bluuebunny/crossref_metadata_2025_split huggingface dataset:
Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia: Italian Delphi-based consensus recommendations
Authors: Carpenedo Monica , Baldacci Erminia , Baratè Claudia , Borchiellini Alessandra , Buccisano Francesco , Calvaruso Giuseppina , Chiurazzi Federico , Fattizzo Bruno , Giuffrida Gaetano , Rossi Elena , Palandri Francesca , Scalzulli Potito Rosario , Siragusa Sergio Mario , Vitucci Angelantonio , Zaja Francesco 
Published: October 2021

Introduction: In patients with primary immune thrombocytopenia (ITP), a short course of steroids is routinely given as first-line therapy. However, the response is often transient and additional therapy is usually needed. Thrombopoietin receptor agonists (TPO-RAs) are frequently used as second-line therapy, although there is little clinical guidance on the timing of their administration and on tapering/discontinuation of the drug. To provide clinical recommendations, we used the Delphi technique to obtain consensus for statements regarding administration and on tapering/discontinuation of second-line TPO-RAs among a group of Italian clinicians with expertise in management of ITP. Methods: The Delphi process was used to obtain agreement on five statements regarding initiation and on tapering/discontinuation of second-line TPO-RAs. Agreement was considered when 75% of participants approved the statement. Eleven experts participated in the voting. Results: Full consensus was reached for three of the five statements. The experts held that an early switch from corticosteroids to a TPO-RA has the dual advantage of sparing patients from corticosteroid abuse and improve long-term clinical outcomes. All felt that dose reduction of TPO-RAs can be considered in patients with a stable response and platelet count >100 × 109/L that is maintained for at least 6 months in the absence of concomitant treatments, although there was less agreement in patients with a platelet count >50 × 109/L. Near consensus was reached regarding the statement that early treatment with a TPO-RA is associated with an increase in clinically significant partial or complete response. The experts also agreed that optimization of tapering and discontinuation of TPO-RA therapy in selected patients can improve the quality of life. Conclusion: The present consensus can help to provide guidance on use of TPO-RAs in daily practice in patients with ITP. Plain language summary Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia There is little guidance on the timing of administration and tapering/discontinuation of thrombopoietin receptor agonists (TPO-RAs) in patients with primary immune thrombocytopenia (ITP). The Delphi technique was used to obtain consensus for five statements. The present consensus among Italian clinicians aims to provide guidance on second-line use of TPO-RAs for patients with ITP in daily practice.
Endotrophin as a novel marker in PCOS and its relation with other adipokines and metabolic parameters: a pilot study
Authors: Guney Gurhan , Taskin Mine Islimye , Baykan Ozgur , Adali Ertan , Gul Tezcan Selin , Sarikaya Serkan , Kaya Cihan , Tolu Ezgi 
Published: October 2021

Background: Polycystic ovary syndrome is known to be the most common hormonal disorder in women of reproductive age. Current evidence shows that regulatory proteins secreted from the adipose tissue called adipokines may have a role in polycystic ovary syndrome. We planned to investigate the role of endotrophin that has never been researched in polycystic ovary syndrome before and its correlation with other metabolic parameters and adipokines such as adiponectin and ghrelin in patients with polycystic ovary syndrome. Methods: Forty-three women ( n: 43) with polycystic ovary syndrome and 43 ( n: 43) women as a control group were enrolled in this cross-sectional study. Serum levels of endotrophin, adiponectin, and ghrelin levels were measured with the enzyme-linked immunosorbent assay method. High-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol levels, luteinizing hormone/follicle-stimulating hormone ratio, total testosterone, and triglyceride levels were measured. Homeostasis model assessment for insulin resistance index, body mass index, Ferriman Gallwey Score, and waist-to-hip ratio were also evaluated. Results: Total testosterone, homeostasis model assessment for insulin resistance, C-reactive protein, luteinizing hormone/follicle-stimulating hormone ratio, and triglyceride levels were higher in patients with polycystic ovary syndrome ( p < 0.01). No difference was detected between the groups in terms of body mass index, Ferriman Gallwey Score, waist-to-hip ratio, total cholesterol, low-density lipoprotein, and high-density lipoprotein levels ( p > 0.05). We did not observe any significant difference in adiponectin and ghrelin levels between the groups ( p > 0.05). Patients with polycystic ovary syndrome had significantly higher endotrophin levels ( p < 0.01). According to our regression analyses [area under the curve: 0.973 (0.935–1.000), 95% confidence interval, 95.2% sensitivity, and 100% specificity], it was shown that endotrophin greater than 92 ng/ml and homeostasis model assessment for insulin resistance greater than 2.5 might be good predictors for polycystic ovary syndrome diagnosis. Conclusion: We demonstrated that endotrophin level is higher in patients with polycystic ovary syndrome and may have predicted polycystic ovary syndrome with increased homeostasis model assessment for insulin resistance index. There was no significant difference in adiponectin and ghrelin levels in the polycystic ovary syndrome group. Endotrophin may have a role in polycystic ovary syndrome etiology rather than other adipokines.
Efficacy and safety of lamotrigine in the treatment of bipolar disorder across the lifespan: a systematic review
Authors: Besag Frank M.C. , Vasey Michael J. , Sharma Aditya N. , Lam Ivan C.H. 
Published: October 2021

