bluuebunny/crossref_metadata_2025 huggingface dataset:
Left Ventricular Dysfunction in Arrhythmogenic Cardiomyopathy: Association With Exercise Exposure, Genetic Basis, and Prognosis
Authors: Lie Øyvind H. , Chivulescu Monica , Rootwelt‐Norberg Christine , Ribe Margareth , Bogsrud Martin Prøven , Lyseggen Erik , Beitnes Jan Otto , Almaas Vibeke , Haugaa Kristina H.
Published: April 2021

Background

Arrhythmogenic cardiomyopathy (AC) is characterized by biventricular dysfunction, exercise intolerance, and high risk of ventricular tachyarrhythmias and sudden death. Predisposing factors for left ventricular (LV) disease manifestation and its prognostic implication in AC are poorly described. We aimed to assess the associations of exercise exposure and genotype with LV dysfunction in AC, and to explore the impact of LV disease progression on adverse arrhythmic outcome.

Methods and Results

We included 168 patients with AC (50% probands, 45% women, 40±16 years old) with 715 echocardiographic exams (4.1±1.7 exams/patient, follow‐up 7.6 [interquartile range (IQR), 5.4–10.9] years) and complete exercise and genetic data in a longitudinal study. LV function by global longitudinal strain was −18.8% [IQR, −19.2% to −18.3%] at presentation and was worse in patients with greater exercise exposure (global longitudinal strain worsening, 0.09% [IQR, 0.01%–0.17%] per 5 MET‐hours/week,
P
=0.02). LV function by global longitudinal strain worsened, with 0.08% [IQR, 0.05%–0.12%] per year; (
P
<0.001), and progression was most evident in patients with desmoplakin genotype (
P
for interaction <0.001). Deterioration of LV function predicted incident ventricular tachyarrhythmia (aborted cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter defibrillator shock) (adjusted odds ratio, 1.1 [IQR, 1.0–1.3] per 1% worsening by global longitudinal strain;
P
=0.02, adjusted for time and previous arrhythmic events).

Conclusions

Greater exercise exposure was associated with worse LV function at first visit of patients with AC but did not significantly affect the rate of LV progression during follow‐up. Progression of LV dysfunction was most pronounced in patients with desmoplakin genotypes. Deterioration of LV function during follow‐up predicted subsequent ventricular tachyarrhythmia and should be considered in risk stratification.
Survival Following Edge‐to‐Edge Transcatheter Mitral Valve Repair in Patients With Cardiogenic Shock: A Nationwide Analysis
Authors: Tang Gilbert H. L. , Estevez‐Loureiro Rodrigo , Yu Yang , Prillinger Julie B. , Zaid Syed , Psotka Mitchell A.
Published: April 2021

Background

Edge‐to‐edge transcatheter mitral valve repair as salvage therapy in high surgical risk patients with severe mitral regurgitation presenting with cardiogenic shock (CS) has been described in small case series, but large clinical results have not been reported. This study aimed to evaluate outcomes of transcatheter mitral valve repair with MitraClip in patients with mitral regurgitation and CS using a large national database.

Methods and Results

From January 2014 to March 2019, we identified hospitalizations for CS in patients with mitral valve disease using data from Centers for Medicare and Medicaid Services. Those with a prior surgical or percutaneous mitral valve intervention were excluded. We compared survival between patients who underwent MitraClip during the index hospitalization and those who did not using propensity‐matched analysis. The analysis included 38 166 patients (mean age, 71±11 years, 41.6% women) of whom 622 (1.6%) underwent MitraClip. MitraClip was increasingly used during CS hospitalizations over the study period (
P
<0.001). After matching, patients receiving MitraClip had significantly lower in‐hospital mortality (odds ratio, 0.6; 95% CI, 0.47–0.77;
P
<0.001) and 1‐year mortality (hazard ratio, 0.76; 95% CI, 0.65–0.88;
P
<0.001) compared with those without MitraClip. The survival benefit associated with MitraClip was consistent across subgroups of interest, with the exception of patients requiring acute mechanical circulatory support or hemodialysis at index.

Conclusions

In patients with mitral regurgitation presenting with CS, use of MitraClip is increasing and associated with greater in‐hospital and 1‐year survival. Further studies are warranted to optimize patient selection and procedure timing for those receiving MitraClip as a treatment option in CS.
“Weil nun Sanct Marten bricht herein/[…] Will seine Ganß besungen sein”
Authors: van de Löcht Joana
Published: April 2021

As the last feast before the beginning of the fasting period (Quadragesima Sancti Martini), the perishable supplies are used up on Martin’s Eve, which provides an opportunity for eating, drinking, and socializing together. In early modern literature, numerous texts – poems and songs, satires, popular literature – deal with Martin’s Eve and especially with the goose eaten there. In this article, a temporal and spatial overview of texts related to the Martin’s Eve celebrations is given, and the genre-specific functions of writing about the goose are explained.
Liedpoetik und soziale Praxis
Authors: Dröse Astrid
Published: April 2021

This article is dedicated to the Leipzig Ovid translator and song poet Johann Georg Schoch. It focusses on Schoch’s major work Neu-erbaueter Poetischer Lust- u[nd] Blumen-Garten (1660). The article analyses the poetics and social references of this collection. The author argues that the bucolic, erotic, and sociable songs are linked by intertextual references to works by other Leipzig authors such as Paul Fleming and Gottfried Finckelthaus. Schoch’s contrafactum of an ode by his student friend David Schirmer (“Immer hin/ fahr immer hin”) shows that the songs function as a keepsake of remembrance and identify both authors as members of a local group. They also provide insights into the social practice of student sociability.
Naturrecht – Socialitas – Empfindsamkeit?
Authors: Schwingenschlögl Michael
Published: April 2021

