bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
Authors: Jiang Vivian Changying , Liu Yang , Jordan Alexa , Leeming Angela , McIntosh Joseph , Huang Shengjian , Zhang Rongjia , Cai Qingsong , Chen Zhihong , Li Yijing , Che Yuxuan , Nie Lei , Karlsson Ingrid , Mårtensson Linda , Kovacek Mathilda , Teige Ingrid , Frendéus Björn , Wang Michael 
Published: April 2022

Abstract
Inevitable relapses remain as the major therapeutic challenge in patients with mantle cell lymphoma (MCL) despite FDA approval of multiple targeted therapies and immunotherapies. Fc gamma receptors (FcγRs) play important roles in regulating antibody-mediated immunity. FcγRIIB, the unique immune-checkpoint inhibitory member of the FcγR family, has been implicated in immune cell desensitization and tumor cell resistance to the anti-CD20 antibody rituximab and other antibody-mediated immunotherapies; however, little is known about its expression and its immune-modulatory function in patients with aggressive MCL, especially those with multi-resistance. In this study, we found that FcγRIIB was ubiquitously expressed in both MCL cell lines and primary patient samples. FcγRIIB expression is significantly higher in CAR T-relapsed patient samples (p < 0.0001) compared to ibrutinib/rituximab-naïve, sensitive or resistant samples. Rituximab-induced CD20 internalization in JeKo-1 cells was completely blocked by concurrent treatment with BI-1206, a recombinant human monoclonal antibody targeting FcγRIIB. Combinational therapies with rituximab-ibrutinib, rituximab-venetoclax and rituximab-CHOP also induced CD20 internalization which was again effectively blocked by BI-1206. BI-1206 significantly enhanced the in vivo anti-MCL efficacy of rituximab-ibrutinib (p = 0.05) and rituximab-venetoclax (p = 0.02), but not the rituximab-CHOP combination in JeKo-1 cell line-derived xenograft models. In patient-derived xenograft (PDX) models, BI-1206, as a single agent, showed high potency (p < 0.0001, compared to vehicle control) in one aggressive PDX model that is resistant to both ibrutinib and venetoclax but sensitive to the combination of rituximab and lenalidomide (the preclinical mimetic of R2 therapy). BI-1206 sensitized the efficacy of rituximab monotherapy in a PDX model with triple resistance to rituximab, ibrutinib and CAR T-therapies (p = 0.030). Moreover, BI-1206 significantly enhanced the efficacy of the rituximab-venetoclax combination (p < 0.05), which led to long-term tumor remission in 25% of mice. Altogether, these data support that targeting this new immune-checkpoint blockade enhances the therapeutic activity of rituximab-based regimens in aggressive MCL models with multi-resistance.

Graphical Abstract
Acute postoperative pain management protocols in podiatric surgery within Australia: a Delphi study
Authors: Ang Ping Ping Joanne , Hugo Burke , Silvester Renee 
Published: April 2022

