bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombolytics in Cardiac Arrest from Pulmonary Embolism: A Systematic Review and Meta Analysis
Authors: Feltes Jordan , Popova Margarita , Hussein Yasir , Pierce Ayal , Yamane David 
Published: December 2023

Background During cardiopulmonary resuscitation, intravenous thrombolytics are commonly used for patients whose underlying etiology of cardiac arrest is presumed to be related to pulmonary embolism (PE). Methods We performed a systematic review and meta-analysis of the existing literature that focused on the use of thrombolytics for cardiac arrest due to presumed or confirmed PE. Outcomes of interest were return of spontaneous circulation (ROSC), survival to hospital discharge, neurologically-intact survival, and bleeding complications. Results Thirteen studies with a total of 803 patients were included in this review. Most studies included were single-armed and retrospective. Thrombolytic agent and dose were heterogeneous between studies. Among those with control groups, intravenous thrombolysis was associated with higher rates of ROSC (OR 2.55, 95% CI = 1.50–4.34), but without a significant difference in survival to hospital discharge (OR 1.41, 95% CI = 0.79–2.41) or bleeding complications (OR 2.21, 0.95–5.17). Conclusions Use of intravenous thrombolytics in cardiac arrest due to confirmed or presumed PE is associated with increased ROSC but not survival to hospital discharge or change in bleeding complications. Larger randomized studies are needed. Currently, we recommend continuing to follow existing consensus guidelines which support use of thrombolytics for this indication.
New Validated Tool to Diagnose Breastfeeding Dysfunction
Authors: Agarwal Rajeev , Eddis-Finbow Mars , Tam Jodie , Broatch Jennifer , Bussey Kimberly J. 
Published: December 2023

Background: Breastfeeding behaviors and experiences exist on a continuum. What differentiates normal from dysfunctional is defined by frequency and severity. No current validated tool addresses the subjective experience of dyads with a predictive score that can be followed over time. Research Aim: To create and validate a self-report tool to assess breastfeeding and evaluate its ability to predict risk of breastfeeding dysfunction. Methods: This study used a cross-sectional design to determine the validity of a novel instrument to assess breastfeeding dysfunction. We gave the initial questionnaire to 2085 breastfeeding dyads. We assessed content validity by comparison with other tools. We used exploratory factor analysis with varimax rotation for concept identification and Cronbach’s alpha for internal consistency. We employed logistic regression to assess the tool’s ability to differentiate between normal breastfeeding and breastfeeding dysfunction. Results: Factor analysis mapped 17 questions to four concepts to create a score (FLIP; flow, latch, injury [to the nipple], and post-feed behavior). Internal consistency and reliability of the scores in these concepts were acceptable (Cronbach’s alpha ≥ 0.087 for all measures). A logistic regression model that controlled for infant age, with a breastfeeding dysfunction risk classification threshold of 60%, yielded a correct classification of 88.7%, with 93.1% sensitivity, 64.6% specificity, and a 6.5% false positive rate. Conclusions: The FLIP score was determined to be a valid and reliable instrument for quantifying the severity of breastfeeding dysfunction in children under 1 year old. Further studies will assess its usefulness in the management of breastfeeding dysfunction.
Mallet Hallux Injury Fixed With Extension Blocking Pin Technique: A Case Report
Authors: Giro Margaret E. , Quazi Nawreen , Elder Waters Michael , Lee Wonyong 
Published: December 2023

Mallet hallux injuries are relatively rare, and management can range from conservative treatment to surgical fixation. Only a few cases of surgically treated are reported, and there is no consensus on the superiority of one technique to others in surgical treatment. We reviewed various options for surgical fixation of Mallet hallux injury and presented a case of mallet hallux injury treated with Kirschner wires with an extension blocking technique. Level of Evidence: V
Intention to use digital mental health solutions: A cross-sectional survey of university students attitudes and perceptions toward online therapy, mental health apps, and chatbots
Authors: Gbollie Elton Fayiah , Bantjes Jason , Jarvis Lucy , Swandevelder Sonja , du Plessis Jean , Shadwell Richard , Davids Charl , Gerber Rone , Holland Nuhaa , Hunt Xanthe 
Published: December 2023