This article surveys various efforts made to explore the origins of the movement of Empfindsamkeit (sentimentalism) by emphasizing the role of natural law theories formed around 1700. The view of sentiment in Tugendempfindsame Literatur matches the anthropology of natural law theories that saw man’s proper state in an equillibrium of self- and other-oriented relations to the world. Conceptions of Geselligkeit connect natural law and Empfindsamkeit. Comparing different understandings of Empfindsamkeit, it may be concluded that a future multifaceted look at the roots of Empfindsamkeit that integrates seemingly opposing perspectives on the subject is both possible and appropriate.
Three new host records of endophytic Neofusicoccum species reported from Dendrobium orchid
Authors: MA XIAO-YA , HYDE KEVIN D. , PHILLIPS ALAN J.L. , KANG JI-CHUAN , CHOMNUNTI PUTARAK , DOILOM MINGKWAN
Published: April 2021

Neofusicoccum species are endophytes, saprobes and opportunistic pathogens of many economic and ornamental plants. There are few reports of Neofusicoccum species are available to be associated with orchids worldwide. In this study, five endophytic Neofusicoccum strains were isolated from Dendrobium orchid leaves and stems in southwestern China and northern Thailand. Morphological characteristics and phylogenetic analysis of the combined partial nuclear rDNA internal transcribed spacer (ITS), partial RNA polymerase Ⅱ second largest subunit (RPB2), part of the translation elongation factor 1 alpha (EF-1α) and beta-tubulin (TUB2) dataset revealed that these isolates belong to two species Neofusicoccum occulatum and N. parvum. This is the first record of Neofusicoccum occulatum associated with Dendrobium chrysanthum while N. parvum associated with D. harveyanum and D. moschatum.
The genus Navicula (Bacillariophyceae, Naviculaceae) from the valley of the Adegoy River (Krasnodar Territory, Russia) and description of two new species
Authors: CHUDAEV DMITRY , JÜTTNER INGRID , LEVKOV ZLATKO
Published: April 2021

This is the first detailed taxonomic study of the genus Navicula in the Krasnodar Territory of the Caucasus region, Russia. During the study of the genus in waterbodies of the Adegoy River valley 15 taxa were recorded. Two species, N. adegoyensis sp. nov. and N. pseudocryptofallax sp. nov., are described as new to science. Their morphology is studied by light and scanning electron microscopy, and comparisons with morphologically similar species are provided. The use of the name N. avenacea for N. lanceolata sensu auct. is discussed. Navicula diversity was higher in the Adegoy River than in pools elsewhere in the river valley.
Presence of the invasive land flatworm Platydemus manokwari (Platyhelminthes, Geoplanidae) in Guadeloupe, Martinique and Saint Martin (French West Indies)
Authors: JUSTINE JEAN-LOU , GEY DELPHINE , VASSEUR JULIE , THÉVENOT JESSICA , COULIS MATHIEU , WINSOR LEIGH
Published: April 2021

The land flatworm Platydemus manokwari (Platyhelminthes, Geoplanidae) is recorded from the islands of Guadeloupe, Martinique, and Saint Martin in the Caribbean arc. Photographs and records were obtained mainly from citizen science and ranged from the end of 2018 to February 2021; several specimens were deposited in the collections of the Muséum National d’Histoire Naturelle in Paris, France. Thirty records were from Guadeloupe, but only one from Martinique and from Saint Martin, respectively. The COI sequences of 3 specimens from Guadeloupe show that they belong to the World haplotype also found in many countries. We also report P. manokwari from Fort Myers, Florida, USA, with molecular characterization, which was also the World haplotype. This is the first published record of P. manokwari for Guadeloupe, Martinique and Saint Martin and the second for islands in the Caribbean, after Puerto Rico.
Review of the Gekko (Japonigekko) subpalmatus complex (Squamata, Sauria, Gekkonidae), with description of a new species from China
Authors: LYU ZHI-TONG , LIN CHAO-YU , REN JIN-LONG , JIANG KE , ZHANG YIN-PENG , QI SHUO , WANG JIAN
Published: April 2021

The gecko species Gekko (Japonigekko) subpalmatus was previously recorded with a relatively wide distribution from eastern, southern, and southeastern China. However, the populations in southern China are currently recognized as another valid species G. (J.) melli. In this study, we conduct a detailed morphological examination and phylogenetic analysis of the populations currently treated as G. (J.) subpalmatus or G. (J.) melli, which are collectively designated as the G. (J.) subpalmatus complex. Our results reveal that the G. (J.) subpalmatus complex comprises three evolutionarily independent taxa. The populations from Zhejiang, eastern China are G. (J.) subpalmatus, those from southern China are G. (J.) melli, while those from the Sichuan Basin, southwestern China represent a cryptic species, Gekko (Japonigekko) cib sp. nov.. Gekko (Japonigekko) cib sp. nov. can be distinguished from all congeners, by its divergence from other complex members in the CYTB and 16S genes, and a combination of morphological characteristics, especially in hemipenial morphology. Historic records of G. (J.) subpalmatus complex are also reviewed.
Why neotypification of Lophorina superba (Pennant, 1781) (Aves: Paradisaeidae) is justified—and necessary
Authors: SCHODDE R. , CHRISTIDIS L. , BATALHA-FILHO H. , ERICSON P.G.P. , IRESTEDT M.
Published: April 2021

