bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge translation following the implementation of a state-wide Paediatric Sepsis Pathway in the emergency department- a multi-centre survey study
Authors: Harley Amanda , Schlapbach Luregn J. , Lister Paula , Massey Debbie , Gilholm Patricia , Johnston Amy N. B.
Published: October 2021

Background

Several health care systems internationally have implemented protocolised sepsis recognition and treatment bundles for children to improve outcomes, as recommended by the Surviving Sepsis Campaign. Successful implementation of clinical pathways is challenging and dependent on nurse engagement. There is limited data on knowledge translation during implementation of sepsis quality improvement programs.

Methods

This cross-sectional, multicentre observational survey study evaluated knowledge and perceptions of Emergency Department nurses in relation to the recognition, escalation and management of paediatric sepsis following implementation of a sepsis pathway. The study was conducted between September 2019 and March 2020 across 14 Emergency Departments in Queensland, Australia. The primary outcome was a sepsis knowledge score. An exploratory factor analysis was conducted to identify factors impacting nurses’ perceptions of recognition, escalation and management of paediatric sepsis and their association with knowledge. Using a logistic mixed effects model we explored associations between knowledge, identified factors and other clinical, demographic and hospital site variables.

Results

In total, 676 nurses responded to the survey and 534 were included in the analysis. The median knowledge score was 57.1% (IQR = 46.7–66.7), with considerable variation observed between sites. The exploratory factor analysis identified five factors contributing to paediatric sepsis recognition, escalation and management, categorised as 1) knowledge and beliefs, 2) social influences, 3) beliefs about capability and skills delivering treatment, 4) beliefs about capability and behaviour and 5) environmental context. Nurses reported strong agreement with statements measuring four of the five factors, responding lowest to the factor pertaining to capability and skills delivering treatment for paediatric sepsis. The factors knowledge and beliefs, capability and skills, and environmental context were positively associated with a higher knowledge score. Years of paediatric experience and dedicated nurse funding for the sepsis quality improvement initiative were also associated with a higher knowledge score.

Conclusion

Translation of evidence to practice such as successful implementation of a sepsis care bundle, relies on effective education of staff and sustained uptake of protocols in daily practice. Our survey findings identify key elements associated with enhanced knowledge including dedicated funding for hospitals to target paediatric sepsis quality improvement projects.
What can we learn from the SARS-COV-2 pandemic about the value of specific radiological examinations?
Authors: Hofmann Bjørn , Andersen Eivind Richter , Kjelle Elin
Published: October 2021

Background

The SARS-COV-2 pandemic provides a natural intervention to assess practical priority setting and internal evaluation of specific health services, such as radiological services. Norway makes an excellent case as it had a very low infection rate and very few cases of COVID-19. Accordingly, the objective of this study is to use the changes in performed outpatient radiological examinations during the first stages of the SARS-COV-2 pandemic to assess the practical evaluation of specific radiological examinations in Norway.

Methods

Data was collected retrospectively from the Norwegian Health Economics Administration (HELFO) in the years 2015–2020. Data included the number of performed outpatient imaging examinations at public hospitals and private imaging centers in Norway and was divided in to three periods based on the level of restrictions on elective health services. Results were analyzed with descriptive statistics.

Results

In the first period there was a 45% reduction in outpatient radiology compared to the same time period in 2015–2019 while in period 2 and 3 there was a 25 and 6% reduction respectively. The study identified a list of specific potential low-value radiological examinations. While some of these are covered by the Choosing Wisely campaign, others are not.

Conclusion

By studying the priority setting practice during the initial phases of the pandemic this study identifies a set of potential low value radiological examinations during the initial phases of the SARS-COV-2 pandemic. These examinations are candidates for closer assessments for health services quality improvement.
‘When will the doctor be around so that I come by?!’ Geo-socio effects on health care supply, access and utilisation: experiences from Kalangala Islands, Uganda
Authors: Kwiringira Japheth Nkiriyehe , Mugisha James , Akugizibwe Mathias , Ariho Paulino
Published: October 2021

Background

The study set out to give an in-depth intersection of geo, eco-socio exposition of the factors relating to geography, healthcare supply and utilization in an island setting. This analysis is informed by what has emerged to be known as social epidemiology. We provide in-depth explanation of context to health care access, utilization and outcomes. We argue that health care delivery has multiple intersections that are experientially complex, multi-layered and multi-dimensional to the disadvantage of vulnerable population segments of society in the study area.

Methods

We used a cross-sectional qualitative exploratory design. Qualitative methods facilitated an in-depth exploration and understanding of this island dispersed and peripheral setting. Data sources included a review of relevant literature and an ethnographic exploration of the lived experiences of community members while seeking and accessing health care. Data collection methods included in-depth interviews (IDI) from selected respondents, observation, focus group discussions (FGDs) and key informant interviews (KII).

