bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of Cardiovascular End Points Ascertainment Leveraging Multisource Electronic Health Records Harmonized Into a Common Data Model in the ADAPTABLE Randomized Clinical Trial
Authors: Marquis-Gravel Guillaume , Hammill Bradley G. , Mulder Hillary , Roe Matthew T. , Robertson Holly R. , Wruck Lisa M. , Sharlow Amber , Harris Debra F. , Pohlman F. Will , Hernandez Adrian F. , Jones W. Schuyler 
Published: December 2021

Background:
The ADAPTABLE trial (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) is the first randomized trial conducted within the National Patient-Centered Clinical Research Network to use the electronic health record data formatted into a common data model as the primary source of end point ascertainment, without confirmation by standard adjudication. The objective of this prespecified study is to assess the validity of nonfatal end points captured from the National Patient-Centered Clinical Research Network, using traditional blinded adjudication as the gold standard.

Methods:
A total of 15 076 participants with established atherosclerotic cardiovascular disease were randomized to two doses of aspirin (81 mg and 325 mg once daily). Nonfatal end points (hospitalization for nonfatal myocardial infarction, nonfatal stroke, and major bleeding requiring transfusion of blood products) were captured with the use of programming algorithms applied to National Patient-Centered Clinical Research Network data. A random subset of end points was independently reviewed by a disease-specific expert adjudicator. The positive predictive value of the programming algorithms were calculated separately for end points listed as primary and as nonprimary diagnoses.

Results:
A total of 225 end points were identified (91 myocardial infarction events, 89 stroke events, and 45 bleeding events), including 142 (63%) that were listed as primary diagnoses. Complete source documents were missing for 14% of events. The positive predictive value were 90%, 72%, and 93% for hospitalizations for myocardial infarction, stroke, and major bleeding, respectively, as compared to adjudication. When only primary diagnoses were considered, positive predictive value were 93%, 91%, and 97%, respectively. When only nonprimary diagnoses were considered, positive predictive value were 82%, 36%, and 71%.

Conclusions:
As compared with blinded adjudication, clinical end point ascertainment from queries of the National Patient-Centered Clinical Research Network distributed harmonized data was valid to identify hospitalizations for myocardial infarction in ADAPTABLE. The proportion of contradicted events was high for hospitalizations for bleeding and strokes when nonprimary diagnoses were analyzed, but not when only primary diagnoses were considered.
Role of Heart Rate Variability in Association Between Glomerular Hyperfiltration and All‐Cause Mortality
Authors: Chang Hao‐Chih , Huang Chi‐Jung , Yang Albert C. , Cheng Hao‐Min , Chuang Shao‐Yuan , Yu Wen‐Chung , Chiang Chern‐En , Chen Chen‐Huan , Sung Shih‐Hsien 
Published: December 2021

Background
Glomerular hyperfiltration (GHF) is paradoxically associated with increased cardiovascular events in healthy individuals, but the pathogenesis remains unclear. We aim to investigate whether GHF is associated with mortality and whether decreased heart rate variability (HRV) is associated with GHF.

Methods and Results
We retrospectively analyzed 1615 participants (aged 66.1±17.3 years, 61.9% men) without prior cardiovascular events. The glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. GHF was defined as glomerular filtration rate >the 95th percentile after stratification for age and sex, whereas normal filtration was defined as the 25th to 75th percentiles. HRV indexes, including time domain, frequency domain, and sample entropy, were measured using 24‐hour ambulatory electrocardiography. Clinical outcomes were defined as all‐cause mortality at 2 years. During a mean follow‐up of 16.5±8.2 months, there were 117 deaths (7.2%). GHF was associated with a higher risk of death (hazard ratio and 95% CIs, 1.97 [1.15–3.37]). Reduced HRV indexes, including time domain, frequency domain, and sample entropy (odds ratio and 95% CIs, 0.79 [0.70–0.89]) were all independently associated with the presence of GHF after accounting for age, sex, mean heart rate, morbidities, and medications. In subgroup analysis, reduced HRV was more predictive of GHF in the young than the elderly. Mediation analysis revealed a significant mediation effect between HRV and GHF in addition to their respective detrimental effects on survival.