AbstractBackgroundThere is limited evidence in the literature to describe an analgesic protocol that takes into consideration the extent of foot and ankle surgery. The aim of this study was to develop a guide for acute postoperative pain management for podiatric surgery in Australia, and to identify opportunities to improve the current list of scheduled medicines available to podiatric surgeons.MethodsA Delphi method involving 3 survey rounds was employed for this study. Twelve expert panellists in the field of podiatric surgery and anaesthesiology were invited to participate, and 10 panellists remained by the end of the study. Round 1 involved 15 open‐ended questions. These answers formed the basis of the 55 statements that were developed for the following 2 survey rounds, where panellists rated the appropriateness of each statement on a 9‐point Likert scale. The third survey round was an opportunity for panellists to revise their answers to each statement in light of the majority response.ResultsFor mild acute postoperative pain, non‐opioid oral analgesics were recommended as an appropriate management option. For moderate and severe acute postoperative pain, both non‐opioid and opioid products were found to be appropriate by the majority. It was agreed that oral opioids be reserved for breakthrough pain at all severity levels. All other statements in the Delphi study pertaining to drug hypersensitivities or allergies, stratification of pain management, opioid prescription concerns, and access to pain medications were accepted as appropriate by the majority of panellists.ConclusionThe agreed approach to acute postoperative pain management for podiatric surgeons in Australia was with a stepwise approach, utilising multimodal therapy, and reserving oral opioids for breakthrough pain. Additionally, there was consensus for podiatric surgeons in Australia to have wider access to alternative analgesics and anti‐emetics that have similar or improved efficacies with better safety profiles.
A novel Vascular Leak Index identifies sepsis patients with a higher risk for in-hospital death and fluid accumulation
Authors: Chandra Jay , Armengol de la Hoz Miguel A. , Lee Gwendolyn , Lee Alexandria , Thoral Patrick , Elbers Paul , Lee Hyung-Chul , Munger John S. , Celi Leo Anthony , Kaufman David A. 
Published: April 2022

Abstract
Purpose
Sepsis is a leading cause of morbidity and mortality worldwide and is characterized by vascular leak. Treatment for sepsis, specifically intravenous fluids, may worsen deterioration in the context of vascular leak. We therefore sought to quantify vascular leak in sepsis patients to guide fluid resuscitation.

Methods
We performed a retrospective cohort study of sepsis patients in four ICU databases in North America, Europe, and Asia. We developed an intuitive vascular leak index (VLI) and explored the relationship between VLI and in-hospital death and fluid balance using generalized additive models (GAM).

Results
Using a GAM, we found that increased VLI is associated with an increased risk of in-hospital death. Patients with a VLI in the highest quartile (Q4), across the four datasets, had a 1.61–2.31 times increased odds of dying in the hospital compared to patients with a VLI in the lowest quartile (Q1). VLI Q2 and Q3 were also associated with increased odds of dying. The relationship between VLI, treated as a continuous variable, and in-hospital death and fluid balance was statistically significant in the three datasets with large sample sizes. Specifically, we observed that as VLI increased, there was increase in the risk for in-hospital death and 36–84 h fluid balance.

Conclusions
Our VLI identifies groups of patients who may be at higher risk for in-hospital death or for fluid accumulation. This relationship persisted in models developed to control for severity of illness and chronic comorbidities.
Plasma disappearance rate of albumin when infused as a 20% solution
Authors: Zdolsek Markus , Wuethrich Patrick Y. , Gunnström Michaela , Zdolsek Joachim H. , Hasselgren Emma , Beilstein Christian M. , Engel Dominique , Hahn Robert G. 
Published: April 2022

Abstract
Background
The transcapillary leakage of albumin is increased by inflammation and major surgery, but whether exogenous albumin also disappears faster is unclear.

Methods
An intravenous infusion of 3 mL/kg of 20% albumin was given over 30 min to 70 subjects consisting of 15 healthy volunteers, 15 post-burn patients, 15 patients who underwent surgery with minor bleeding, 10 who underwent surgery with major bleeding (mean, 1.1 L) and 15 postoperative patients. Blood Hb and plasma albumin were measured on 15 occasions over 5 h. The rate of albumin disappearance from the plasma was quantitated with population kinetic methodology and reported as the half-life (T1/2).

Results
No differences were observed for T1/2 between volunteers, post-burn patients, patients who underwent surgery with minor bleeding and postoperative patients. The T1/2 averaged 16.2 h, which corresponds to 3.8% of the amount infused per h. Two groups showed plasma concentrations of C-reactive protein of approximately 60 mg/L and still had a similarly long T1/2 for albumin. By contrast, patients undergoing surgery associated with major hemorrhage had a shorter T1/2, corresponding to 15% of the infused albumin per h. In addition, our analyses show that the T1/2 differ greatly depending on whether the calculations consider plasma volume changes and blood losses.

