bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular mechanism by which CDCP1 promotes proneural-mesenchymal transformation in primary glioblastoma
Authors: Lin Zhiying , Zhang Zhu , Zheng Haojie , Xu Haiyan , Wang Yajuan , Chen Chao , Liu Junlu , Yi Guozhong , Li Zhiyong , Wang Xiaoyan , Huang Guanglong
Published: April 2022

Background

Compared with the proneural (PN) subtype of glioblastoma (GBM), the mesenchymal (MES) subtype is more invasive and immune evasive and is closely related to poor prognosis. Here, we used transcriptome data and experimental evidence to indicate that CUB domain-containing protein 1 (CDCP1) is a novel regulator that facilitates the transformation of PN-GBM to MES-GBM.

Methods

The mRNA expression data of CDCP1 in glioma were collected from the TCGA, CGGA and GEO databases, and in vitro experiments verified CDCP1 expression in glioma tissue samples. Independent prognostic analysis revealed the correlation of the CDCP1 expression level and patient survival. Bioinformatics analysis and experiments verified the biological function of CDCP1. Multivariate proportional hazards models and a PPI network were used to select key genes. A prognostic risk model for predicting the survival of glioma patients was constructed based on the selected genes.

Results

The results showed that the expression of CDCP1 increased with increasing tumor grade and that the overexpression of CDCP1 correlated with a poor prognosis. CDCP1 was highly expressed in MES-GBM but weakly expressed in PN-GBM. The risk model (considering CDCP1 combined with CD44 and ITGAM expression) could represent a tool for predicting survival and prognosis in glioma patients.

Conclusions

Our study indicates that CDCP1 plays an important role in facilitating the transformation of PN-GBM to MES-GBM.
RPL15 promotes hepatocellular carcinoma progression via regulation of RPs-MDM2-p53 signaling pathway
Authors: Shi Rui , Liu Zirong
Published: April 2022

Backround

RPL15 has been found to participate in human tumorigenesis. However, its function and regulatory mechanism in hepatocellular carcinoma (HCC) development are still unclear. Current study investigated the effects of RPL15 in HCC.

Methods

The expression of RPL15 in clinical tissues and cell lines of HCC was detected by RT-qPCR, Western blotting, and Immunohistochemistry (IHC). Colony formation, CCK-8, flow cytometry, Wound healing and Transwell invasion assays, were used to detect the carcinoma progression of HCC cells with RPL15 overexpression or knockdown in vitro. A xenograft model was constructed to assess the effect of RPL15 knockdown on HCC cells in vivo. The expression of CDK2 and Cyclin E1 related to cell cycles, Bax and Bcl-2 related to cell apoptosis, E-cadherin, N-cadherin and Vimentin related to epithelial–mesenchymal transition (EMT), p53 and p21 related to p53 signaling pathway, were detected by Western blotting. The connection between p53, MDM2 and RPL5/11 affected by RPL15 was analyzed using immunoprecipitation and Cycloheximide (CHX) chase assay.

Results

Elevated RPL15 was identified in HCC tissues, which was not only a prediction for the poor prognosis of HCC patients, but also associated with the malignant progression of HCC. RPL15 silencing arrested HCC cell cycle, suppressed HCC cell colony formation, proliferation, invasion, and migration, and induce cell apoptosis. On the contrary, RPL15 upregulation exerted opposite effects. Results also indicated that HCC cell invasion and migration were associated with EMT, and that the RPs-MDM2-p53 pathway was implicated in RPL15-mediated oncogenic transformation. In addition, RPL15 knockdown significantly suppressed HCC xenografts growth.

Conclusions

RPL15 played crucial roles in HCC progression and metastasis, serving as a promising candidate for targeted therapies.
From inflammatory bowel disease to colorectal cancer: what’s the role of miRNAs?
Authors: Vaghari-Tabari Mostafa , Targhazeh Niloufar , Moein Soheila , Qujeq Durdi , Alemi Forough , Majidina Maryam , Younesi Simin , Asemi Zatollah , Yousefi Bahman
Published: April 2022

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn’s disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20–22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
B7-H4 expression is upregulated by PKCδ activation and contributes to PKCδ-induced cell motility in colorectal cancer
Authors: Zhou Bin , Lu Youwei , Zhao Zhiming , Shi Tongguo , Wu Hongya , Chen Weichang , Zhang Liang , Zhang Xueguang
Published: April 2022

Introduction

B7-H4 is overexpressed in colorectal cancer (CRC) and plays an important role in tumor growth and immunosuppression. However, the exact mechanism that regulates B7-H4 expression remains largely unknown. Here, we investigated whether protein kinase C δ (PKCδ) regulates the expression of B7-H4 in CRC.