Background Globally, the high prevalence of mental disorders among university students is a growing public health problem, yet a small minority of students with mental health problems receive treatment. Digital mental health solutions could bridge treatment gaps and overcome many barriers students face accessing treatment. However, there is scant evidence, especially in South Africa (SA), relating to university students’ use of and intention to use digital mental health solutions or their attitudes towards these technologies. We aim to explore university 2students attitudes towards and perceptions of digital mental health solutions, and the factors associated with their intention to use them. Methods University students from four SA universities ( n = 17 838) completed an online survey to assess experience with, attitudes and perceptions of, and intentions to use, digital mental health solutions. We conducted an exploratory factor analysis to identify factors underlying attitudes and perceptions, and then used multivariate ordinal regression analysis was used to investigate the factors’ association with students’ intention to use digital mental health solutions. Results Intention to use digital mental health solutions was high, and attitudes towards and perceptions of digital mental health solutions were largely positive. Importantly, our analysis also shows that 12.6% of users were willing to utilise some form of digital mental health solutions but were unwilling to utilise traditional face-to-face therapies. The greatest proportion of variance was explained by the factor ‘Attitudes towards digital technologies’ utility to improve student counselling services, provided they are safe’. Conclusion SA university students are already engaging with digital mental health solutions, and their intention to do so is high. Certain attitudes and perceptions, particularly concerning the utility, effectiveness, and safety, underlie willingness to engage with these solutions, providing potential targets for interventions to increase uptake.
What Benefits Might a Family Expect From Using Spiritual Coping Mechanisms When Providing Care for People With Schizophrenia? Literature Review
Authors: Rohmi Faizatur , Yusuf Ah , Fitriasari Rizky , Agustinus Hardiyanto 
Published: December 2023

Introduction Caring for people with schizophrenia has consequences, one of which is stressors during care. Families as caregivers often using coping strategies that involve relationships with self, others, or the transcendent/God or nature and also may include religious/spiritual practices. Objectives This literature review aims to identify the benefit of using spiritual coping as used by a family schizophrenia caregiver. The variable is spiritual coping. Methods This literature review method used PRISMA methodology for systematic reviews. Search was conducted in March 2017, updated in August 2022 and submitted in April 2023 for the publication process, limited to English by using electronic databases: Scopus, ScienceDirect, Sage, ProQuest, and PubMed. Results Fifteen studies were included in this review. Two synthesized findings emerged: spiritual coping strategies used by family caregivers give positive effects for family. Conclusion When the stress or crisis phase is experienced while caring for people with schizophrenia, the family who acts as a caregiver reveals the meaning of life they have and that they feel hopelessness and helplessness. In an effort to overcome the family's burden as caregivers, they often use spiritual coping, which is important to increase the caregiver's wellbeing.
Engaging with communities in rural, coastal and low-income areas to understand barriers to palliative care and bereavement support: reflections on a community engagement programme in South-west England
Authors: Hansford Lorraine , Wyatt Katrina , Creanor Siobhan , Davies Jennie , Horne Gillian , Lynn Amanda , McCready Sheena , Pearce Susie , Peeler Anna , Rhys Ann , Sallnow Libby , Harding Richard 
Published: December 2023

Background: England’s South-west Peninsula is largely rural, has a high proportion of over 65s, and has areas of rural and coastal deprivation. Rural and low-income populations face inequities at end of life and little is known about the support needs of rural, coastal and low-income communities. Objectives: To understand how to foster community support for dying and grieving well, a regional, multi-sectoral research partnership developed a community engagement programme to explore experiences of seeking support, issues important to people and the community support they valued. This article shares what people told us about the role that communities can play at end of life, and reflects on learning from our process of engaging communities in conversations about dying. Design and methods: A programme of varied community engagement which included: the use of the ‘Departure Lounge’ installation and four focus groups with interested individuals in a range of community settings; the co-creation of a ‘Community Conversation’ toolkit to facilitate conversations with individuals with experience of end-of-life care and their carers with Community Builders; a focus group with Community Builders and a storytelling project with three bereaved individuals. Results: People valued community support at the end of life or in bereavement that offered connection with others, peer support without judgement, responded to their individual needs and helped them to access services. Creative methods of engagement show potential to help researchers and practitioners better understand the needs and priorities of underserved populations. Collaboration with existing community groups was key to engagement, and contextual factors influenced levels of engagement. Conclusion: Local community organizations are well placed to support people at end of life. This work highlighted the potential for partnership with palliative care and bereavement organizations, who could offer opportunities to develop people’s knowledge and skills, and together generate sustainable solutions to meet local need.
Glutaminase Upregulation As a Mechanism of Chemotherapy Resistance in High-Risk Leukemia
Authors: Nalesnik Gregory Harrison , Dovat Sinisa , Bogush Daniel , Schramm Joseph 
Published: December 2023