Conclusion
The disappearance rate of the albumin in 20% preparations was low in volunteers, in patients with moderately severe inflammation, and in postoperative patients.
Expansion of the prime editing modality with Cas9 from Francisella novicida
Authors: Oh Yeounsun , Lee Wi-jae , Hur Junho K. , Song Woo Jeung , Lee Youngjeon , Kim Hanseop , Gwon Lee Wha , Kim Young-Hyun , Park Young-Ho , Kim Chan Hyoung , Lim Kyung-Seob , Song Bong-Seok , Huh Jae-Won , Kim Sun-Uk , Jun Bong-Hyun , Jung Cheulhee , Lee Seung Hwan 
Published: April 2022

AbstractPrime editing can induce a desired base substitution, insertion, or deletion in a target gene using reverse transcriptase after nick formation by CRISPR nickase. In this study, we develop a technology that can be used to insert or replace external bases in the target DNA sequence by linking reverse transcriptase to the Francisella novicida Cas9, which is a CRISPR-Cas9 ortholog. Using FnCas9(H969A) nickase, the targeting limitation of existing Streptococcus pyogenes Cas9 nickase [SpCas9(H840A)]-based prime editing is dramatically extended, and accurate prime editing is induced specifically for the target genes in human cell lines.
Local euchromatin enrichment in lamina-associated domains anticipates their repositioning in the adipogenic lineage
Authors: Madsen-Østerbye Julia , Abdelhalim Mohamed , Baudement Marie-Odile , Collas Philippe 
Published: April 2022

Abstract
Background
Interactions of chromatin with the nuclear lamina via lamina-associated domains (LADs) confer structural stability to the genome. The dynamics of positioning of LADs during differentiation, and how LADs impinge on developmental gene expression, remains, however, elusive.

Results
We examined changes in the association of lamin B1 with the genome in the first 72 h of differentiation of adipose stem cells into adipocytes. We demonstrate a repositioning of entire stand-alone LADs and of LAD edges as a prominent nuclear structural feature of early adipogenesis. Whereas adipogenic genes are released from LADs, LADs sequester downregulated or repressed genes irrelevant for the adipose lineage. However, LAD repositioning only partly concurs with gene expression changes. Differentially expressed genes in LADs, including LADs conserved throughout differentiation, reside in local euchromatic and lamin-depleted sub-domains. In these sub-domains, pre-differentiation histone modification profiles correlate with the LAD versus inter-LAD outcome of these genes during adipogenic commitment. Lastly, we link differentially expressed genes in LADs to short-range enhancers which overall co-partition with these genes in LADs versus inter-LADs during differentiation.

Conclusions
We conclude that LADs are predictable structural features of adipose nuclear architecture that restrain non-adipogenic genes in a repressive environment.
Efficacy and safety of lumbrokinase plus aspirin versus aspirin alone for acute ischemic stroke (LUCENT): study protocol for a multicenter randomized controlled trial
Authors: Chen Ying , Liu Yan , Zhang Jingjing , Zhou Kehua , Zhang Xuecheng , Dai Hengheng , Yang Baolin , Shang Hongcai 
Published: April 2022

Abstract
Background
Lumbrokinase has been widely used for patients with acute ischemic stroke (AIS) in China; however, because rigorously designed studies are lacking, safety and efficacy of lumbrokinase in the treatment of acute ischemic stroke remains largely unknown. In this multicenter, randomized, and controlled trial, we aim to compare lumbrokinase plus aspirin versus aspirin alone in patients with acute ischemic stroke.