We review Irestedt et al.’s (2017) neotypification of the senior species name superba Pennant, 1781 in the bird-of-paradise genus Lophorina in response to Elliott et al. (2020) who challenged the resultant shift in name from the small isolate in New Guinea’s Vogelkop to the widespread species in the island’s central cordillera. In nine male plumage traits which differentiate the two species, six of which had been identified as novel by Irestedt et al., we show that the only two figures of the perished male holotype of superba match the central cordillera species more closely than the Vogelkop. We find as well that not only was the trading of bird-of-paradise skins from the central cordillera to coastal ports in the Vogelkop feasible before European contact, but application of superba to the central cordillera species also promotes nomenclatural stability: the name has been used overwhelmingly at species rank for that widespread form throughout post-19th century media. Re-assessment of Irestedt et al.’s point-by-point justification of neotypification under Article 75.3 of the ICZN (1999) Code establishes, furthermore, that their case meets the requirements of every condition specified in the article; the neotypification is thus valid. Elliott et al.’s alternative to fix superba to the Vogelkop isolate by type locality restriction is not Code-compliant, nor is their evidence for interpreting J.R. Forster as the author of the name. In conclusion, we lay out the correct nomenclature for the taxa of Lophorina under the Code.
Classification of Action Verbs of Bloom’s Taxonomy Cognitive Domain: An Empirical Study
Authors: Das Syaamantak , Das Mandal Shyamal Kumar , Basu Anupam
Published: April 2021

It was observed from previous researches that Bloom’s Taxonomy action verbs (BTAVs) are overlapping in multiple cognitive levels, causing ambiguity about the real sense of the word. A data set of BTAVs was ranked using a statistical classification. Four categories of BTAVs were identified, out of which 153 BTAVs (86.44%) are classified into a single cognitive level. In the remaining 24 BTAVs, 21 follow a specific transition from one cognitive level to another. The proposed research reduced the cognitive level’s ambiguity and made the classification more robust, making it easier for teachers to create and set the cognitive levels.
Low awareness of high sodium intake among older Chinese people
Authors: Chau Pui-Hing , Lok Kris Yuet-Wan , Leung Angela Yee-Man , Chow Sze , Lo Wing-Tung , Li Siu-Fan , Fu Alice Ka-Lai , Cheung Bernard Man-Yung
Published: April 2021

Awareness is one of the first steps in a lifestyle modification process. Since older adults are at a higher risk of hypertension, maintaining low sodium intake is of utmost importance. Yet, it is uncertain if older adults have an awareness of their sodium intake. This study aimed to explore self-perceived sodium intake among older Chinese people and compare it with various measures of sodium intake. A cross-sectional study was conducted in Hong Kong in 2015. Data were collected from 24-h urinary sodium excretion (UNa24) measurements, dietary sodium intake by 24-h diet recalls and self-perceived salt intake levels among the older Hong Kong population. Kappa statistics and a paired t-test were used to compare the different measures. Fifty-nine participants provided complete 24-h urine samples. The mean (±SD) UNa24 of participants was 2846 ± 1253 mg, of which 74.6% exceeded the recommended daily sodium intake. About 87.8% of participants with UNa24 values >2000 mg perceived their sodium intake as too little or just right. The kappa statistic between UNa24 and self-perception was insignificantly different from zero (κ = −0.003, p-value = 0.909). The UNa24 estimates were significantly higher than those estimated from the 24-h diet recalls by 1203 mg ( p-value <0.001). The findings imply that the low awareness of excessive sodium intake should be raised among older people to promote a healthy intake of sodium.
Quadrotor UAV attitude stabilization using fuzzy robust control
Authors: Lara Alabazares David , Rabhi Abdelhamid , Pegard Claude , Torres Garcia Fernando , Romero Galvan Gerardo
Published: April 2021

In this paper, a robust controller for attitude stabilization of a small quadrotor helicopter is developed. The TS (Takagi-Sugeno) fuzzy model approach and the [Formula: see text] robust control are combined to produce the proposed algorithm. Besides, disturbances and parametric uncertainties are considered. First, the nonlinear model of the vehicle is linearized around several operating points to obtain the representation of a TS fuzzy model, which represents the nonlinearity of the system dynamics. Then, a robust fuzzy controller is synthesized which guarantees desired control performances. The given controller is designed using numerical tools such as linear matrix inequalities (LMI). Finally, simulation results and real-time experiments are presented to validate the performance of the proposed scheme to robustly stabilize the quadrotor dynamics at the desired reference.
Splintering Organizational Subjectivities: Older workers and the dynamics of recognition, vulnerability and resistance
Authors: Cutcher Leanne , Riach Kathleen , Tyler Melissa
Published: April 2021

Drawing on insights from Judith Butler’s writing on the dynamics of subjectivity, vulnerability and resistance, this paper explores how older workers negotiate organizational recognition schemes that are based on age-related ideals. The paper draws on observational, documentary and interview data from an Australian call centre where older workers are both championed as a valuable potential recruitment pool and managed through age-biased discourses. Our analysis shows how older workers’ resistance to being positioned as simultaneously valuable and vulnerable leads them to disrupt the normative conditions upon which organizational recognition is premised. We emphasize the importance of an ‘aged’ perspective on workplace recognition in order to better understand how the dynamics of vulnerability and resistance not only shape older worker identities and experiences but also disrupt organizational recognition regimes, exposing the mutual vulnerability of older workers and their managers.
The downside of downsizing: Persistence of racial disparities following state prison reform
Authors: Lerman Amy E , Mooney Alyssa C
Published: April 2021