Conclusions
Reduced HRV was independently associated with the presence of GHF. Autonomic dysfunction may be involved in the pathogenesis of adverse outcomes of GHF in individuals without prior cardiovascular events.
We Should Widen Access to Physician-Assisted Death
Authors: MacKenzie Jordan , Lerner Adam 
Published: December 2021

Abstract
Typical philosophical discussions of physician-assisted death (“pad”) have focused on whether the practice can be permissible. We address a different question: assuming that pad can be morally permissible, how far does that permission extend? We will argue that granting requests for pad may be permissible even when the pad recipient can no longer speak for themselves. In particular, we argue against the ‘competency requirement’ that constrains pad-eligibility to presently-competent patients in most countries that have legalized pad. We think pad on terminally ill, incapacitated patients can be morally permissible in cases where advance directives or suitable surrogate decision-makers are available, and should be legally permissible in such cases as well. We argue that this view should be accepted on pain of inconsistency: by allowing surrogate decision-makers to request withdrawal of life-sustaining care on behalf of patients and by allowing patients to request pad, we rule out any plausible justification for imposing a competency requirement on pad.
Exeter Book Riddle 48, Line 7b
Authors: Getz Robert 
Published: December 2021

Abstract
The emendation of the manuscript reading beþuncan to beþencan in line 7b of the Exeter Book’s Riddle 48 has been widely accepted. The Old English Dialogues, however, provide evidence that a strong passive participle beþuncen had been introduced into the paradigm of the weak verb beþencan (to entrust) in the Mercian dialect, admitting the possibility that beþuncan is a genuine preterite plural form. The passive participle brungen, attested in Mercian, is a possible analogical basis for the development of beþuncen in the same dialect, from which other strong forms may subsequently have arisen. The meter and the motives for scribal alteration in Riddle 48 make it probable that beþuncan is original and that it is rather ongietan in line 6a that should be emended.
Im Spannungsfeld zwischen hochdeutscher Norm und niederdeutscher Sprachkompetenz
Authors: Raag Nicolaus Janos 
Published: December 2021

Abstract
This article contains an edition of a 17th-century Low German letter addressed to the German congregation in Stockholm. Seen against the shift of writing language from Low to High German, this letter is analyzed in respect to code-mixing, which is shown to fulfill a communicative function. Furthermore the author here suggests that the code-mixing observed in the letter can be described as congruent lexicalization, where Low German syntactic structures are filled with both Low and High German lexical material.
Kabul, a Forgotten Mughal Capital: Gardens, City, and Court at the Turn of the Sixteenth Century
Authors: Parodi Laura E. 
Published: December 2021

Abstract
Kabul was the seat of Mughal power during the first half of the sixteenth century, and—it is argued here—provided inspiration for the better-known Mughal metropoles of Hindustan. Sources suggest that the topography of Kabul was already well established, along with its major landmarks, decades before Babur made it the seat of his court in 1504. Among these landmarks were three remarkable royal gardens (all Timurid foundations), which performed complementary functions. The one known today as Bagh-i Babur acquired funerary connotations with the burial of Babur’s mother there in 1505, if not earlier. The Bagh-i Shahrara hosted the governor as well as distinguished guests, including widowed or divorced princesses and imperial visitors. The Chaharbagh was the seat of the court. Its functional units included residential quarters for the ruler and the harem, a courtyard of audience, administrative quarters, and service provisions. In this study, Kabul and its gardens are compared with Mughal counterparts in Hindustan, and (more briefly) with Timurid Herat and Safavid Isfahan. This comparison contributes to an understanding of the unique position occupied by gardens in the Timurid realm and in the courts of their Mughal and Safavid successors.
Archaeology and Cultural Policy in Ottoman Tunisia Part II: Muhammad Khaznadar (1871–99)
Authors: Moumni Ridha 
Published: December 2021