Methods

By using immunohistochemical (IHC) and immunofluorescence (IF) staining, we analyzed the expression of B7-H4 and phospho-PKCδ (p-PKCδ) in 225 colorectal tumor samples and determined the clinical significance of the expression patterns. In vitro experiments were performed with the CRC cell lines HCT116 and SW620 to detect the effect of PKCδ activation on B7-H4 expression, and xenograft-bearing mice were treated with rottlerin to monitor the expression of B7-H4 and tumor metastasis.

Results

The B7-H4 expression level was significantly correlated with the p-PKCδ level (r = 0.378, P < 0.001) in tumor tissues. Coexpression of p-PKCδ and B7-H4 was significantly associated with moderate/poor differentiation (P = 0.024), lymph node metastasis (P = 0.001) and advanced Dukes’ stage (P = 0.002). Western blot analysis showed that Phorbol-12-Myristate-13-Acetate (TPA) increased B7-H4 expression in a concentration-dependent manner and that rottlerin abrogated the TPA-induced increase in B7-H4 expression. The protein levels of B7-H4 and p-STAT3 were significantly reduced by a PKCδ-specific siRNA. Moreover, the STAT3 inhibitor cryptotanshinone significantly decreased the B7-H4 protein level in CRC cells. Knockdown of B7-H4 or PKCδ suppressed cell migration and motility. Rottlerin also inhibited B7-H4 expression and tumor metastasis in vivo.

Conclusion

The B7-H4 expression level is significantly correlated with the p-PKCδ level and tumor metastasis in CRC samples. B7-H4 expression is upregulated by STAT3 activation via PKCδ and plays roles in PKCδ-induced cancer cell motility and metastasis, suggesting that the PKCδ/STAT3/B7-H4 axis may be a potential therapeutic target for CRC.
Community health workers and health equity in low- and middle-income countries: systematic review and recommendations for policy and practice
Authors: Ahmed Sonia , Chase Liana E. , Wagnild Janelle , Akhter Nasima , Sturridge Scarlett , Clarke Andrew , Chowdhary Pari , Mukami Diana , Kasim Adetayo , Hampshire Kate
Published: April 2022

Background

The deployment of Community Health Workers (CHWs) is widely promoted as a strategy for reducing health inequities in low- and middle-income countries (LMIC). Yet there is limited evidence on whether and how CHW programmes achieve this. This systematic review aimed to synthesise research findings on the following questions: (1) How effective are CHW interventions at reaching the most disadvantaged groups in LMIC contexts? and (2) What evidence exists on whether and how these programmes reduce health inequities in the populations they serve?

Methods

We searched six academic databases for recent (2014–2020) studies reporting on CHW programme access, utilisation, quality, and effects on health outcomes/behaviours in relation to potential stratifiers of health opportunities and outcomes (e.g., gender, socioeconomic status, place of residence). Quantitative data were extracted, tabulated, and subjected to meta-analysis where appropriate. Qualitative findings were synthesised using thematic analysis.

Results

One hundred sixty-seven studies met the search criteria, reporting on CHW interventions in 33 LMIC. Quantitative synthesis showed that CHW programmes successfully reach many (although not all) marginalized groups, but that health inequalities often persist in the populations they serve. Qualitative findings suggest that disadvantaged groups experienced barriers to taking up CHW health advice and referrals and point to a range of strategies for improving the reach and impact of CHW programmes in these groups. Ensuring fair working conditions for CHWs and expanding opportunities for advocacy were also revealed as being important for bridging health equity gaps.

Conclusion

In order to optimise the equity impacts of CHW programmes, we need to move beyond seeing CHWs as a temporary sticking plaster, and instead build meaningful partnerships between CHWs, communities and policy-makers to confront and address the underlying structures of inequity.

