bluuebunny/crossref_metadata_2025 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.
COVID‐19, Social Determinants of Health, and Opportunities for Preventing Cardiovascular Disease: A Conceptual Framework
Authors: Russo Rienna G. , Li Yan , Ðoàn Lan N. , Ali Shahmir H. , Siscovick David , Kwon Simona C. , Yi Stella S.
Published: December 2021

The COVID‐19 pandemic has disrupted the social, economic, and health care systems in the United States and shined a spotlight on the burden of disease associated with social determinants of health (SDOH). Addressing SDOH, while a challenge, provides important opportunities to mitigate cardiovascular disease incidence, morbidity, and mortality. We present a conceptual framework to examine the differential effects of the COVID‐19 pandemic on SDOH across demographically diverse populations, focusing on the short‐ and long‐term development of cardiovascular disease, as well as future research opportunities for cardiovascular disease prevention. The COVID‐19 pandemic exerted negative shifts in SDOH and cardiovascular risk factors (ie, smoking, body mass index, physical activity, dietary behavior, cholesterol, blood pressure, and blood sugar). For example, evidence suggests that unemployment and food insecurity have increased, whereas health care access and income have decreased; changes to SDOH have resulted in increases in loneliness and processed food consumption, as well as decreases in physical activity and hypertension management. We found that policy measures enacted to mitigate economic, social, and health issues inadequately protected populations. Low‐income and racial and ethnic minority communities, historically underserved populations, were not only disproportionately adversely affected by the pandemic but also less likely to receive assistance, likely attributable in part to the deep structural inequities pervasive in our society. Effective and culturally appropriate interventions are needed to mitigate the negative health impacts of historical systems, policies, and programs that created and maintain structural racism, especially for immigrants, racial and ethnic minorities, and populations experiencing social disadvantage.
We Should Widen Access to Physician-Assisted Death
Authors: MacKenzie Jordan , Lerner Adam
Published: December 2021

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

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

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

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

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

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.
6. What Are Schools For?
Authors: Graham Philip
Published: December 2021

After joining the Oxfordshire Education Authority in 1950s and serving as Chairman of the Music Sub-Committee, Mary was approached to become headmistress of Oxford High School (OHSG), an independent school for girls. She was appointed in 1966 despite minimal teaching experience. She stayed in this post for six years, making an immediate impact by her decisive style of leadership and distinctive dress. Successful in arranging for inadequate teachers to leave, she took particular interest in the school music curriculum, learning to play the horn to fill a gap in the school orchestra. She involved sixth formers in the development of school policies and is remembered by ex-students interviewed by the author as ambitious for and highly encouraging to them. She took a number of vulnerable students into her own home. She dealt capably with the problems arising from the increasing use of illicit drugs and earlier sexual experience during the permissive 1960s. She left OHSG in 1972 ostensibly to support Geoffrey in his new role as Principal of Hertford College, but also so that she could concentrate on writing a new philosophical book, Imagination (1976). After leaving the school, she wrote prolifically on secondary education, especially in Schools of Thought (1977) and A Common Policy for Education (1989). The content of these books is described as well as their reception by contemporary philosophers.
7. All Change for Special Education
Authors: Graham Philip
Published: December 2021

Early in 1974, Mary Warnock was asked by Margaret Thatcher, then Secretary of State for Education, to chair a Committee of Enquiry into the Education of Handicapped Children and Young People, later to be renamed children with special needs. The author was a member of this committee. Mary gave a vivid description of the members of the committee in Nature and Mortality (2003). Accompanied by the author, Mary visited the East Coast of the United States to learn about special education there. The working of the committee and Mary’s style of chairmanship are described. The report of the committee was published in March 1978 with the title Special Educational Needs. The main recommendations, some of which were radical and innovative, are described. There should be more integration between special and mainstream schools. The concept of a continuum of special needs was introduced. Children’s educational needs should be protected by statements made by multi-disciplinary teams. Henceforth, parents were to be seen as partners. The report was widely welcomed and legislation following its recommendations was rapidly enacted, but, crucially, no extra funding was made available. The report was later attacked on the inaccurate charge that it recommended special schools should be abolished. Mary recanted unnecessarily as the report explicitly saw a continuing role for special schools. The fortieth anniversary of the publication of the report in 2018 was an occasion for recognition of the enduring national and international impact of the report’s recommendations.
9. What Are Universities For?
Authors: Graham Philip
Published: December 2021