Abstract
This article is the second part of a study focusing on Muhammad Khaznadar’s role in the history of archaeology in nineteenth-century Tunisia. Whereas part I traced the meteoric rise of Muhammad Khaznadar as a Tunisian cultural figure, the second part of this inquiry examines Khaznadar’s fall from power and the end of his monopoly over the country’s antiquities. Following the dismissal of his father, Mustafa Khaznadar, as grand vizier in 1873, Muhammad’s artifacts were seized by the bey. The Khaznadar collection then attracted the attention of the new grand vizier, Khayr al-Din (1873–78). Influenced by the activities of Muhammad Khaznadar, Khayr al-Din sought to create a national museum of antiquities. However, this project came to an end with Khayr al-Din’s dismissal and the subsequent arrival of French colonizers, who established the Bardo Museum (then called the Alaoui Museum) in 1888. The historical narrative written by the French colonial authority erased the memory of prominent Tunisian archaeologists and collectors who had been active in the preceding decades. This article seeks to highlight the important contributions of local Tunisians to the development of archaeological research and policies surrounding Tunisian cultural heritage in the nineteenth century.
Does tvátpitāraḥ = εὐπάτωρ?
Authors: Lundquist Jesse 
Published: December 2021

Abstract
A standard comparison in Indo-European linguistics equates Vedic tvátpitāraḥ ‘having you as father’ and Ancient Greek compounds in -πατωρ, e.g., εὐπάτωρ ‘having a good father, lineage’. Many scholars describe this equation as resulting from “Internal Derivation”: the second-member of the compound would exhibit amphikinetic inflection, internally derived from a noun with hysterokinetic inflection. This paper reassesses the philological evidence for the long-vowel forms of Vedic -pitār-. Because the long-vowel forms are confined to one Vedic school (Taittirīyans), it is argued that the short-vowel forms such as -pitar- reflect the inherited Indic vowel length in these compounds. Following this reassessment, I question to what extent the second-members of possessive compounds (e.g., Gk. -πατωρ) reflect an “amphikinetic” paradigm. I argue that the forms are “amphikinetic” only to the extent that they show an o-grade suffix in Greek, and that defining such second-members as amphikinetic both overgenerates (predicts unattested forms) and undergenerates (fails to predict attested accents).
Mary Warnock
Authors: Graham Philip 
Published: December 2021

This biography illuminates the life and thought of Baroness Mary Warnock, whose active years spanned the second half of the twentieth century, a period during which opportunities for middle-class women rapidly and vastly improved.
Warnock was described as ‘probably the most celebrated philosopher in Britain.’ She began her career as an Oxford University philosophy don and went on to become headmistress of an independent girls’ school. Warnock subsequently chaired two select committees which produced reports of lasting significance, first to children with special needs, and second to childless couples. She then became Mistress of Girton College, Cambridge, and an active member of the House of Lords. Alongside these positions, Warnock wrote twenty books, ranging from the fields of philosophy to education and medical ethics. Her ideas were largely in tune with contemporary progressive thinking but late in life Warnock’s extreme championing of assisted dying for older people won her enemies even among progressives.
This authorised biography, written by a friend of the subject, will be of great value to the general reader with an interest in philosophy, ethics, twentieth-century cultural history, and the changing role of women from the 1950s onwards.
Relapsed ALL: CAR T vs transplant vs novel therapies
Authors: Frey Noelle V. 
Published: December 2021