Nationwide, prison populations have declined nearly 5% from their peak, and 16 states have seen double-digit declines. It is unclear, though, how decarceration has affected racial disparities. Using national data, we find substantial variation in state prison populations from 2005–2018, with increases in some states and declines in others. However, although declines in the overall state prison population were associated with declines for all groups, states with rising prison populations experienced slight upticks in prison rates among the white population, while rates among Black and Latinx populations declined. As a result, greater progress in overall decarceration within states did not translate to larger reductions in racial disparities. At the same time, we do not find evidence that a decline in prison populations is associated with a rise in jail incarceration for any racial/ethnic group. In additional exploratory analyses, we suggest that recent incarceration trends may be driven by changes in returns to prison for probation and parole violations, rather than commitments for new crimes. Our results make clear that while efforts to reverse mass incarceration have reduced the size of prison populations in some states, they have not yet made substantial progress in resolving the crisis of race in American criminal justice.
Atmospheric pressure chemical ionisation mass spectrometry for the routine analysis of low molecular weight analytes
Authors: Gates Paul J
Published: April 2021

The routine analysis of low molecular weight analytes by mass spectrometry is often complicated by the lability of the analyte’s functional groups and/or the lack of moieties that can be easily charged. If a molecule is too labile this precludes analysis by techniques such as electron ionisation or chemical ionisation as the analyte will undergo thermal decomposition prior to ionisation as well as spontaneous fragmentation during the ionisation process. If the analyte has a low propensity to form ions in electrospray ionisation (i.e., lacks acidic or basic sites) then often no analyte related ions are observed. In this paper, the robustness and versatility of the established method of atmospheric pressure chemical ionisation is demonstrated for the analysis of low molecular weight analytes. The utility of the technique is demonstrated through the analysis of 30 reference standards of varying functionality, and further by the analysis of 75 synthetic samples which were problematic when analysed by electron or electrospray ionisation. The resulting spectra are dominated by intact molecular species ([M+H]+ and M+ in positive ion mode and [M − H]− and [M + Cl]− in negative ion mode) along with logical neutral losses reminiscent of what you might expect from the analyte’s structure (losses of H2O from alcohols or CO from aldehydes etc). This paper presents atmospheric pressure chemical ionisation as an essential tool for broadening the chemical space of successful analyses for any routine mass spectrometry service laboratory of facility.
Plagiarism of the implicit concept in interior design projects: Does it exist?
Authors: Alawad Abeer A , Bettaieb Donia M , Malek Raif B
Published: April 2021

Design spaces can be read in two complementary structural and compositional dimensions: the implicit dimension, and the formal dimension. This study aimed to answer the following questions: What are the phases of the original idea transformation in the design process? Does taking advantage of the implicit dimension of others’ interior spaces count as inspiration or plagiarism? Participants comprised nine postgraduate students, who were asked to copy others’ project ideas by applying four design phases: idea source, test, choice, and output. The results showed that plagiarism of the concept of others’ work could not occur unless the concept copies the structural, functional, and aesthetic aspects of the design space at the level of its components and the relationships between them. Otherwise, taking advantage of the implicit dimension of others’ project ideas can be an inspiration. The results are expected to increase awareness among interior design instructors in higher education.
Guardians of the Frequency: Neuronal Regulation by Microglia
Authors: Eyal Sara
Published: April 2021

[Box: see text]
Osteochondral Allograft Transplantation for Osteochondritis Dissecans of the Medial Femoral Condyle
Authors: Torres LeeAnne , Dennis Eric , Dogariu Lauren , Waterman Brian R.
Published: April 2021

Background:

While the data are not as robust as in the adult population, osteochondral allograft transplantation has proven to be an effective treatment for osteochondritis dissecans (OCD) lesions of the knee in the pediatric and adolescent populations.

Indications:

The primary indication for osteochondral allograft transplantation is a symptomatic, full-thickness, localized cartilage lesion. Acceptable underlying causes include trauma, avascular necrosis, and OCD lesions. As these are pediatric and adolescent patients, they are not candidates for joint arthroplasty. In this case, the patient is a 16-year-old girl with a 1.5 cm × 1.2 cm OCD lesion of the medial femoral condyle.

Technique Description:

The patient was positioned supine with a tourniquet on the thigh. The lesion was identified on the medial femoral condyle and exposed. A guidepin was placed in the center of the lesion and a 15 mm reamer was used to ream to a depth of 6 to 7 mm. The wound was copiously irrigated. A corresponding 15 mm plug was harvested from the donor graft and prepared to match the morphology of the condyle. The 12 o’clock position was marked with a fresh marking pen to maintain orientation. The graft was lavaged with a pulsavac and bathed in autologous conditioned plasma. The recipient bed was prepared with 0.0045 K wire, and then the donor graft was placed in proper position and impacted with a tamp, flush with the surrounding cartilage. The tourniquet was deflated and the surgical site was closed in a layered fashion.

Results:

Studies of adult patients have demonstrated survival rates of greater than 80% for osteochondral allograft transplantation, with pain improvement of 74% to 85%, and return to competitive athletics of 88%. While there is a paucity of studies looking at osteochondral allograft transplantation in pediatric and adolescent populations, outcomes appear to be similar to that of the adult population.