In early 1984, Mary was appointed Mistress of Girton College, Cambridge. Shortly afterwards, she was made a member of the House of Lords. Her book Imagination, (1976), the contents of which are described in some detail, had already indicated her views on what should be the aims of university education. Margaret Thatcher had been elected Prime Minister in 1979, with universities in her sights. Significant financial cuts had been made to all universities, with the arts and humanities particularly targeted. Mary looked back at her time at Girton without pleasure and interviews with many contemporary fellows suggest she failed to engage with them. Increasing deafness and preoccupation with Geoffrey’s health were partly responsible. She did however engage well with the undergraduates. Her main achievements were in the promotion of fundraising and, in particular, securing a large donation for a music fellowship. She left Girton in 1991 with relief. In 1988, Kenneth Baker, the Secretary of State for Education, brought in sweeping reforms to both universities and schools. Financial support for universities was henceforth to be largely guided by commercial considerations and there would be far more government intervention. Mary strongly objected to these policies and wrote A Common Policy for Education (1988) and Universities: Knowing our Minds (1989), both largely polemics against these reforms. During her time at Girton, she also wrote a philosophical book, Memory (1987), which discusses the way biography and autobiography might deal with differing accounts of the past. The reception of this book by contemporary philosophers is described.
Relapsed ALL: CAR T vs transplant vs novel therapies
Authors: Frey Noelle V.
Published: December 2021

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

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

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

From 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

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

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

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.
Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management
Authors: Hammill Adrienne M. , Wusik Katie , Kasthuri Raj S.
Published: December 2021

Hereditary hemorrhagic telangiectasia (HHT), the second most common inherited bleeding disorder, is associated with the development of malformed blood vessels. Abnormal blood vessels may be small and cutaneous or mucosal (telangiectasia), with frequent complications of bleeding, or large and visceral (arteriovenous malformations [AVMs]), with additional risks that can lead to significant morbidity and even mortality. HHT can present in many different ways and can be difficult to recognize, particularly in younger patients in the absence of a known family history of disease or epistaxis, its most common manifestation. HHT is commonly diagnosed using the established Curaçao clinical criteria, which include (1) family history, (2) recurrent epistaxis, (3) telangiectasia, and (4) visceral AVMs. Fulfillment of 3 or more criteria provides a definite diagnosis of HHT, whereas 2 criteria constitute a possible diagnosis of HHT. However, these criteria are insufficient in children to rule out disease due to the age-dependent development of some of these criteria. Genetic testing, when positive, can provide definitive diagnosis of HHT in all age groups. Clinical course is often complicated by significant epistaxis and/or gastrointestinal bleeding, leading to anemia in half of adult patients with HHT. The management paradigm has recently shifted from surgical approaches to medical treatments aimed at control of chronic bleeding, such as antifibrinolytic and antiangiogenic agents, combined with aggressive iron replacement with intravenous iron. Guidelines for management of HHT, including screening and treatment, were determined by expert consensus and originally published in 2009 with updates and new guidelines in 2020.
Chronic thromboembolic pulmonary hypertension: anticoagulation and beyond
Authors: Martin Karlyn A. , Cuttica Michael J.
Published: December 2021

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication in pulmonary embolism (PE) survivors, characterized by chronic vascular occlusion and pulmonary hypertension. The identification and diagnosis of CTEPH requires a stepwise approach, starting with symptom evaluation, functional evaluation, screening imaging, and progressing to interventional hemodynamic assessment. On the backbone of anticoagulation, CTEPH management necessitates a multidisciplinary approach. Surgical pulmonary thromboendarterectomy (PTE) is the only potentially curative option. In nonoperable disease or residual disease after PTE, interventional balloon pulmonary angioplasty and/or pulmonary-vasodilator therapies can be offered, in collaboration with interventional and vascular pulmonary colleagues. As it is a disease that can cause high morbidity and mortality, CTEPH requires a high index of suspicion to diagnose and treat in patients following PE.
Infectious complications and vaccines
Authors: Ljungman Per
Published: December 2021