Methods
A total of 220 eligible participants will be randomized to either the intervention or control group with a 1:1 ratio. These participants must be diagnosed with acute ischemic stroke for the first time, whose symptoms appear within 72 h. Their NIHSS score must be greater than 5 and less than 15, and their age must be between 35 and 85 years old. They must have not received intravenous thrombolysis, arterial thrombolysis, or intravascular intervention. Participants in the intervention group will be treated with lumbrokinase plus aspirin for the first 90 days. Participants in the control group will use placebo plus aspirin for the first 90 days. Then, all participants will be treated with aspirin only and followed up for another 90 days (180-day follow-up). The primary outcome is the modified Rankin Scale (mRS) score. The secondary outcomes are National Institutes of Health Stroke Scale (NIHSS) score, Activity of Daily Living (ADL) Scale score, coagulation function, and serum hypersensitive C-reactive protein. The exploratory outcomes are fasting lipid panel, recurrence rate, the occurrence of cardiovascular and cerebrovascular events, and the mortality rate. Safety evaluations include liver function and kidney function, serum fibrinogen, adverse events, serious adverse events, and bleeding events. Adherence of participants will also be assessed.

Discussion
This trial will investigate the efficacy and safety of lumbrokinase plus aspirin as compared to aspirin alone in the treatment of acute ischemic stroke.

Trial registration
Chinese Clinical Trial Registry, ChiCTR2000032952. Registered on May 16, 2020.
Effect of multimodal intervention care on cachexia in patients with advanced cancer compared to conventional management (MIRACLE): an open-label, parallel, randomized, phase 2 trial
Authors: Maeng Chi Hoon , Kim Bo-Hyung , Chon Jinmann , Kang Won Sub , Kang Kyounglan , Woo Mihye , Hong Il Ki , Lee Junhee , Lee Kil Yeon 
Published: April 2022

AbstractBackgroundCancer cachexia (CC) is a multifactorial process characterized by progressive weight loss, muscle mass, and fat tissue wasting, which adversely affects the quality of life and survival of patients with advanced stages of cancer. CC has a complex and multifactorial pathophysiology, and there is no established standard treatment. Therefore, it is often irreversible and a single treatment modality is unlikely to suppress its progression. We are conducting a randomized trial to investigate the efficacy and safety of a multimodal intervention compared to the best supportive care for patients who received palliative chemotherapy.MethodsPatients with lung or gastrointestinal cancers undergoing palliative chemotherapy are eligible. Patients are randomized into a multimodal intervention care (MIC) arm versus a conventional palliative care (CPC) arm. MIC includes ibuprofen, omega-3-fatty acid, oral nutritional supplement, weekly physical, psychiatric assessment, nutritional counseling, and complementary and alternative medicine. CPC includes basic nutritional counseling and megestrol acetate as needed (i.e., anorexia ≥ grade 2). All interventions are performed for 12 weeks per subject. The co-primary outcomes are change (kg) in total lean body mass and handgrip strength (kg) from the baseline. A total of 112 patients will be assigned to the two arms (56 in each group).DiscussionThe purpose of this study is to evaluate the effect of MIC in preventing or alleviating CC in patients who underwent palliative chemotherapy. As there is no established single treatment for CC, it is expected that the results of this clinical trial will provide new insights to significantly improve the quality of life of patients with cancer. Considering the complex mechanisms of cachexia, the effect of MIC rather than a single specific drug is more promising. In this study, we did not overly restrict the type of cancer or chemotherapy. Therefore, we attempted to measure the effects of complex interventions while preserving clinical situations. Thus, it is expected that the results of this study can be applied effectively to real-world practice.Trial registrationThis clinical trial was registered in the Clinical Research Information Service (KCT0004967), Korean Clinical Trial Registry on April 27, 2020, andClinicalTrial.gov(NCT 04907864) on June 1, 2021.
Health care effects and medical benefits of a smartphone-based diabetes self-management application: study protocol for a randomized controlled trial
Authors: Ehrmann D. , Eichinger V. , Vesper I. , Kober J. , Kraus M. , Schäfer V. , Hermanns N. , Kulzer B. , Silbermann S. 
Published: April 2022

Abstract
Background
Diabetes self-management is a mainstay of diabetes care, but the implementation of self-management regimens into daily life is complex and often results in discouragement and distress. Modern approaches such as smartphone-based self-management applications are therefore needed to support people with diabetes. Since reimbursability would increase the availability of such digital applications to people with diabetes, we designed a study that meets all scientific and methodological requirements set by the German Digital Healthcare Act to allow reimbursement for a specific application (mySugr PRO). Here, we report the protocol of this study that aims at evaluating the efficacy of the digital self-management application with regard to patient-reported outcomes and medical benefits.