Background: Bipolar disorder (BD) is a cyclic mood disorder characterised by alternating episodes of mania/hypomania and depression interspersed with euthymic periods. Lamotrigine (LTG) demonstrated some mood improvement in patients treated for epilepsy, leading to clinical studies in patients with BD and its eventual introduction as maintenance therapy for the prevention of depressive relapse in euthymic patients. Most current clinical guidelines include LTG as a recommended treatment option for the maintenance phase in adult BD, consistent with its global licencing status. Aims: To review the evidence for the efficacy and safety of LTG in the treatment of all phases of BD. Methods: PubMed was searched for double-blind, randomised, placebo-controlled trials using the keywords: LTG, Lamictal, ‘bipolar disorder’, ‘bipolar affective disorder’, ‘bipolar I’, ‘bipolar II’, cyclothymia, mania, manic, depression, depressive, ‘randomised controlled trial’, ‘randomised trial’, RCT and ‘placebo-controlled’ and corresponding MeSH terms. Eligible articles published in English were reviewed. Results: Thirteen studies were identified. The strongest evidence supports utility in the prevention of recurrence and relapse, particularly depressive relapse, in stabilised patients. Some evidence suggests efficacy in acute bipolar depression, but findings are inconsistent. There is little or no strong evidence in support of efficacy in acute mania, unipolar depression, or rapid-cycling BD. Few controlled trials have evaluated LTG in bipolar II or in paediatric patients. Indications for safety, tolerability and patient acceptability are relatively favourable, provided there is slow dose escalation to reduce the probability of skin rash. Conclusion: On the balance of efficacy and tolerability, LTG might be considered a first-line drug for BD, except for acute manic episodes or where rapid symptom control is required. In terms of efficacy alone, however, the evidence favours other medications.
Effect of aripiprazole as an adjunct to atypical antipsychotics on weight and metabolic profile: a 12-week open-label trial
Authors: Gupta Bhanu , Chee Kok-Seng , Neo Li-Qi , Tang Charmaine , Hariram Jayaraman , Tan Geoffrey Chern-Yee , Verma Swapna , Basu Sutapa , Appan Deva-Priya , Ting Chan-Chun , Abdin Edimansyah , Lee Jimmy 
Published: October 2021

Background: Atypical antipsychotics are widely prescribed, yet have been associated with weight gain and metabolic syndrome. Aim: To study the effect of adjunct low-dose aripiprazole on weight and metabolic parameters of subjects on atypical antipsychotics (olanzapine, clozapine or risperidone). Methods: The study was carried out as an open-label trial with a fixed dose of 5 mg aripiprazole added to the patient’s current antipsychotic for 12 weeks. The primary outcome measure was mean change in weight, while secondary outcome measures included change in waist circumference; fasting blood glucose; HbA1c; triglycerides; total, HDL and LDL cholesterol levels; functioning; and neurocognition. Results: For the overall study ( n = 55), there was no significant effect of adjunct aripiprazole on the weight of the subjects. However, the clozapine group achieved significant weight loss ( p = 0.002) and also had significant improvements in total cholesterol ( p < 0.001), HDL ( p = 0.016), LDL ( p = 0.044) and triglyceride levels ( p = 0.038). The olanzapine group had significant improvement in triglycerides ( p = 0.001), and other metabolic parameters for this group showed improvement trends, but did not reach statistical significance. The risperidone group did not show any significant improvement in weight or metabolic parameters. Conclusions: The study adds support to the adjunctive use of aripiprazole to clozapine for weight loss and improvement in metabolic profile, and for reduction in cardiometabolic risk for patients on olanzapine. Trial Registration: Clinicaltrials.gov identifier: NCT02949752
Towards development of guidelines for virtual administration of paediatric standardized language and literacy assessments: Considerations for clinicians and researchers
Authors: Wood Emily , Bhalloo Insiya , McCaig Brittany , Feraru Cristina , Molnar Monika 
Published: October 2021