Trial registration

PROSPERO registration number CRD42020177333.
Tranexamic acid alters the immunophenotype of phagocytes after lower limb surgery
Authors: Draxler Dominik F. , Hanafi Gryselda , Zahra Saffanah , McCutcheon Fiona , Ho Heidi , Keragala Charithani B. , Liu Zikou , Daly David , Painter Thomas , Wallace Sophia , Plebanski Magdalena , Myles Paul S. , Medcalf Robert L.
Published: April 2022

Background

Tranexamic acid (TXA) is an antifibrinolytic agent frequently used in elective surgery to reduce blood loss. We recently found it also acts as a potent immune-modulator in patients undergoing cardiac surgery.

Methods

Patients undergoing lower limb surgery were enrolled into the “Tranexamic Acid in Lower Limb Arthroplasty” (TALLAS) pilot study. The cellular immune response was characterised longitudinally pre- and post-operatively using full blood examination (FBE) and comprehensive immune cell phenotyping by flowcytometry. Red blood cells and platelets were determined in the FBE and levels of T cell cytokines and the plasmin-antiplasmin complex determined using ELISA.

Results

TXA administration increased the proportion of circulating CD141+ conventional dendritic cells (cDC) on post-operative day (POD) 3. It also reduced the expression of CD83 and TNFR2 on classical monocytes and levels of circulating IL-10 at the end of surgery (EOS) time point, whilst increasing the expression of CCR4 on natural killer (NK) cells at EOS, and reducing TNFR2 on POD-3 on NK cells. Red blood cells and platelets were decreased to a lower extent at POD-1 in the TXA group, representing reduced blood loss.

Conclusion

In this investigation we have extended our examination on the immunomodulatory effects of TXA in surgery by also characterising the end of surgery time point and including B cells and neutrophils in our immune analysis, elucidating new immunophenotypic changes in phagocytes as well as NK cells. This study enhances our understanding of TXA-mediated effects on the haemostatic and immune response in surgery, validating changes in important functional immune cell subsets in orthopaedic patients.
Neutrophil degranulation and myocardial infarction
Authors: Zhang Nan , Aiyasiding Xiahenazi , Li Wen-jing , Liao Hai-han , Tang Qi-zhu
Published: April 2022

Myocardial infarction (MI) is one of the most common cardiac emergencies with high morbidity and is a leading cause of death worldwide. Since MI could develop into a life-threatening emergency and could also seriously affect the life quality of patients, continuous efforts have been made to create an effective strategy to prevent the occurrence of MI and reduce MI-related mortality. Numerous studies have confirmed that neutrophils play important roles in inflammation and innate immunity, which provide the first line of defense against microorganisms by producing inflammatory cytokines and chemokines, releasing reactive oxygen species, and degranulating components of neutrophil cytoplasmic granules to kill pathogens. Recently, researchers reported that neutrophils are closely related to the severity and prognosis of patients with MI, and neutrophil to lymphocyte ratio in post-MI patients had predictive value for major adverse cardiac events. Neutrophils have been increasingly recognized to exert important functions in MI. Especially, granule proteins released by neutrophil degranulation after neutrophil activation have been suggested to involve in the process of MI. This article reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies.

Graphical abstract

Neutrophils played a crucial role throughout the process of MI, and neutrophil degranulation was the crucial step for the regulative function of neutrophils. Both neutrophils infiltrating and neutrophil degranulation take part in the injury and repair process immediately after the onset of MI. Since different granule subsets (e g. MPO, NE, NGAL, MMP‐8, MMP‐9, cathelicidin, arginase and azurocidin) released from neutrophil degranulation show different effects through diverse mechanisms in MI. In this review, we reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Myeloperoxidase (MPO); Neutrophil elastase (NE); Neutrophil gelatinase-associated lipocalin (NGAL); Matrix metalloproteinase 8 (MMP‐8); Matrix metalloproteinase 9 (MMP‐9).
Cisplatin resistance-related multi-omics differences and the establishment of machine learning models
Authors: Sui Qihai , Chen Zhencong , Hu Zhengyang , Huang Yiwei , Liang Jiaqi , Bi Guoshu , Bian Yunyi , Zhao Mengnan , Zhan Cheng , Lin Zongwu , Wang Qun , Tan Lijie
Published: April 2022

Objectives

Platinum-based chemotherapies are currently the first-line treatment of non-small cell lung cancer. This study will improve our understanding of the causes of resistance to cisplatin, especially in lung adenocarcinoma (LUAD) and provide a reference for therapeutic decisions in clinical practice.