Infections are a major cause of morbidity and can result in mortality in long-term survivors after allogeneic hematopoietic cell transplantation. Chronic graft-versus-host disease and delayed immune reconstitution are recognized risk factors. Different strategies must be utilized depending on the individual patient's situation but include prolonged antimicrobial prophylaxis and vaccination. Some important infections due to pathogens preventable by vaccination are pneumococci, influenza, varicella-zoster virus, and SARS-CoV-2. Despite the fact that such recommendations have been in place for decades, implementation of these recommendations has been reported to be poor.
Advances in the management of α-thalassemia major: reasons to be optimistic
Authors: Horvei Paulina , MacKenzie Tippi , Kharbanda Sandhya
Published: December 2021

α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with β-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition.
How to recognize and manage COVID-19-associated coagulopathy
Authors: Gerber Gloria F. , Chaturvedi Shruti
Published: December 2021

COVID-19 is frequently associated with abnormalities on coagulation testing and a coagulopathy driven by inflammation, intravascular coagulation activation, and microvascular thrombosis. Elevated D-dimer is the most common finding and is a predictor of adverse outcomes including thrombosis, critical illness, and death. Although COVID-19-associated coagulopathy has some similarities to disseminated intravascular coagulation, the platelet count is usually preserved, coagulation times are usually normal or minimally prolonged, and thrombosis is more common than bleeding, at least in noncritically ill patients. Bleeding is uncommon but may be a significant problem in critically ill patients, including those who may develop a consumptive coagulopathy with frank disseminated intravascular coagulation and those on extracorporeal membrane oxygenation. Blood product support to correct coagulopathy is reserved for bleeding patients or those requiring invasive procedures. Current recommendations suggest that all hospitalized patients should receive at least a prophylactic dose of anticoagulation. Results from a multiplatform randomized clinical trial suggest that therapeutically dosed anticoagulation may improve outcomes, including the need for organ support and mortality in moderately ill patients but not in those requiring critical care. The results of ongoing trials evaluating the impact of different antithrombotic strategies (therapeutic agents and intensity) on COVID-19 outcomes are eagerly awaited and are expected to have important implications for patient management. We also discuss COVID-19 vaccine-associated cytopenias and bleeding as well as vaccine-induced thrombotic thrombocytopenia, in which thrombosis is associated with thrombocytopenia, elevated D-dimer, and, frequently, hypofibrinogenemia.
COVID-19 and thrombosis: searching for evidence
Authors: Thilagar Bright , Beidoun Mohamad , Rhoades Ruben , Kaatz Scott
Published: December 2021

Early in the pandemic, COVID-19-related increases in rates of venous and arterial thromboembolism were seen. Many observational studies suggested a benefit of prophylactic anticoagulation for hospitalized patients using various dosing strategies. Randomized trials were initiated to compare the efficacy of these different options in acutely ill and critically ill inpatients as the concept of immune-mediated inflammatory microthrombosis emerged. We present a case-based review of how we approach thromboembolic prophylaxis in COVID-19 and briefly discuss the epidemiology, the pathophysiology, and the rare occurrence of vaccine-induced thrombotic thrombocytopenia.
Advances in MGUS diagnosis, risk stratification, and management: introducing myeloma-defining genomic events
Authors: Landgren Ola
Published: December 2021