Results

We report based on the health care systems model which posits that, health care activities are diverse but interconnected in a complex way. The identified themes are; the role of geography, access (geographical and financial) to health services, demand and utilization, Supplies, staffing and logistical barriers and a permissive and transient society. When and how to travel for care was beyond a matter of having a health need/ being sick and need arising. A motivated workforce is as critical as health facilities themselves in determining healthcare outcomes.

Conclusion

Geography doesn’t work and affect health outcomes in isolation. Measures that target only individuals will not be adequate to tackle health inequalities because aspects of the collective social group and physical environment may also need to be changed in order to reduce health variations.
Association between particulate matter containing EPFRs and neutrophilic asthma through AhR and Th17
Authors: Harding Jeffrey N. , Gross Maureen , Patel Vivek , Potter Steven , Cormier Stephania A.
Published: October 2021

Background

Epidemiological data associate high levels of combustion-derived particulate matter (PM) with deleterious respiratory outcomes, but the mechanism underlying those outcomes remains elusive. It has been acknowledged by the World Health Organization that PM exposure contributes to more than 4.2 million all-cause mortalities worldwide each year. Current literature demonstrates that PM exacerbates respiratory diseases, impairs lung function, results in chronic respiratory illnesses, and is associated with increased mortality. The proposed mechanisms revolve around oxidative stress and inflammation promoting pulmonary physiological remodeling. However, our previous data found that PM is capable of inducing T helper cell 17 (Th17) immune responses via aryl hydrocarbon receptor (Ahr) activation, which was associated with neutrophilic invasion characteristic of steroid insensitive asthma.

Methods

In the present study, we utilized a combination of microarray and single cell RNA sequencing data to analyze the immunological landscape in mouse lungs following acute exposure to combustion derived particulate matter.

Results

We present data that suggest epithelial cells produce specific cytokines in the aryl hydrocarbon receptor (Ahr) pathway that inform dendritic cells to initiate the production of pathogenic T helper (eTh17) cells. Using single-cell RNA sequencing analysis, we observed that upon exposure epithelial cells acquire a transcriptomic profile indicative of increased Il-17 signaling, Ahr activation, Egfr signaling, and T cell receptor and co-stimulatory signaling pathways. Epithelial cells further showed, Ahr activation is brought on by Ahr/ARNT nuclear translocation and activation of tyrosine kinase c-src, Egfr, and subsequently Erk1/2 pathways.

Conclusions

Collectively, our data corroborates that PM initiates an eTh17 specific inflammatory response causing neutrophilic asthma through pathways in epithelial, dendritic, and T cells that promote eTh17 differentiation during initial PM exposure.
Characteristics of the nocturnal desaturation waveform pattern of SpO2 in COPD patients: an observational study
Authors: Yoshizaki Asuka , Nagano Tatsuya , Izumi Shintaro , Nishiuma Teruaki , Nakata Kyosuke , Yamamoto Masatsugu , Yasuda Yuichiro , Hazama Daisuke , Umezawa Kanoko , Katsurada Naoko , Tachihara Motoko , Nishimura Yoshihiro , Kobayashi Kazuyuki
Published: October 2021

Background

Nocturnal desaturation is common in patients with chronic obstructive pulmonary disease (COPD) and impacts disease exacerbation and prognosis. In our previous study, we developed a diagnostic algorithm to classify nocturnal desaturation from SpO2 waveform patterns based on data from patients receiving home oxygen therapy. In this study, we aimed to investigate nocturnal desaturation in patients with COPD based on SpO2 waveform patterns and the associations between the waveforms and clinical data.

Methods

We investigated patients diagnosed with COPD and measured SpO2 and nasal airflow with a type 4 portable long-term recordable pulse oximeter. Then, we classified the SpO2 waveforms with the algorithm and compared the clinical data.

Results

One hundred fifty-three patients (136 male and 17 female) were analysed. One hundred twenty-eight of the 153 (83.7%) patients had nocturnal desaturation, with an intermittent pattern (70.6%), sustained pattern (13.1%) and periodic pattern (68.0%). Intriguingly, desaturation with an intermittent pattern was associated with the apnoea-hypopnea index obtained with the portable monitor, and desaturation with a sustained pattern was associated with the cumulative percentage of time at a SpO2 below 90%.