Discussion/Conclusion:

Osteochondral allograft transplantation is a viable treatment option for pediatric and adolescent patients with symptomatic cartilage lesions. It allows for joint preservation and provides significant improvement of pain with high rates of return to athletics.
Emerging therapies for inv(16) AML
Authors: Surapally Sridevi , Tenen Daniel G. , Pulikkan John A.
Published: April 2021

The core binding factor composed of CBFβ and RUNX subunits plays a critical role in most hematopoietic lineages and is deregulated in acute myeloid leukemia (AML). The fusion oncogene CBFβ-SMMHC expressed in AML with the chromosome inversion inv(16)(p13q22) acts as a driver oncogene in hematopoietic stem cells and induces AML. This review focuses on novel insights regarding the molecular mechanisms involved in CBFβ-SMMHC–driven leukemogenesis and recent advances in therapeutic approaches to target CBFβ-SMMHC in inv(16) AML.
The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma
Authors: Chihara Dai , Dores Graça M. , Flowers Christopher R. , Morton Lindsay M.
Published: April 2021

Lymphoma survivors have a significantly higher risk of developing second primary lymphoma than the general population; however, bidirectional risks of developing B- and T-cell lymphomas (BCLs and TCLs) specifically are less well understood. We used population-based cancer registry data to estimate the subtype-specific risks of second primary lymphoma among patients with first BCL (n = 288 478) or TCL (n = 23 747). We observed nearly fivefold increased bidirectional risk between BCL and TCL overall (TCL following BCL: standardized incidence ratio [SIR] = 4.7, 95% confidence interval [CI] = 4.2-5.2; BCL following TCL: SIR = 4.7, 95% CI = 4.1-5.2), but the risk varied substantially by lymphoma subtype. The highest SIRs were observed between Hodgkin lymphoma (HL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (PTCL-NOS following HL: SIR = 27.5; HL following PTCL-NOS: SIR = 31.6). Strikingly elevated risks also were notable for angioimmunoblastic T-cell lymphoma (AITL) and diffuse large B-cell lymphoma (DLBCL) (AITL following DLBCL: SIR = 9.7; DLBCL following AITL: SIR = 15.3). These increased risks were strongest within the first year following diagnosis but remained persistently elevated even at ≥5 years. In contrast, SIRs were <5 for all associations of TCL with chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. These patterns support etiologic heterogeneity among lymphoma subtypes and provide further insights into lymphomagenesis.
Oral Arsenic Plus Retinoic Acid Versus Intravenous Arsenic Plus Retinoic Acid for Non-High Risk Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trials
Authors: Zhu Honghu , Wu Depei , Zhang Xi , LIU Lin , Ma Jun , Shao Zonghong , Ren Hanyun , Hu Jianda , Xu Kailin , Wang Jing-Wen , Song Yongping , Fang Mei-Yun , Huang Xiao-Jun
Published: April 2021

Objective

Intravenous arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non high-risk acute promyelocytic leukemia (APL), resulting in cure rates exceeding 95%. Pilot study of treatment with oral arsenic named the Realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy has shown high efficacy, convenient and economical. This randomized, multicenter, phase 3 noninferiority trial was designed to test the efficacy and safety of an oral RIF and ATRA compared with intravenous ATO for newly diagnosed non high-risk APL patients.

Methods

We conducted a phase 3, multicenter trial comparing RIF plus ATRA with ATO plus ATRA in patients with non high-risk APL (white-cell count, ≤10×109 per liter) between 2014 and 2017. In all, 109 patients were randomly assigned (2:1) to oral RIF (60 mg/kg) plus ATRA (25 mg/m2) or ATO (0.16mg/kg) plus ATRA (25 mg/m2) as induction therapy until complete hematologic remission. Postremission therapy included RIF or ATO on a schedule of 4 weeks on and 4 weeks off and ATRA on a schedule of 2 weeks on and 2 weeks off for 7 months.

The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival (EFS) at 2 years in the two groups was not greater than 10%.

Results

Complete remission was achieved in all 69 patients in the RIF-ATRA group who could be evaluated (3 withdraw during the induction) and in 34 of 36 patients in the ATO-ATRA group (2 died and another one withdraw during the induction) (100% vs. 94.4%, p= 0.12).

The median follow-up was 32 months. Two-year EFS rates were 97.1% in the RIF-ATRA group (n=69) and 94.4% in the ATO-ATRA group (n=36). The EFS rate difference was 2.7% (95% CI,-5.8% to11.1%). The lower limit of the 95%CI for EFS rate difference was greater than-10% noninferiority margin, confirming noninferiority (noninferiority P=0.0017). There is no difference about relapse rate and overall survival between two groups (all p >0.05).

Conclusions

RIF plus ATRA is not inferior to ATO plus ATRA in the treatment of patients with non high-risk APL (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054).

Disclosures

No relevant conflicts of interest to declare.
Catalytically Active UCH-L1 Is Required for MYC Driven B-Cell Lymphomagenesis
Authors: Bedekovics Tibor , Hussain Sajjad , Galardy Paul J.
Published: April 2021