In the 1960s, Dr Jan Waldenström argued that patients who had monoclonal proteins without any symptoms or evidence of end-organ damage represented a benign monoclonal gammopathy. In 1978, Dr Robert Kyle introduced the concept of “monoclonal gammopathy of undetermined significance” (MGUS) given that, at diagnosis, it was not possible with available methods (ie, serum protein electrophoresis to define the concentration of M-proteins and microscopy to determine the plasma cell percentage in bone marrow aspirates) to determine which patients would ultimately progress to multiple myeloma. The application of low-input whole-genome sequencing (WGS) technology has circumvented previous problems related to volume of clonal plasma cells and contamination by normal plasma cells and allowed for the interrogation of the WGS landscape of MGUS. As discussed in this chapter, the distribution of genetic events reveals striking differences and the existence of 2 biologically and clinically distinct entities of asymptomatic monoclonal gammopathies. Thus, we already have genomic tools to identify “myeloma-defining genomic events,” and consequently, it is reasonable to consider updating our preferred terminologies. When the clinical field is ready to move forward, we should be able to consolidate current terminologies—from current 7 clinical categories: low-risk MGUS, intermediate-risk MGUS, high-risk MGUS, low-risk smoldering myeloma, intermediate-risk smoldering myeloma, high-risk smoldering myeloma, and multiple myeloma—to future 3 genomic-based categories: monoclonal gammopathy, early detection of multiple myeloma (in which myeloma-defining genomic events already have been acquired), and multiple myeloma (patients who are already progressing and clinically defined cases). Ongoing investigations will continue to advance the field.
Evidence-Based Minireview: Molecular precision and clinical uncertainty: should molecular profiling be routinely used to guide risk stratification in MDS?
Authors: Richardson Daniel R. , DeZern Amy E.
Published: December 2021

This is a focused clinical vignette and review of the literature in MDS to discuss the application of molecular sequencing for risk stratification in MDS. The authors utilize an exemplar patient case and explain the advantages and disadvantages, based on available data, of routine use of this testing for MDS patients.
Spatial frequency analysis detects altered tissue organization following hamstring strain injury at time of injury but not return to sport
Authors: Crawford Scott K. , Wille Christa M. , Stiffler-Joachim Mikel R. , Lee Kenneth S. , Bashford Greg R. , Heiderscheit Bryan C.
Published: December 2021

Background

Hamstring strain injury (HSI) diagnosis is often corroborated using ultrasound. Spatial frequency analysis (SFA) is a quantitative ultrasound method that has proven useful in characterizing altered tissue organization. The purpose of this study was to determine changes in muscular tissue organization using SFA following HSI.

Methods

Ultrasound B-mode images were captured at time of injury (TOI) and return to sport (RTS) in collegiate athletes who sustained an HSI. Spatial frequency parameters extracted from two-dimensional Fourier Transforms in user-defined regions of interest (ROI) were analyzed. Separate ROIs encompassed injured and adjacent tissue within the same image of the injured limb and mirrored locations in the contralateral limb at TOI. The ROIs for RTS images were drawn to correspond to the injury-matched location determined from TOI imaging. Peak spatial frequency radius (PSFR) and the fascicular banded pattern relative to image background (Mmax%) were compared between injured and adjacent portions within the same image with separate paired t-tests. Within-image differences of SFA parameters in the injured limb were calculated and compared between TOI and RTS with Wilcoxon rank sum tests.

Results

Within the injured limb at TOI, PSFR differences in injured and healthy regions did not strictly meet statistical significance (p = 0.06), while Mmax% was different between regions (p < 0.001). No differences were observed between regions in the contralateral limb at TOI (PSFR, p = 0.16; Mmax%, p = 0.30). Significant within-image differences in PSFR (p = 0.03) and Mmax% (p = 0.04) at RTS were detected relative to TOI.

Conclusions

These findings are a first step in determining the usefulness of SFA in muscle injury characterization and provide quantitative assessment of both fascicular disruption and edema presence in acute HSI.
Catastrophic health expenditure and its determinants in households with lung cancer patients in China: a retrospective cohort study
Authors: Sun Cheng-yao , Shi Ju-fang , Fu Wen-qi , Zhang Xin , Liu Guo-xiang , Chen Wan-qing , He Jie
Published: December 2021

Background

Numerous studies have examined catastrophic health expenditures (CHE) worldwide, mostly focusing on general or common chronic populations, rather than particularly vulnerable groups. This study assessed the medical expenditure and compensation of lung cancer, and explored the extent and influencing factors of CHE among households with lung cancer patients in China.

Methods

During 2018–2019, a hospital-based multicenter retrospective survey was conducted in seven provinces/municipalities across China as a part of the Cancer Screening Program of Urban China. CHE was measured according to the proportion of out-of-pocket (OOP) health payments of households on non-food expenditures. Chi-square tests and logistic regression analysis was adjusted to determine the factors that significantly influenced the likelihood of a household with lung cancer patient to incur in CHE.