Objectives: Previous virtual care literature within the field of speech-language pathology has primarily focused on validating the virtual use of intervention programmes. There are fewer articles addressing the validity of conducting virtual assessments, particularly standardized assessment of oral language and literacy abilities in children. In addition, there is a lack of practical, useful recommendations available to support clinicians and researchers on how to conduct these assessment measures virtually. Given the recent rapid rise in virtual care and research as a result of the Coronavirus-19 pandemic, clinicians and researchers require guidance on best practices for virtual administration of these tools imminently. This article seeks to fill this gap in the literature by providing such recommendations. Methods: We (a) completed a narrative review of the extant literature, and (b) conducted semi-structured interviews with a group of 12 clinicians, students and researchers who had administered standardized language and literacy assessments with a variety of monolingual and multilingual school-aged children, with and without speech and language difficulties, in clinical and research settings. Six themes: candidacy for virtual assessment, communication and collaboration with caregivers, technology and equipment, virtual administration, ethics, consent and confidentiality, and considerations for bilingual populations were identified as a result of these two processes and were used to develop a set of recommendations to guide the use of standardized assessments in a virtual setting. In line with the Guidelines International Network, these recommendations were rated by group members, and reviewed by external stakeholders. A quasi-Delphi consensus procedure was used to reach agreement on ratings for recommendations. Results: We have developed and outlined several recommendations for clinicians and researchers to guide their use of standardized language and literacy assessments in virtual care, across six key themes. Conclusions: This article is one of the first to share practical recommendations for virtual assessment in the domain of oral language and literacy assessment for clinicians and researchers. We hope the current recommendations will facilitate future clinical research in this area, and as the body of research in this field grows, this article will act as a basis for the development of formal Clinical Practice Guidelines.
Incidence and Factors Affecting the Occurrence of Lateral Hinge Fracture After Medial Opening-Wedge High Tibial Osteotomy
Authors: Lee Sang-June , Kim Jae-Hwa , Baek Eugene , Ryu Han-Seung , Han Donghun , Choi Wonchul 
Published: October 2021

Background: Few clinical studies have reported the predictors of lateral hinge fracture (LHF) after medial opening-wedge high tibial osteotomy (MOWHTO). Purpose/Hypothesis: The purpose was to compare the incidence of LHF on plain radiographs versus computed tomography (CT) scans and to investigate the factors related to the development of LHF after MOWHTO. We hypothesized that (1) a higher LHF detection rate would be seen on CT scans versus plain radiographs and (2) LHF incidence would be related to opening gap width and hinge position. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A total of 97 MOWHTO cases were included. The presence and types of LHF were determined from plain radiographs and CT scans. Radiographic parameters were measured on plain radiographs taken 6 weeks postoperatively. Anterior and posterior opening gap widths, coronal and sagittal osteotomy slopes, and fibular height were calculated from CT scans. The wedge-hinge relationship and the zone of hinge position were assessed, and the patient and radiographic factors related to LHF occurrence were evaluated. Results: Seventeen LHF cases (20.5%) were detected on plain radiographs, while significantly more (37 cases; 44.6%) were found on CT scans ( P = .001). Based on Takeuchi classification, 28 LHF cases were considered type 1, 7 were type 2, and 2 were type 3. Logistic regression analysis revealed that opening gap width (odds ratio, 1.615; 95% confidence interval, 1.232-2.118; P = .001) and posterior opening gap width (odds ratio, 3.731; 95% confidence interval, 1.642-4.351; P = .008,) differed significantly between patients with versus without LHF. Other patient and radiographic factors were not significantly related to LHF occurrence. Receiver operating characteristic curve analysis identified the opening gap width cutoff values for LHF as 11.0 mm (area under the curve, 0.81; sensitivity, 78.4%; specificity, 73.9%). Conclusion: The incidence of LHF after MOWHTO can be underestimated on plain radiographs compared with CT scans. Only large opening gap width, especially posterior gap width, was found to have a statistically significant relationship with occurrence of LHF. Therefore, special caution for possible LHF may be needed if a large correction is planned.
ETV6-NCOA2 fusion induces T/myeloid mixed-phenotype leukemia through transformation of nonthymic hematopoietic progenitor cells
Authors: Fishman Hila , Madiwale Shreyas , Geron Ifat , Bari Vase , Van Loocke Wouter , Kirschenbaum Yael , Ganmore Itamar , Kugler Eitan , Rein-Gil Avigail , Friedlander Gilgi , Schiby Ginette , Birger Yehudit , Strehl Sabine , Soulier Jean , Knoechel Birgit , Ferrando Adolfo , Noy-Lotan Sharon , Nagler Arnon , Mulloy James C. , Van Vlierberghe Pieter , Izraeli Shai 
Published: October 2021