Many types of cancers are characterized by elevated glutamine consumption. Glutaminase is a therapeutic target to arrest cancer cell development. Ikaros (IKZF1) is a DNA-binding, zinc finger protein that functions as a transcriptional regulator and a tumor suppressor in leukemia. Ikaros activity is essential for normal hematopoiesis and immune development and is expressed at high levels in most hematopoietic cells. Deletion of IKZF1 leads to the downregulation and upregulation of many important genes and is a predictor of poor outcomes in leukemia. We hypothesize that upregulation of glutaminase in cancer cells with IKZF1 deletion may be a mechanism whereby high-risk leukemias convey chemotherapy resistance. Conversely, Ikaros may help keep healthy hematopoietic cells in-check by preventing over-expression of glutaminase.
To test this hypothesis, we exposed two lines of B-ALL cells to the allosteric and selective glutaminase inhibitor BPTES. One cell line had IKZF1 intact (Nalm-6 scramble) and one had IKZF1 deleted via a CRISPR knockout (Nalm-6 IK KO). Treatments were done in triplicate with an exposure time of 72 hours. WST-1 viability assay was used to obtain an IC50 value for each cell line. Leukemia cells with IKZF1 knocked out had a two-fold higher IC50 than cells with IKZF1 intact. This indicates that IKZF1 deletion may convey chemotherapy resistance by upregulating glutaminase and implies that strategies targeting glutaminase may improve treatment outcomes in high-risk leukemia patients.
Deep Learning for Morphology-Based, Bone Marrow Cell Classification
Authors: Sun Shenghuan , Cleave Jacob , Wang Linlin , Lucas Fabienne , Brown Laura , Spector Jacob , Boiocchi Leonardo , Baik Jeeyeon , Zhu Menglei , Ardon Orly , Lu Chuanyi M. , Dogan Ahmet , Goldgof Dmitry , Carmichael Iain , Prakash Sonam , Butte Atul , Goldgof Gregory Mark 
Published: December 2023

The morphological classification of cells in bone marrow aspirate (BMA) is central to the diagnosis of hematologic diseases, including leukemias. Despite being a critical task, its monotonous, time-consuming nature and dependency on highly skilled clinical experts makes it prone to human error. Such errors can lead to delays and misdiagnoses that negatively impact patient care. To counter these challenges, we curated an expansive dataset of more than 40,000 hematopathologist consensus-annotated single-cell images, extracted from BMA whole slide images (WSIs), each annotated into one of 23 distinct morphologic classes.
We then utilized this data to develop DeepHeme, a convolutional neural network classifier designed for bone marrow cell typing tasks. DeepHeme achieves state-of-the-art performance in both the breadth of differentiable classes and accuracy across these classes. By comparing its performance to that of individual hematopathologists from three premier academic medical centers, using our gold standard consensus-labelled images, we found our AI algorithm either matched or surpassed the average performance across all classes. In addition, we integrated DeepHeme with internally developed region classifier and cell detection algorithms, culminating in a comprehensive diagnostic pipeline for whole slide cell differential.
We next tested DeepHeme on slides from an external hospital system at a major cancer center to evaluate the generalizability of our model, a necessary precondition to widespread application. DeepHeme demonstrated a high level of generalizability, evidenced by a decrease of only 4% in the mean F-1 score, from 0.89 to 0.85, across all 23 cell classes. Lastly, to improve access to the DeepHeme algorithm results and encourage further real-world generalizability testing, we developed a web application that allows scientists and clinicians to test the DeepHeme algorithm on either test images from our study or their own user-uploaded aspirates.
Novel Anti-TMPRSS6 Monoclonal Antibody Provides a Potential Therapeutic Approach for the Treatment of Polycythemia Vera
Authors: Chen Buxin , Wang Jean , Huang Lei , Bujold Matthew , Du Xin 
Published: December 2023