Mature B-cell lymphomas are common in children and adults. While increasing biological knowledge has greatly improved the classification of these diseases, the ability to stratify therapy based on this knowledge is limited. As the outcomes for patients with relapsed/refractory disease is poor, it is important to optimize the upfront approach to these patients making enhanced biomarker discovery essential. We recently found that the de-ubiquitinase UCH-L1 is strongly induced in normal GC B-cells, is highly expressed in germinal center type diffuse large B-cell lymphoma, and is a potent prognostic factor associated with poor outcomes in this disease. Using transgenic mice (Uchl1Tg), we observed that deregulated UCH-L1 drives spontaneous B-cell lymphomagenesis and significantly accelerates disease when combined with the Iμ-HABCL6 or Eμ- myc models of GC derived lymphoma. At the molecular level, we showed that UCH-L1 regulates mTOR complex assembly and promotes AKT signaling. It has been alternatively hypothesized that stabilization of mono-ubiquitin is an essential function of UCH-L1 - a mechanism that does not require catalytic activity. To determine the impact of UCH-L1 catalytic activity on lymphoma development, we generated mice carrying a catalytically inactive transgene (Uchl1TgC90A). Consistent with our prior work, we observed that UCH-L1 promotes AKT phosphorylation and suppresses mTORC1 activity towards 4EBP1 and S6K in splenocytes in a manor dependent on catalytic activity. To examine the impact on lymphomagenesis, we crossed Uchl1Tg and Uchl1TgC90A mice with the Eμ- myc model. While we again found the wild-type transgene to accelerate Myc driven lymphoma development, there was no such effect of the C90A construct, indicating that the catalytic activity of UCH-L1 is required for its oncogenic activity. To further examine its role in MYC driven lymphomagenesis we crossed Eμ- myc mice with homozygous null Uchl1 mice and found that Uchl1 loss leads to a significant improvement in lymphoma free survival, indicating that UCH-L1 is a key cooperating factor with MYC in lymphoma. Consistent with this, gene expression profiling from lymphomas arising in Uchl1Tg mice share a striking similarity to those driven by MYC and constitutive PI3 kinase signaling (MYC/P110*) but are distinct from those seen in Iμ-HABCL6 or Lig4 null mice. These data indicate an mechanistic interplay between UCH-L1 and MYC in B-cell lymphoma and suggest that UCH-L1 inhibition may be an effective approach in B-cell lymphomas expressing MYC.

Disclosures

Galardy: Mission Therapeutics: Research Funding; Abvie: Equity Ownership; Abbot labs: Equity Ownership.
Acute Chest Syndrome Among Hospitalized Children with Vaso-Occlusive Crisis: A Nationwide Study in the United States
Authors: Takahashi Takuto , Okubo Yusuke , Handa Atsuhiko , Miller Scott T.
Published: April 2021

Background: Acute chest syndrome (ACS) remains a leading cause of mortality among children with sickle cell disease (SCD); overall, nearly 50% of ACS is diagnosed during hospitalizations for other complications including painful vaso-occlusive crises (VOC).

Methods: The present study assesses epidemiological features of children hospitalized with VOC and evaluates factors potentially associated with development of ACS utilizing the large national all-payer Kid's Inpatient Database over a recent 9 year period. Records of children (age < 20 years) were reviewed from 2003, 2006, 2009, and 2012) and multivariable logistic regression was used to assess risk factors and adjust for patient and hospital characteristics.

Results: Total annual hospitalization rates with VOC were variable, ranging from 26.4 per 100,000 children in 2009 to 29.5 in 2012. Multivariable logistic regression analysis showed children age 5-9 years had 2.38 times higher odds of developing ACS than children age 15-19 (95%CI, 2.22 to 2.56). Comorbidity of asthma was a risk factor for ACS (OR, 1.44; 95%CI, 1.36 to 1.53). ACS was as common in Hb SC patients hospitalized for VOC as those with SS.

Conclusion: These data demonstrate that despite increasing use of hydroxyurea in children shown in other reports, there has been no reduction in hospitalization rate for pain, and even young children are at risk for ACS. Though de novo ACS is less common in Hb SC, vigilance and prophylactic measures are required for those hospitalized for pain. Further studies are needed to assess the efficacy of prophylactic interventions including bronchodilator therapy for asthmatics hospitalized for VOC.

Disclosures

Miller: Pfizer Pharmaceutical: Research Funding.
The Impact of Electrical Calf Muscle Stimulation on the Residual Venous Obstruction and DVT Recurrence after Cessation of Standard Anticoagulation
Authors: Lobastov Kirill , Ryzhkin Vladimir , Vorontsova Athena , Schastlivtsev Iliya , Barinov Victor , Laberko Leonid , Rodoman Grigory
Published: April 2021

Aim. To assess the efficacy of electrical calf muscle stimulation (EMS) in patients with post-thrombotic syndrome (PTS) and residual venous obstruction (RVO) after cessation of a standard anticoagulation.

Methods. This was a prospective comparative clinical trial with masked outcome assessor involving patients after the first episode of unprovoked femoro-popliteal DVT who have completed a standard 6-month course of anticoagulation and had signs of RVO in the affected veins and Villalta score of 5 and more.

Totally were enrolled 60 patients in the age of 40-86 years (mean - 58,5 ± 11,4), 38 men and 22 women, divided into two groups of 30 participants. In both groups (main and control) PTS was treated by active walking (at least 5,000 steps per day controlled by an individual pedometer), below-knee graduated compression stockings (23-32 mm Hg) and micronized purified flavonoid fraction (2-month course twice a year). In the main group, EMS with «Veinoplus VI» device (3 procedures of 30 minutes every day) also was used. The main endpoint of the study was symptomatic or asymptomatic recurrent venous thrombosis confirmed by duplex ultrasound (DUS). The additional criteria of treatment efficacy were changes in the degree of current venous stenosis. The patients were followed up for 12 months with monthly DUS, aimed to reveal recurrent DVT, and 6-monthly DUS with evaluation of stenosis degree.

Results. RVO was represented by an average of 48%-stenosis of the common femoral vein in 12 patients, 53%-stenosis of the superficial femoral vein in 16 cases and 55%-stenosis of the popliteal vein in all participants. Through 12-month follow up the degree of stenosis decreased in all affected veins in both groups (p<0,05). The most vivid dynamics was found in the popliteal vein: 60.8% - 55.1% - 28.8% in the main group and 50.9% - 30.1% - 27.3% in the control group (p<0,0001) with significant differences between the groups (p=0.004)

Recurrence of venous thrombosis was found in 7 of 30 patients in the control group and in 0 of 30 patients in the main group (23.3% vs 0%, p=0.011). In 5 cases the recurrent DVT was silent and revealed by regular DUS and only in 2 cases it had a clinical manifestation. 4 of 5 silent cases were presented with re-occlusion of the early affected vein.

