s withdrawal doctrine, and the decline of US hegemony and its policy implications. The article concludes that the future challenge for NATO cohesion not only would be the possibility of US abdication or abandonment, but also other members’ balancing the United States as the hegemon.
Pre-Eminent or Subordinate? An Organisational Environment Perspective on the EU’s Security Cooperation with asean and ecowas
Authors: Müller Lukas Maximilian 
Published: December 2021

Abstract
Security cooperation with other regional organisations (ros) has long been a facet of EU foreign policy. The EU’s relationships with the Association of Southeast Asian Nations (asean) and the Economic Community of West African States (ecowas) illustrate the variety of the EU’s engagement. In West Africa, the EU is a pre-eminent actor, occasionally dictating an agenda and marginalising ecowas. In Southeast Asia, the EU remains subordinate, facing an uphill battle for relevance in the security sphere and a closer relationship to asean. Prevailing explanations focus on the EU’s internal characteristics or bilateral cooperation dynamics, but fail to fully explain this discrepancy. Based on new interview information, this article argues that the organisational environment also affects the EU’s security cooperation with asean and ecowas. The presence of competitive environments limits the EU’s role in security cooperation and relegates it to a subordinate role. In the absence of competition, the EU is allowed to become pre-eminent.
A Challenge to the Liberal Peace? European Union Peacebuilding faces China in Nepal
Authors: Strasheim Julia , Bogati Subindra 
Published: December 2021

Abstract
How does China’s rising presence in Nepal affect the European Union’s own peacebuilding efforts in the country? As a global peace and security actor, the EU has followed the liberal peacebuilding model that promotes peace by strengthening democratic institutions. China’s rise as a “pragmatic” peacebuilder is often called non-conducive to this approach, but how this dynamic plays out has rarely been studied with detailed case evidence. We narrow this gap using the case of Nepal. Drawing on interviews conducted between 2015 and 2020, we find that China’s rise has decreased the EU’s leverage in promoting peace in the areas of civil society, human rights, and constitution-building. But some setbacks in the peace process were unrelated to China. Instead, they were also linked to the EU’s own reform neglects and policy differences, and to local perceptions about peacebuilders, showing how external and internal challenges jointly affect the EU’s role as peacebuilder.
The Arbitration Panel Report in Ukraine – Export Prohibition on Wood Products: Lessons from the ‘Pegasus’ of International Adjudication
Authors: Pogoretskyy Vitaliy 
Published: December 2021

Abstract
The Arbitration Panel’s decision in Ukraine – Export Prohibition on Wood Products suggests the emerging trend among some Word Trade Organization (WTO) Members to settle their trade irritants regionally. This dispute was adjudicated between the EU and Ukraine, which are both WTO Members, under the WTO rules that are incorporated by reference into the Association Agreement between these parties and by the Arbitration Panel the two members of which are well-known WTO adjudicators. The dispute settlement proceedings in this case thus illustrate how regional dispute settlement mechanisms work in practice and shed some light on whether these mechanisms could serve as a viable alternative to the WTO at the time of the ongoing WTO dispute settlement crisis. Moreover, from a substantive perspective, some may view this decision as an important milestone in international economic law, which contributes to the long-standing debate on how the right balance should be struck between trade and environmental considerations, in this case, the conservation of forests. This article, however, addresses several important shortcomings in the Arbitration Panel’s reasoning, which appear to diminish the relevance of the decision beyond the dispute at hand.
Law of the Sea and the Pandemic—Humanitarian Principles under Siege?
Authors: Mossop Joanna 
Published: December 2021

Abstract
In the COVID-19 pandemic two particular issues have arisen in relation to borders and the law of the sea: the right of ships—particularly cruise ships—to enter port and the ongoing restrictions on seafarers aboard merchant ships. In these cases, the sovereign interests of states in preventing the spread of a dangerous virus have been pitted against the humanitarian interests of those onboard the vessels. This article first describes the humanitarian concerns created by states’ responses to the emergence of COVID-19. It then discusses the various legal principles that apply to the situation, primarily the International Health Regulations, the doctrine of distress and the Maritime Labour Convention. Finally, it considers whether any lessons can be learned from this experience to hopefully lessen humanitarian problems if another pandemic happens in the future.
International Human Rights Law and the Protection of Medical Scientists against State Inference during COVID-19
Authors: Liljeblad Jonathan 
Published: December 2021

Abstract
The global COVID-19 pandemic has hosted a rising trend of state interference in medical science research against the virus. Such illiberal actions are counterproductive to hopes of addressing the virus because they impede the operations of scientific inquiry and threaten the integrity of scientific findings. State efforts to interfere in pandemic science work involve constraints upon medical scientists researching the virus. Such constraints risk violating the human rights of the scientists involved in COVID-19 research. International human rights law provides means of protecting scientists against state interference, and the reach of international human rights instruments approaches a scale comparable to the global reach of the pandemic. As a result, the exercise of international human rights law on behalf of medical scientists against state interference furthers the global urgency to resolve the COVID-19 pandemic.
The UN Security Council’s Response to COVID-19: From the Centre to the Periphery?
Authors: Farrall Jeremy , Michaelsen Christopher 
Published: December 2021