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) triggered by activating mutations in JAK2, an important kinase in the principal signaling pathway of the erythropoietin receptor. Most of the clinical manifestations of PV are caused by increased erythrocyte count, leading to increased risk of pulmonary hypertension and thrombosis. The mainstay of therapy for PV is therapeutic phlebotomy to reduce the hematocrit (HCT) level and minimize the risk of thrombosis, however, the effect of phlebotomy is transient until patients become iron deficient. Therefore, systemic iron restriction could be effective in treating PV patients.
Transmembrane serine protease 6 (TMPRSS6) is a negative regulator hepcidin, the master regulator of iron homeostasis. Increasing genetic, preclinical and clinical evidence has demonstrated that inhibition of TMPRSS6 can potently elevated hepcidin levels, thereby achieving systemic iron restriction.
Previously, we reported the generation of anti-TMPRSS6 antibody MWTx-003 and its efficacy in reducing iron overload and improving ineffective erythropoiesis in a mouse model of β-thalassemia. In this study, we explored therapeutic application of MWTx-003 in PV using a Jak2 V617F bone marrow transplantation mouse model. The mouse model exhibits typical PV phenotypes of erythrocytosis and elevated HCT levels. In the PV mice, treatment with MWTx-003 (2-10 mg/kg, i.p., every 4 days for 3 weeks) led to significantly reduced HCT levels, red blood cell (RBC) counts and hemoglobin (HGB) concentration that were comparable to that of wildtype control mice. These effects were evident in a dose-dependent manner and observed as early as two weeks into treatment. It is worth noting that in the 10 mg/kg dose group, a worsening splenomegaly and expansion of early erythroid progenitors were observed after 3 weeks of treatment, and these findings are typical of iron-restricted erythropoiesis in mice. Taken together, the anti-TMPRSS6 antibody offers a promising therapeutic approach in the management of PV, where erythrocytosis and high HCT levels are associated with poor outcomes. A Phase I clinical trial with MWTx-003 in healthy volunteers has been initiated in China.
The Selective CDK9 Inhibitor VIP152 Overcame Therapeutic Resistance in Mantle Cell Lymphoma
Authors: Lee William , Jiang Vivian Changying , Zhang Tianci , Yan Fangfang , Cai Qingsong , McIntosh Joseph , Liu Yang , Wang Michael L. 
Published: December 2023