Methods

Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA) and Zhongshan hospital affiliated to Fudan University (zs-cohort) were used to identify the multi-omics differences related to platinum chemotherapy. Cisplatin-resistant mRNA and miRNA models were constructed by Logistic regression, classification and regression tree and C4.5 decision tree classification algorithm with previous feature selection performed via least absolute shrinkage and selection operator (LASSO). qRT-PCR and western-blotting of A549 and H358 cells, as well as single-cell Seq data of tumor samples were applied to verify the tendency of certain genes.

Results

661 cell lines were divided into three groups according to the IC50 value of cisplatin, and the top 1/3 (220) with a small IC50 value were defined as the sensitive group while the last 1/3 (220) were enrolled in the insensitive group. TP53 was the most common mutation in the insensitive group, in contrast to TTN in the sensitive group. 1348 mRNA, 80 miRNA, and 15 metabolites were differentially expressed between 2 groups (P < 0.05). According to the LASSO penalized logistic modeling, 6 of the 1348 mRNAs, FOXA2, BATF3, SIX1, HOXA1, ZBTB38, IRF5, were selected as the associated features with cisplatin resistance and for the contribution of predictive mRNA model (all of adjusted P-values < 0.001). Three of 6 (BATF3, IRF5, ZBTB38) genes were finally verified in cell level and patients in zs-cohort.

Conclusions

Somatic mutations, mRNA expressions, miRNA expressions, metabolites and methylation were related to the resistance of cisplatin. The models we created could help in the prediction of the reaction and prognosis of patients given platinum-based chemotherapies.
The global prevalence of oropharyngeal dysphagia in different populations: a systematic review and meta-analysis
Authors: Rajati Fatemeh , Ahmadi Nassim , Naghibzadeh Zahra Al-sadat , Kazeminia Mohsen
Published: April 2022

Background

Oropharyngeal dysphagia (OD) refers to any abnormality in the physiology of swallowing in the upper gastrointestinal tract, which leads to the related clinical complications, such as malnutrition, dehydration, and sever complication, such as aspiration pneumonia, suffocation, and eventually, premature death. The previous studies indicated a various range of prevalence of OD. The present systematic review and meta-analysis aimed to standardize the global prevalence of OD in different populations.

Methods

A systematic literature review was conducted using Embase, Scopus, PubMed, Web of Science (WoS) databases, and Google Scholar motor engine using related MeSH/Emtree and Free Text words, with no time limitation until November 2021. The heterogeneity among studies was quantified using I2 index and the random effects model was used, due to the high heterogeneity among the results of studies included in the meta-analysis.

Results

The systematic literature search retrieved 2092 studies. After excluding the irrelevant studies, ultimately 27 articles with a sample size of 9841 were included in the meta-analysis. After combining the studies, the overall estimate of the global prevalence rate of OD was 43.8% (95% CI 33.3–54.9%) and the highest prevalence rate was estimated in Africa with 64.2% (95% CI 53.2–73.9%). Given the subgroup analysis based on the study population, the highest prevalence of OD was related to Dementia with 72.4% (95% CI 26.7–95.0%). The results of meta-regression indicated that the prevalence of OD has an increasing trend with the enhancement of year of publication and mean age.

Conclusion

The results of the present systematic review and meta-analysis revealed that the prevalence of OD is high in different populations and its trend has been increasing in recent years. Therefore, the appropriate strategies should be applied to reduce the prevalence of OD by finding its causation and monitoring at all levels, as well as providing feedback to hospitals.
Recommendations for breastfeeding during Coronavirus Disease 2019 (COVID-19) pandemic
Authors: Liu Xiyao , Chen Haoyue , An Meijing , Yang Wangxing , Wen Yujie , Cai Zhihuan , Wang Lulu , Zhou Qianling
Published: April 2022

Background

Coronavirus Disease 2019 (COVID-19) has spread worldwide. The safety of breastfeeding of SARS-CoV-2-positive women has not yet reached a consensus among the scientific community, healthcare providers, experts in lactation care, health organizations and governments. This study was conducted to summarize the latest evidence about the safety of breastfeeding among suspected/confirmed infected mothers and to summarize the recommendations on breastfeeding during COVID-19 from different organizations.