Abstract
Chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has expanded the treatment options for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The approval of tisagenlecleucel for pediatric and young adult patients with r/r ALL has allowed broader access for some patients, but the treatment of older adults is available (at the time of this writing) only within a clinical trial. High remission rates have been consistently observed with varied CART19 products and treatment platforms, but durability of remissions and thus the potential role of a consolidative allogeneic stem cell transplant (SCT) is more uncertain and likely to vary by product and population treated. The immunologic characteristics of CARTs that confer high response rates also account for the life-threatening toxicities of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, the severity of which also varies by patient and disease characteristics and product. Further considerations informing a decision to treat include feasibility of leukapheresis and timeline of manufacture, alternative treatment options available, and the appropriateness of a potential consolidative allogeneic SCT. Advances in the field are under way to improve rate and duration of responses and to mitigate toxicity.
Frontline treatment in CLL: the case for time-limited treatment
Authors: Lévy Vincent , Delmer Alain , Cymbalista Florence 
Published: December 2021

Abstract
Over the last decade, the advent of Bruton tyrosine kinase inhibitors (BTKi) has profoundly modified the therapeutic strategy in chronic lymphocytic leukemia (CLL), introducing the concept of treatment until progression. Initially, the bcl-2 inhibitor venetoclax (VEN) was used as a single agent and then was rapidly combined in VEN-based regimens associated with either anti-CD20 or with BTKi. These regimens yielded a high rate of complete remission, leading to their use as a fixed duration treatment. The decision between continuous treatment with BTKi and VEN-based combinations relies mostly on comorbidities, comedications, and patient/physician preferences. Notably, with BTKi, cardiovascular comorbidities, hypertension, and potential pharmacological interactions should be carefully evaluated. On the other hand, the risk of tumor lysis syndrome with VEN should be monitored at treatment initiation. TP53 alteration and IGHV mutational status should also be assessed, as they remain important for therapeutic decisions. Fit patients with a TP53 wild type and IGHV-mutated CLL may still benefit from fludarabine-cyclophosphamide-rituximab chemoimmunotherapy (CIT), as it may result in a very long remission duration. VEN-based treatments are well tolerated, and no additional toxicity has been observed when combined with anti-CD20 or BTKi. The 1-year fixed-duration association of VEN plus obinutuzumab was evaluated in frontline for older adult patients. Nonetheless, considering the favorable outcome, an extension of indication for fit younger patients is expected. The association of VEN and BTKi is promising, even if the follow-up is still short. It is currently being tested against CIT, BTKi continuous treatment, and VEN plus anti-CD20.
Increasing access to allogeneic hematopoietic cell transplant: an international perspective
Authors: Rocha Vanderson , Fatobene Giancarlo , Niederwieser Dietger ,   for the Brazilian Society of Bone Marrow Transplantation and the Worldwide Network for Blood and Marrow Transplantation
Published: December 2021

Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly complex, costly procedure for patients with oncologic, hematologic, genetic, and immunologic diseases. Demographics and socioeconomic status as well as donor availability and type of health care system are important factors that influence access to and outcomes following allo-HCT. The last decade has seen an increase in the numbers of allo-HCTs and teams all over the world, with no signs of saturation. More than 80 000 procedures are being performed annually, with 1 million allo-HCTs estimated to take place by the end of 2024. Many factors have contributed to this, including increased numbers of eligible patients (older adults with or without comorbidities) and available donors (unrelated and haploidentical), improved supportive care, and decreased early and late post-HCT mortalities. This increase is also directly linked to macro- and microeconomic indicators that affect health care both regionally and globally. Despite this global increase in the number of allo-HCTs and transplant centers, there is an enormous need for increased access to and improved outcomes following allo-HCT in resource-constrained countries. The reduction of poverty, global economic changes, greater access to information, exchange of technologies, and use of artificial intelligence, mobile health, and telehealth are certainly creating unprecedented opportunities to establish collaborations and share experiences and thus increase patient access to allo-HCT. A specific research agenda to address issues of allo-HCT in resource-constrained settings is urgently warranted.
Immunology 101: fundamental immunology for the practicing hematologist
Authors: Carty Shannon A. 
Published: December 2021