Abstract
This article examines the UN Security Council’s response to the escalating COVID-19 pandemic in 2020, which has been criticised as hesitant and half-hearted. It argues that the Council’s inability to respond more assertively to the COVID threat was more predictable than surprising. Indeed, the Council’s approach to the COVID threat tended to follow, rather than diverge from, its past practice, exhibiting three increasingly entrenched features of Council decision-making in a crisis. First, the Council is hesitant and ill-equipped to respond to non-traditional or unorthodox threats to international peace and security, even where relevant precedents exist to support such a response. Second, the Council struggles to act when there is friction between permanent members. Third, when all else fails, the Council can still do reliably well on process.
Drawing Lines at Sea: Australia’s Five Decades of Maritime Boundary Delimitation
Authors: Østhagen Andreas 
Published: December 2021

Abstract
Boundaries in the ocean are man-made constructs of importance to everything from oil and gas production, to fisheries and environmental protection. How do states delineate such ownership and rights? These are the core questions examined in this article, which studies Australia’s maritime boundary agreements, starting with Indonesia in 1971 and ending with Timor-Leste in 2019. In addition to depicting and documenting the main drivers and impediments to these agreements whenever Australia has had to negotiate with a third country, it examines Australia’s approach to boundary-making at sea more generally. Drawing on international law and political science, this article shows why we need understand the interplay between security politics, legal considerations and domestic interests in order to understand what motivates states to settle their maritime disputes.
Emergent Constraints on CMIP6 Climate Warming Projections: Contrasting Cloud- and Surface Temperature–Based Constraints
Authors: Liang Yongxiao , Gillett Nathan P. , Monahan Adam H. 
Published: December 2021

AbstractThe latest Coupled Model Intercomparison Project (CMIP6) multimodel ensemble shows a broader range of projected warming than the previous-generation CMIP5 ensemble. We show that the projected warming is well correlated with tropical and subtropical low-level cloud properties. These physically meaningful relations enable us to use observed cloud properties to constrain future climate warming. We develop multivariate linear regression models with metrics selected from a set of potential constraints based on a stepwise selection approach. The resulting linear regression model using two low-cloud metrics shows better cross-validated results than regression models that use single metrics as constraints. Application of a regression model using the low-cloud metrics to climate projections results in similar estimates of the mean, but substantially narrower uncertainty ranges, of projected twenty-first-century warming when compared with unconstrained simulations. The resulting projected global-mean warming in 2081–2100 relative to 1995–2014 is 2.84–5.12 K (5%–95% range) for Shared Socioeconomic Pathway (SSP) 5–8.5 compared with a range of 2.34–5.81 K for unconstrained projections, and 0.60–1.70 K for SSP1–2.6 compared to an unconstrained range of 0.38–2.04 K. We provide evidence for a higher lower bound of the projected warming range than that obtained from constrained projections based on the past global-mean temperature trend. Consideration of the impact of the sea surface temperature pattern effect on the recent observed warming trend, which is not well captured in the CMIP6 ensemble, indicates that the relatively low projected warming resulting from the global-mean temperature trend constraint may not be reliable and provides further justification for the use of climatologically based cloud metrics to constrain projections.
Prospective comparison of magnetic resonance imaging and computed tomography in diagnosing occult scaphoid fractures
Authors: Sahu Ajay , Kuek Dorothy KC , MacCormick Andrew , Gozzard Charles , Ninan Tishi , Fullilove Sue , Suresh Priya 
Published: December 2021

Background Suspected scaphoid fracture (SF) after a fall on an outstretched hand is a common presentation in the emergency department. Magnetic resonance imaging (MRI) or computed tomography (CT) has been suggested to assist in the diagnosis or exclusion of SF. Purpose To compare MRI and CT at diagnosing occult SFs. Material and Methods We routinely perform CT scans in patients with clinically suspected occult SF, after 7–10 days of injury following two negative radiographs. All eligible patients with a clinically suspected SF, but negative radiographs and a negative CT, underwent an MRI scan to assess further for evidence of occult fracture. Results A total of 100 patients were included in our study. MRI showed fractures in 16% of the time (in 15 patients) when plain radiographs and CT did not. Of these fractures, 8% were SFs. In addition to fractures, 10% had bone bruising. A total of 25% of patients with fractures and bone bruising were referred to the hand surgery team for further follow-up. Conclusion The study demonstrated that MRI would identify a radiographically occult SF more often than CT. This supports NICE guidelines which recommend MRI as the best early diagnostic tool for occult SFs.