Introduction
Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma. Even most advanced therapies are generally followed by resistance and relapse, creating an urgent need for novel drugs to overcome resistance. Our and other studies have shown transcriptome is abnormally reprogrammed in patients with therapeutic resistance. CDK9, as a master transcriptional regulator, is overexpressed in tumors after subsequent relapses to BTK inhibitors (BTKi) and CAR-T therapy. VIP152 is a highly potent and selective CDK9 inhibitor under preclinical and early clinical development. As yet, its potency and safety in patients with MCL, especially those with multiple therapeutic resistances, has not been addressed.
Method
We performed single-cell RNA sequencing and bulk RNA sequencing to investigate enriched cancer hallmarks in MCL. Cell viability assays were conducted in a time- and dose-dependent manner to assess the in vitro efficacy of VIP152. Apoptosis assays and western blots were used to identify relevant pathways in bypassing resistances. Cell line-derived xenograft and patient-derived xenograft models of MCL created in immunodeficient mice were used to monitor tumor growth and thus determine the in vivo efficacy of VIP152 in overcoming therapeutic resistances.
Results
Based on single-cell RNA sequencing and bulk RNA sequencing, we found that the cancer hallmark MYC-TARGETS is progressively enriched in MCL patients with subsequent failures to BTKi and CAR-T therapy. CDK9 was found to be overexpressed in CAR-T-relapsed patients compared to CAR-T-naïve but BTKi-refractory/relapsed patients. We hypothesized that CDK9 overexpression and activity may greatly contribute to the transcriptomic reprogramming in patients with therapeutic resistance. Targeting CDK9-mediated transcription with the specific CDK9 inhibitor VIP152 was highly effective in MCL cell lines at low nanomolar range (55-172 nM). VIP152 robustly induced apoptosis in a time- and dose-dependent manner, which was largely dependent on caspase-3 activity. It markedly inhibited CDK9 phosphorylation and down streaming signaling, and suppressed the expression of short-lived proteins like MYC, MCL-1, and cyclin D1 that are critical for MCL cell survival and proliferation. VIP152 effectively inhibited the tumor growth of MCL cell line-derived xenograft models in vivo (P&lt;0.001) with no apparent adverse effects in mice. Moreover, VIP152 markedly inhibited the growth of three patient-derived xenograft tumor models, overcoming BTKi resistance (P&lt;0.001), BTKi-venetoclax dual resistance (P&lt;0.01), and BTKi-CAR-T dual resistance (P&lt;0.001).
Conclusion
These data showed that CDK9 was a promising target for treating MCL and using VIP152 to specifically target it was efficacious in overcoming a variety of therapeutic resistances in MCL.
Molecular Determinants of Sensitivity to Polatuzumab-Vedotin in Diffuse Large B-Cell Lymphoma
Authors: Corcoran Sean R , Choi Jaewoo , Fenner Rachel E , Yu Xin , Scheich Sebastian , Hsiao Tony , Schevchenko Galina , Morris Vivian M , Phelan James D , Papachristou Evangelia K , Kishore Kamal , D'Santos Clive S , Ji Yanlong , Pittaluga Stefania , Wright George , Urlaub Henning , Pan Kuan-Ting , Oellerich Thomas , Muppidi Jagan R. , Hodson Daniel James , Staudt Louis M. 
Published: December 2023

Purpose: Polatuzumab Vedotin (Pola-V) is an antibody-drug conjugate directed to the B cell surface antigen CD79B. When combined with conventional immunochemotherapy, Pola-V improves outcomes in DLBCL overall; however, there is noted heterogeneity in response to Pola-V, with germinal center b-cell (GCB) DLBCL showing no added benefit to the addition of Pola-V compared to standard immunochemotherapy. We aimed to identify molecular determinants of sensitivity or resistance to Pola-V. We hypothesized that these might lead us to innovative strategies to improve on-target tumor killing by Pola-V, or to find novel biomarkers that predict drug resistance.
Methods: We employed combined drug-sensitization and CD79B-sorted CRISPR-Cas9 screening to identify molecular determinants of sensitivity to CD79B-directed, tumor killing by Pola-V in 9 cell lines representing different molecular subtypes of DLBCL.
Results: Our results reveal the striking impact of epitope glycosylation, specifically a2,6 sialylation, on the binding of Pola-V to CD79B and thereby its ability to kill tumor cells. Specifically, we identify the exact glycosylated residues on CD79A and CD79B which create a glycan shield around the Pola-V binding site, precluding binding to its target. We show how genetic, pharmacological and enzymatic approaches that remove terminal sialic acid residues from these N-linked glycans lead to enhanced tumor killing by Pola-V. We hypothesize and test multiple methods of targeting this pathway in order to enhance Pola-V killing both in vitro and in vivo. Finally, we reveal a previously unappreciated role for the ubiquitin ligase KLHL6 in regulating CD79B protein abundance and surface expression of the B cell antigen receptor (BCR), including how this pathway is used by physiological germinal center B cells and how it is corrupted to enhance BCR expression in GCB DLBCL.
Conclusions: These findings unravel the molecular basis of response heterogeneity to Pola-V and identify approaches that might be deployed therapeutically to enhance the efficacy of CD79B-specific tumor killing. In addition, we identify how KLHL6 determines expression of the BCR in both physiological and malignant germinal center B cells, and how KLHL6 mutation may modulate sensitivity of GCB DLBCL tumors to Pola-V.