Methods/design
This multicenter, open-label, randomized, parallel-group, controlled trial will evaluate the health care effects and medical benefits of mySugr PRO. A total of 466 people with diabetes will be randomly allocated (2:1 randomization) to the interventional group (n = 311) that will use the digital self-management application during the 12-week study period or the control group (n = 155; no usage of the application). Baseline and follow-up examinations will assess diabetes distress as the primary endpoint as well as empowerment, HbA1c, blood glucose data, self-management, general well-being, and treatment satisfaction as secondary endpoints. Statistical analyses will use an intention-to-treat procedure (using multiple imputation for missing values) as well as a per-protocol approach for sensitivity analysis.

Discussion
To the best of our knowledge, this study will be one of the largest diabetes-specific evaluations of a digital health application supporting people with diabetes in their diabetes self-management that follow the requirements of the German Digital Healthcare Act.

Trial registration
German Clinical Trial Register DRKS00022923. Registered on 22 October 2020.
Advanced nursing practice and interprofessional dementia care (InDePendent): study protocol for a multi-center, cluster-randomized, controlled, interventional trial
Authors: Kleinke Fabian , Michalowsky Bernhard , Rädke Anika , Platen Moritz , Mühlichen Franka , Scharf Annelie , Mohr Wiebke , Penndorf Peter , Bahls Thomas , van den Berg Neeltje , Hoffmann Wolfgang 
Published: April 2022

AbstractBackgroundA redistribution of tasks between specialized nurses and primary care physicians, i.e., models of advanced nursing practice, has the potential to improve the treatment and care of the growing number of people with dementia (PwD). Especially in rural areas with limited access to primary care physicians and specialists, these models might improve PwD’s quality of life and well-being. However, such care models are not available in Germany in regular healthcare. This study examines the acceptance, safety, efficacy, and health economic efficiency of an advanced nursing practice model for PwD in the primary care setting in Germany.MethodsInDePendent is a two-arm, multi-center, cluster-randomized controlled intervention study. Inclusion criteria are age ≥70 years, cognitively impaired (DemTect ≤8) or formally diagnosed with dementia, and living in the own home. Patients will be recruited by general practitioners or specialists. Randomization is carried out at the physicians’ level in a ratio of 1:2 (intervention vs. waiting-control group). After study inclusion, all participants will receive a baseline assessment and a follow-up assessment after 6 months. Patients of the intervention group will receive advanced dementia care management for 6 months, carried out by specialized nurses, who will conduct certain tasks, usually carried out by primary care physicians. This includes a standardized assessment of the patients’ unmet needs, the generation and implementation of an individualized care plan to address the patients’ needs in close coordination with the GP. PwD in the waiting-control group will receive routine care for 6 months and subsequently become part of the intervention group. The primary outcome is the number of unmet needs after 6 months measured by the Camberwell Assessment of Need for the Elderly (CANE). The primary analysis after 6 months is carried out using multilevel models and will be based on the intention-to-treat principle. Secondary outcomes are quality of life, caregiver burden, acceptance, and cost-effectiveness. In total,n=465 participants are needed to assess significant differences in the number of unmet needs between the intervention and control groups.DiscussionThe study will provide evidence about the acceptance, efficacy, and cost-effectiveness of an innovative interprofessional concept based on advanced nursing care. Results will contribute to the implementation of such models in the German healthcare system. The goal is to improve the current treatment and care situation for PwD and their caregivers and to expand nursing roles.Trial registrationClinicalTrials.govNCT04741932. Registered on 2 February 2021.