Abstract
Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation that creates the ETV6-NCOA2 fusion with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1-activating mutations. Similarly, cotransduction of human cord blood CD34+ progenitors with ETV6-NCOA2 and a nontransforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern were similar to those of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse nonthymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at an early immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration.
SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma
Authors: Wilke Anne C. , Doebele Carmen , Zindel Alena , Lee Kwang Seok , Rieke Sara A. , Ceribelli Michele , Comoglio Federico , Phelan James D. , Wang James Q. , Pikman Yana , Jahn Dominique , Häupl Björn , Schneider Constanze , Scheich Sebastian , Tosto Frances A. , Bohnenberger Hanibal , Stauder Philipp , Schnütgen Frank , Slabicki Mikolaj , Coulibaly Zana A. , Wolf Sebastian , Bojarczuk Kamil , Chapuy Björn , Brandts Christian H. , Stroebel Philipp , Lewis Caroline A. , Engelke Michael , Xu Xincheng , Kim Hahn , Dang Thanh Hung , Schmitz Roland , Hodson Daniel J. , Stegmaier Kimberly , Urlaub Henning , Serve Hubert , Schmitt Clemens A. , Kreuz Fernando , Knittel Gero , Rabinowitz Joshua D. , Reinhardt Hans Christian , Vander Heiden Matthew G. , Thomas Craig , Staudt Louis M. , Zenz Thorsten , Oellerich Thomas 
Published: October 2021

Abstract
Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.
Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2+ diffuse large B-cell lymphomas
Authors: Shen Yajie , Zhou Jingqi , Nie Kui , Cheng Shuhua , Chen Zhengming , Wang Wenhan , Wei Weiqing , Jiang Daiji , Peng Zijing , Ren Yizhuo , Zhang Yirong , Fan Qiuju , Richards Kristy L. , Qi Yitao , Cheng Jinke , Tam Wayne , Ma Jiao 
Published: October 2021

Abstract
Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation–sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.
Infectious complications of CAR T-cell therapy across novel antigen targets in the first 30 days
Authors: Mikkilineni Lekha , Yates Bonnie , Steinberg Seth M. , Shahani Shilpa A. , Molina John C. , Palmore Tara , Lee Daniel W. , Kaplan Rosandra N. , Mackall Crystal L. , Fry Terry J. , Gea-Banacloche Juan , Jerussi Theresa , Nussenblatt Veronique , Kochenderfer James N. , Shah Nirali N. 
Published: October 2021

Abstract
Infections are a known complication of chimeric antigen receptor (CAR) T-cell therapy with data largely emerging from CD19 CAR T-cell targeting. As CAR T-cell therapy continues to evolve, infection risks and management thereof will become increasingly important to optimize outcomes across the spectrum of antigens and disease targeted. We retrospectively characterized infectious complications occurring in 162 children and adults treated among 5 phase 1 CAR T-cell clinical trials. Trials included targeting of CD19, CD22, disialoganglioside (GD2) or B-cell maturation antigen (BCMA). Fifty-three patients (32.7%) had 76 infections between lymphocyte depleting (LD) chemotherapy and day 30 (D30); with the majority of infections (61, 80.3%) occurring between day 0 (D0) and D30. By trial, the highest proportion of infections was seen with CD22 CAR T cells (n = 23/53; 43.4%), followed by BCMA CAR T cells (n = 9/24; 37.5%). By disease, patients with multiple myeloma had the highest proportion of infections (9/24; 37.5%) followed by acute lymphoblastic leukemia (36/102; 35.3%). Grade 4 infections were rare (n = 4; 2.5%). Between D0 and D30, bacteremia and bacterial site infections were the most common infection type. In univariate analysis, increasing prior lines of therapy, recent infection within 100 days of LD chemotherapy, corticosteroid or tocilizumab use, and fever and neutropenia were associated with a higher risk of infection. In a multivariable analysis, only prior lines of therapy and recent infection were associated with higher risk of infection. In conclusion, we provide a broad overview of infection risk within the first 30 days post infusion across a host of multiple targets and diseases, elucidating both unique characteristics and commonalities highlighting aspects important to improving patient outcomes.