Results

In total, 470 households with lung cancer patients were included in the analysis. Health insurance was shown to protect some households from the impact of CHE. Nonetheless, CHE incidence (78.1%) and intensity (14.02% for average distance and 22.56% for relative distance) were still relatively high among households with lung cancer patients. The incidence was lower in households covered by the Urban Employee Basic Medical Insurance (UEMBI) insurance, with higher income level and shorter disease course.

Conclusion

More attention is needed for CHE incidence among vulnerable populations in China. Households with lung cancer patients were shown to be more likely to develop CHE. Therefore, policy makers should focus on improving the financial protection and reducing the economic burden of this disease.
Same-sex behavior disclosure to health care providers associated with greater awareness of pre-exposure prophylaxis
Authors: Cao Wangnan , You Xinyi , Li Jinghua , Peng Liping , Gu Jing , Hao Chun , Hou Fengsu , Wei Dannuo , Deng Yang , Hao Yuantao , Mo Phoenix Kit-han
Published: December 2021

Background

This study aimed to determine whether the disclosure of same-sex behavior to health care providers (HCPs) is associated with higher rates of prior human immunodeficiency virus (HIV) testing experience and greater awareness of immediate antiretroviral therapy (ART), Undetectable = Untransmittable (U=U), and pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM).

Methods

We conducted a cross-sectional survey among 689 adult males in Chengdu, China who self-reported having had anal intercourse with at least one man in the past 6 months. We measured same-sex behavior disclosure to three types of HCPs (hospital clinicians, community-based organization peer educators, and Center for Disease Control and Prevention public health specialists), and the awareness of immediate ART, U=U, and PrEP.

Results

Of the 689 enrolled participants, 31.4% had disclosed their same-sex behavior to some or all of the clinicians, 83.9% had done so to the peer educators, and 56.8% had done so to the public health specialists. Approximately four in five (82.1%) of the participants had ever been tested for HIV. The awareness rate was 84.8% for immediate ART, 20.2% for U=U, and 50.7% for PrEP. After controlling for significant background variables, same-sex behavior disclosure to clinicians was associated with greater awareness of PrEP (adjusted odds ratio [AOR] = 1.64; 95% confidence interval [CI]: 1.08–2.48), but similar findings were not reported regarding disclosure to peer educators or public health specialist. Same-sex behavior disclosure to any types of HCPs was not associated with HIV testing experience, and awareness of immediate ART or U=U.

Conclusions

The rates of same-sex behavior disclosure varied with different types of HCPs. Disclosure to clinicians was associated with greater awareness of PrEP, but not awareness of immediate ART or U=U.
An analysis of health inequalities depending on educational level using nationally representative survey data in Japan, 2019
Authors: Okui Tasuku
Published: December 2021

Background

In recent years, socioeconomic differences in health statuses and behaviors have not been investigated from the nationally representative survey data in Japan. In this study, we showed differences in representative health behaviors and statuses depending on educational level using a nationally representative survey data in Japan.

Methods

Aggregated (not individual level) data from the Comprehensive Survey of Living Conditions in 2019 were used to examine the association between educational level and outcome status of psychological distress (K6 scores > = 5), self-rated health, smoking, alcohol drinking, and cancer screening participation (stomach, lung, colorectal, breast, and uterine cancers). Data of 217,179 households in Japan were aggregated by the Ministry of Health, Labour, and Welfare in the survey, and the data of the estimated number of household members and persons corresponding to each response option for the questions in all of Japan were used. Five-year age groups from 20 to 24 to 80–84 years and over 84 years were analyzed, and the prevalence or participation rate by educational level were calculated. In addition, the age-standardized prevalence or participation rate according to educational level were also calculated by sex. Moreover, a Poisson regression model was applied for evaluating an association of educational level with the outcomes.

Results

As a result, a clear gradient by educational level was observed in almost all the age groups for the prevalence of psychological distress, poor self-rated health, and smoking and participation rates in cancer screening, and high educational level were associated with better health-related behaviors and statuses. Conversely, drinking prevalence was shown to be higher rather in highly educated people. In addition, a statistically significant association of educational level with all the outcomes was observed.

Conclusion

It was shown that disparities in health behaviors and statuses still persisted in recent years, and the findings suggested that further measures should be taken to tackle this disparity.