AbstractFrom an evolutionary perspective, the immune system developed primarily to protect the host from pathogens. In the continuous balance between killing pathogens and protecting host tissues, selective pressures have shaped the discriminatory functions of the immune system. In addition to protection against microbial pathogens, the immune system also plays a critical role in antitumor immunity. Immune dysfunction, either under- or overactivity, is found in a wide range of hematologic disorders. Here we review the fundamental features of the immune system and the key concepts critical to understanding the impact of immune dysfunction on hematologic disorders.
How immunodeficiency can lead to malignancy
Authors: Pai Sung-Yun , Lurain Kathryn , Yarchoan Robert 
Published: December 2021

Abstract
Immunodeficiency, whether acquired in the case of human immunodeficiency virus (HIV) infection or congenital due to inborn errors of immunity (IEIs), presents clinically with not only infection and immune dysregulation but also increased risk of malignancy. The range of malignancies seen is relatively limited and attributable to the particular cellular and molecular defects in each disease. CD4+ T-cell lymphopenia in people living with HIV infection (PLWH) and certain IEIs drive the predisposition to aggressive B-cell non-Hodgkin lymphomas, including certain rare subtypes rarely seen in immunocompetent individuals. PLWH and IEI that lead to profound T-cell lymphopenia or dysfunction also are at risk of cancers related to oncogenic viruses such as Kaposi sarcoma herpesvirus, Epstein-Barr virus, human papillomavirus (HPV), and Merkel cell polyomavirus. IEIs that affect natural killer cell development and/or function heavily predispose to HPV-associated epithelial cancers. Defects in DNA repair pathways compromise T- and B-lymphocyte development during immune receptor rearrangement in addition to affecting hematopoietic and epithelial DNA damage responses, resulting in both hematologic and nonhematologic cancers. Treatment of cancers in immunodeficient individuals should be curative in intent and pursued in close consultation with disease experts in immunology and infectious disease.
Diagnosis and clinical management of red cell membrane disorders
Authors: Kalfa Theodosia A. 
Published: December 2021

Abstract
Heterogeneous red blood cell (RBC) membrane disorders and hydration defects often present with the common clinical findings of hemolytic anemia, but they may require substantially different management, based on their pathophysiology. An accurate and timely diagnosis is essential to avoid inappropriate interventions and prevent complications. Advances in genetic testing availability within the last decade, combined with extensive foundational knowledge on RBC membrane structure and function, now facilitate the correct diagnosis in patients with a variety of hereditary hemolytic anemias (HHAs). Studies in patient cohorts with well-defined genetic diagnoses have revealed complications such as iron overload in hereditary xerocytosis, which is amenable to monitoring, prevention, and treatment, and demonstrated that splenectomy is not always an effective or safe treatment for any patient with HHA. However, a multitude of variants of unknown clinical significance have been discovered by genetic evaluation, requiring interpretation by thorough phenotypic assessment in clinical and/or research laboratories. Here we discuss genotype-phenotype correlations and corresponding clinical management in patients with RBC membranopathies and propose an algorithm for the laboratory workup of patients presenting with symptoms and signs of hemolytic anemia, with a clinical case that exemplifies such a workup.
Lower risk but high risk
Authors: DeZern Amy E. 
Published: December 2021

Abstract
Risk stratification is crucial to the appropriate management of most cancers, but in patients with myelodysplastic syndromes (MDS), for whom expected survival can vary from a few months to more than a decade, accurate disease prognostication is especially important. Currently, patients with MDS are often grouped into higher-risk (HR) vs lower-risk (LR) disease using clinical prognostic scoring systems, but these systems have limitations. Factors such as molecular genetic information or disease characteristics not captured in the International Prognostic Scoring System–Revised (IPSS-R) can alter risk stratification and identify a subset of patients with LR-MDS who actually behave more like those with HR-MDS. This review describes the current identification and management of patients with LR-MDS whose condition is likely to behave in a less favorable manner than predicted by the IPSS-R.