Conclusions. There is an ongoing process of deep veins recanalization during 12 months after cessation of anticoagulation in patients with RVO and PTS. Using of EMS in complex treatment of PTS allows to reduce the rate of recurrent DVT and increase the speed of recanalization.

Disclosures

Lobastov: "Gemakor Labs" Ltd: Honoraria, Research Funding; "BEHO+" Ltd: Honoraria, Research Funding. Ryzhkin: "BEHO+" Ltd: Research Funding. Laberko: "Gemakor Labs" Ltd: Honoraria, Research Funding; "BEHO+" Ltd: Honoraria. Rodoman: "Gemakor Labs" Ltd: Research Funding.
Comparative Risk of Acute Kidney Injury with Oral Anticoagulant Use Among Patients with Nonvalvular Atrial Fibrillation
Authors: Klil-Drori Adi J. , Azoulay Laurent , Nie Rui , Renoux Christel , Nessim Sharon J. , Filion Kristian B.
Published: April 2021

Background: Acute kidney injury (AKI) is common in patients with nonvalvular atrial fibrillation (NVAF) taking oral anticoagulants (OAC), especially in those with underlying chronic kidney disease (CKD). However, little is known on the comparative risk of AKI with the use of different OAC, including the direct acting oral anticoagulants (DOACs).

Methods: We conducted a population-based cohort study using the administrative healthcare databases of Quebec, Canada. Patients with NVAF who were new users of oral anticoagulants between 2011 and 2014 were followed for hospitalized AKI, stratified by CKD status. Hazard ratios (HR) and corresponding 95% CI for hospitalized AKI with the use of dabigatran, rivaroxaban, and apixaban versus warfarin and versus each other in pairwise analyses, were assessed using Cox proportional hazards models. Estimates were stratified by the deciles of a disease risk score for AKI obtained from a historic cohort of 25,513 warfarin users with NVAF. The disease risk score included important demographic and clinical covariates weighted by their association with AKI.

Results: Our cohort of 26,357 patients with NVAF included 22,084 without, and 4273 with CKD. The rates of AKI hospitalization were 3.2 (95% CI 2.9-3.4) and 16.5 (95% CI 15.3-17.9) per 100 person-years, respectively. Among patients without CKD, apixaban (HR, 0.25; 95% CI, 0.14-0.44), rivaroxaban (HR, 0.50; 95% CI, 0.40-0.64), and dabigatran (HR, 0.68; 95% CI 0.57-0.81) were associated with a decreased risk of AKI compared with warfarin (Table 1). Similar findings were observed in the CKD cohort (Table 2). Compared with apixaban, dabigatran was associated with increased AKI risk in patients without (HR, 2.58; 95% CI, 1.42-4.67) and with (HR, 2.08; 95% CI, 1.01-4.26) CKD, as was rivaroxaban (without CKD - HR, 2.29 [95% CI, 1.24-4.20]; with CKD - HR, 1.98 [95% CI, 0.95-4.11]). Rivaroxaban was associated with decreased risk of AKI in patients without CKD (HR, 0.76; 95% CI, 0.58-0.99), compared with dabigatran.

Conclusions: Use of all DOACs was associated with decreased risk of AKI compared with warfarin. Apixaban was associated with the lowest comparative risk of AKI among DOACs, and rivaroxaban was suggested to be more protective than dabigatran in patients without CKD. While these findings await further confirmation, worsening renal function while on DOAC treatment has been associated with increased risk of major bleeding. Thus, suggested differences in the renal safety of DOACs should be incorporated in informed prescription and monitoring of these drugs.

Disclosures

Renoux: Bayer Pharmaceuticals: Research Funding; Canadian Foundation for Innovation: Research Funding.
Recreation of Fetal Neonatal Alloimmune Thrombocytopenia in CRISPR/Cas9 Gene-Edited Mice Expressing the Human Platelet Alloantigen, HPA-1a
Authors: Zhi Huiying , Ahlen Maria Therese , Skogen Bjørn , Newman Peter
Published: April 2021

Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening alloimmune disorder caused by maternal antibodies directed against fetal platelet alloantigens. The human platelet alloantigens, (HPA)-1a/HPA-1b (also known as the PlA1 alloantigen system), residing on the integrin β3 subunit (= platelet membrane glycoprotein IIIa), is the most frequently implicated HPA for causing FNAIT in Caucasians, and a single Leu33Pro amino acid polymorphism is responsible for generating the HPA-1a and HPA-1b epitopes. Neither human nor mouse anti-HPA-1a antibodies recognize murine GPIIIa due to amino acid differences both within and surrounding the polymorphic amino acid, which lies within a long flexible loop in PSI domain of the molecule. As a result, there are currently no authentic mouse models of FNAIT capable of recapitulating the human alloimmune response to this clinically-important platelet antigen. We employed CRISPR/Cas9 gene editing technology to generate mice expressing the human HPA-1a allogeneic epitope. Four critical amino acid substitutions (A30P32L33D39) were introduced into the PSI domain of murine GPIIIa. The resulting humanized form of murine GPIIIa, termed APLD, reacted in a variety of immunoassays with both murine monoclonal (mAb) and human maternal polyclonal antibodies specific for the human HPA-1a epitope. Intraperitoneal injection of an anti-HPA-1a mAb induced thrombocytopenia in APLD, but not wild-type, mice. Importantly, wild-type mice immunized with murine APLD transgenic platelets generated a high-titer HPA-1a-specific antibody response, demonstrating that the humanized form of murine GPIIIa is immunogenic in mice. Finally, pre-immunized female wild-type mice bred with APLD males gave birth to neonatal mice that exhibited profound thrombocytopenia, with the maternal titer directly related to the degree of thrombocytopenia in the neonates. Recapitulating the essential features of FNAIT in mice will facilitate the investigation of a wide-range of clinically-important issues in the diagnosis, treatment, and management of platelet alloimmune disorders.