Methods

A comprehensive literature review of publications about the safety of breastfeeding among SARS-CoV-2-infected mothers was conducted. Scientific databases were searched up to 26 May 2021. The evidence was summarized into five perspectives according to a framework proposed by van de Perre et al. with certain modifications. Moreover, websites of different health organizations were visited to gather the recommendations for breastfeeding.

Results

The current evidence demonstrated that the majority of infants breastfed by infected mothers were negative for SARS-CoV-2. Breast milk samples from suspected/infected mothers mainly demonstrated negative results in SARS-CoV-2 viral tests. There was insufficient evidence proving the infectivity of breast milk from infected mothers. Recent studies found other transmission modalities (e.g., milk containers, skin) associated with breastfeeding. Specific antibodies in the breast milk of infected mothers were also found, implying protective effects for their breastfed children. According to van de Perre’s criteria, the breast milk of infected mothers was unlikely to transmit SARS-CoV-2. Owing to the low quality of the current evidence, studies with a more robust design are needed to strengthen the conclusion regarding the safety of breastfeeding. Further studies to follow up the health status of infants who were directly breastfed by their suspected/infected mothers, to collect breast milk samples at multiple time points for viral tests and to examine specific antibodies in breast milk samples are warranted. Current recommendations on breastfeeding during COVID-19 from different organizations are controversial, while direct breastfeeding with contact precautions is generally suggested as the first choice for infected mothers.

Conclusions

This review determined the safety of breastfeeding and identified the focus for further research during the COVID-19 pandemic. Recommendations on breastfeeding are suggested to be updated in a timely manner according to the latest evidence.
Ganetespib selectively sensitizes cancer cells for proximal and distal spread-out Bragg peak proton irradiation
Authors: Deycmar Simon , Mara Elisabeth , Kerschbaum-Gruber Sylvia , Waller Verena , Georg Dietmar , Pruschy Martin
Published: April 2022

Objective

Hypersensitivity towards proton versus photon irradiation was demonstrated in homologous recombination repair (HRR)-deficient cell lines. Hence, combined treatment concepts targeting HRR provide a rational for potential pharmaceutical exploitation. The HSP90 inhibitor ganetespib (STA-9090) downregulates a multitude of HRR-associated proteins and sensitizes for certain chemotherapeutics. Thus, the radiosensitizing effect of HSP90-inhibiting ganetespib was investigated for reference photon irradiation and proton irradiation at a proximal and distal position in a spread-out Bragg peak (SOBP).

Methods

A549 and FaDu cells were treated with low-dose (2 nM resp. 1 nM) ganetespib and irradiated with 200 kV photons. Proton irradiation was performed at a proximal and a distal position within a SOBP, with corresponding dose-averaged linear-energy transfer (LETD) values of 2.1 and 4.5 keV/µm, respectively. Cellular survival data was fitted to the linear-quadratic model to calculate relative biological effectiveness (RBE) and the dose-modifying factor (DMF). Additionally, A549 cells were treated with increasing doses of ganetespib and investigated by flow cytometry, immunoblotting, and immunofluorescence microscopy to investigate cell cycle distribution, Rad51 protein levels, and γH2AX foci, respectively.

Results

Low-dosed ganetespib significantly sensitized both cancer cell lines exclusively for proton irradiation at both investigated LETD, resulting in increased RBE values of 10–40%. In comparison to photon irradiation, the fraction of cells in S/G2/M phase was elevated in response to proton irradiation with 10 nM ganetespib consistently reducing this population. No changes in cell cycle distribution were detected in unirradiated cells by ganetespib alone. Protein levels of Rad51 are downregulated in irradiated A549 cells by 10 nM and also 2 nM ganetespib within 24 h. Immunofluorescence staining demonstrated similar induction and removal of γH2AX foci, irrespective of irradiation type or ganetespib administration.

Conclusion

Our findings illustrate a proton-specific sensitizing effect of low-dosed ganetespib in both employed cell lines and at both investigated SOBP positions. We provide additional experimental data on cellular response and a rational for future combinatorial approaches with proton radiotherapy.
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

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

Background

There 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.

Methods

A 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.

Results

For 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.

Conclusion

The 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

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

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

Prime 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

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

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

Background

Cancer 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.

Methods

Patients 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).

Discussion

The 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 registration

This 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

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

Background

A 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.

Methods

InDePendent 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.

Discussion

The 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 registration

ClinicalTrials.govNCT04741932. Registered on 2 February 2021.