Disclosures

No relevant conflicts of interest to declare.
Examining the CREB Transcriptional Program in Erythropoiesis
Authors: Chung Jacky , Paw Barry H. , Lodish Harvey , Ghamari Alireza , Cantor Alan B.
Published: April 2021

The erythropoietin (EPO) signal transduction network regulates a plethora of critical cellular functions during red blood cell maturation including proliferation and iron metabolism. Recently, it has been discovered that EPO signaling also controls heme metabolism through activation of the protein kinase A (PKA) pathway. The activation of PKA by EPO leads to the mitochondrial phosphorylation of the terminal heme enzyme, ferrochelatase (FECH), to ramp up heme production. In addition to FECH, a second principal PKA target is the CREB transcription factor, leading to the hypothesis that the EPO-PKA signaling pathway also regulates gene expression during red cell maturation. Here, we tested this hypothesis using biochemical and bioinformatics approaches. We found that CREB becomes phosphorylated in human and murine erythroid cells in an EPO-dependent manner. Using pharmacologic inhibitors, we confirmed that CREB phosphorylation is downstream of JAK2 and PKA signaling. Moreover, we found enrichment of a previously identified CREB-gene signature within the erythroid transcriptional program. To date, our work suggests that CREB plays a role during red cell development as an effector of EPO signaling. Further work will be required to understand the function of CREB target genes.

Disclosures

No relevant conflicts of interest to declare.
In Vivo Effects of LSD1 Inhibition By Small Chemical Inhibitors in Sickle Cell Mice
Authors: Le Cuong , Myers Greggory , Habara Alawi , Jearawiriyapaisarn Natee , Lee Mary , Chui David H.K. , Steinberg Martin H. , Engel James , Cui Shuaiying
Published: April 2021

For the past decades the principal strategy for treating the β-globinopathies [sickle cell disease (SCD) and β-thalassemia] has been to devise methods for increasing the levels of fetal hemoglobin (HbF) in adult erythroid cells, as a strong clinical literature has demonstrated that high HbF levels ameliorate disease pathophysiology.

We originally reported the lysine-specific histone demethylase 1 (LSD1) as a new protein involved in the regulation of the fetal γ-globin genes. Inhibition of LSD1 using either RNAi or by the momoamine oxidase inhibitor tranylcypromine in primary human erythroid progenitor cells induces HbF to therapeutic levels. Thus, inhibition of LSD1 activity presents a novel exploratory avenue as a therapeutic strategy to treat SCD. Subsequent studies using another inhibitor RN-1 showed that RN-1 treatment of SCD mice results in increased HbF synthesis and leads to effective improvement of many aspects of the disease pathology normally associated with sickle cell disease.

Here we report studies designed to examine the in vivo effects of some additional, publically available small molecule chemical inhibitors of LSD1 on HbF synthesis and erythroid physiology in SCD mice. In control SCD mice treated with DMSO only, the number of HbF positive cells was about 2.5% of total in RBC, while in SCD mice exposed to GSK-LSD1, or OG-L002, there was a statistically significant increase in the percentage of HbF positive cells after 4 weeks of treatment (up to 8%, or 6% respectively). Furthermore, sickled RBCs and reticulocytes are significantly reduced while the number of mature erythrocytes increased markedly in the peripheral blood of GSK-LSD1, or OG-L002 treated SCD mice. These findings suggest that GSK-LSD1 and/or OG-L002 could be potentially new HbF inducers based on LSD1 inhibition. We believe that these experiments will be of wide general interest and will be the foundation for development of small molecule therapeutics with which to treat hemoglobinopathies.

Disclosures

No relevant conflicts of interest to declare.
Emerging T Cell Engineering Approaches: New Targets and New Cell Sources
Authors: Dotti Gianpietro
Published: April 2021

The field of chimeric antigen receptors (CARs) in hematologic malignancies has been largely dominated by the adoptive transfer of T cells expressing the CD19-specific CAR for therapy of acute lymphoid leukemia and non-Hodgkin's lymphomas. More recently other target antigens have been tested in phase I studies with the aim to either mitigate the B cell aplasia, caused by CD19-specific CAR-Ts in B-lymphoid malignancies, or to target other malignancies non-expressing CD19. Two new targets such as k-light chain of human immunoglobulins to target B-cell lymphomas and CD30 to target Hodgkin's lymphoma have completed phase I studies showing antitumor activity. Efforts are also dedicated to contain the toxicities associated with the infusion of CD19.CAR-T cells by including safety switches. The inducible-Caspase9 (iC9) may represent a precise strategy to modulate these toxicities by eliminating CAR-Ts in a dose-dependent manner, allowing either a selective containment of CAR-T cell expansion or complete deletion. Finally, while polyclonal activated T cells are generally used in clinical trials as a platform to engraft CARs, other sources like NK cells and NKT cells can potentially be explored in specific clinical situations such as after allogeneic T-cells, since both NK and NKT cells do not carry the risk of graft-versus-host disease (GVHD).

Disclosures

Dotti: Cell Medica and BluebirdBio: Research Funding.