Conclusions

We found that nocturnal desaturation was frequently observed in patients with COPD and could be classified into 3 types of waveform patterns.
The lung microbiome in end-stage Lymphangioleiomyomatosis
Authors: Ng Julie , Pacheco-Rodriguez Gustavo , Begley Lesa , Huang Yvonne J. , Poli Sergio , Perrella Mark A. , Rosas Ivan O. , Moss Joel , El-Chemaly Souheil
Published: October 2021

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease with mortality driven primarily by respiratory failure. Patients with LAM frequently have respiratory infections, suggestive of a dysregulated microbiome. Here we demonstrate that end-stage LAM patients have a distinct microbiome signature compared to patients with end-stage chronic obstructive pulmonary disease.
Exploring the oncostatin M (OSM) feed-forward signaling of glioblastoma via STAT3 in pan-cancer analysis
Authors: Chen Miao , Ren Ruiyang , Lin Weimin , Xiang Lisha , Zhao Zhihe , Shao Bin
Published: October 2021

Background

Oncostatin M (OSM) has been reported to be a key regulating factor in the process of tumor development. Previous studies have demonstrated both the promotion and inhibition effects of OSM in tumors, therefore inspiring controversies. However, no systematic assessment of OSM across various cancers is available, and the mechanisms behind OSM-related cancer progression remain to be elucidated.

Methods

Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, we conducted a pan-cancer analysis on OSM to explore its tumor-related functions across cancers as well as its correlations with specific molecules, cells in the tumor microenvironment. Considering the results of pan-cancer analysis, we chose the specific tumor glioblastoma multiforme (GBM) to screen out the OSM-induced signaling pathways and intercellular communications in tumor progression. Wound scratch assay, invasion assay and qRT-PCR were performed to verify the biological effects of OSM on glioblastoma cells.

Results

Higher OSM level was found in most tumor tissues compared with corresponding normal tissues, and the enhanced OSM expression was observed to be strongly related to patients’ poor prognosis in several cancers. Moreover, the expression of OSM was associated with stromal and immune cell infiltration in the tumor microenvironment, and OSM-related immune checkpoint and chemokine co-expression were also observed. Our results suggested that OSM could communicate extensively with the tumor microenvironment. Taking GBM as an example, our study found that two critical signaling pathways in OSM-related tumor progression by KEGG enrichment analysis: Jak-STAT and NF-κB pathways. Single-cell RNA sequencing data analysis of GBM revealed that OSM was mainly secreted by microglia, and cell–cell interaction analysis proved that OSM-OSMR is an important pathway for OSM to stimulate malignant cells. In vitro, OSM treatment could facilitate the migration and invasion of glioblastoma cells, meanwhile promote the proneural-mesenchymal transition. The administration of STAT3 inhibitors effectively suppressed the OSM-mediated biological effects, which proved the key role of STAT3 in OSM signaling.

Conclusion

Taken together, our study provides a comprehensive understanding with regard to the tumor progression under the regulation of OSM. OSM seems to be closely related to chronic inflammation and tumor development in the tumor microenvironment. As an important inflammatory factor in the tumor microenvironment, OSM may serve as a potential immunotherapeutic target for cancer treatment, especially for GBM.
Ferroptosis-related gene AKR1C1 predicts the prognosis of non-small cell lung cancer
Authors: Huang Fangfang , Zheng Yushi , Li Xiaoling , Luo Hui , Luo Lianxiang
Published: October 2021

Background

Ferroptosis is a newly discovered mode of cell death distinct from apoptosis and necrosis, and its activation contributes to anticancer therapy in a variety of cancers. However, the prognostic value of ferroptosis-related genes in non-small cell lung cancer (NSCLC) remains to be further investigated.

Methods

NSCLC transcriptome mRNA-seq data set and corresponding clinical data set were downloaded from the Cancer Genome Atlas (TCGA). Then, bioinformatics approaches were subsequently employed to identify potential prognostic markers. Finally, the effects of candidate markers on NSCLC cell proliferation, migration, and ferroptosis were assessed by CCK8, colony formation, wound-healing assay, and functional assays related to ferroptosis.

Results

A total of 37 common differentially expressed genes were screened based TCGA database. Six overall survival associated genes (ENPP2, ULK1, CP, LURAP1L, HIC1, AKR1C1) were selected to build survival model, of which hub gene AKR1C1 was with high expression and low ferroptosis level in NSCLC tumor. Further research showed that AKR1C1 was related with many pathways involved in the process of ferroptosis and associated with diverse cancer-infiltrating immune cells. Moreover, the results of in vitro experiments indicated that the expression of AKR1C1 was upregulated in NSCLC cell lines, and silencing AKR1C1 can inhibit the proliferation and migration of NSCLC cells and promote the occurrence of ferroptosis.

Conclusions

Our study revealed the potential role of ferroptosis-related gene AKR1C1 in NSCLC, which can be used for prognostic prediction in NSCLC.
FABP4 is an independent risk factor for lymph node metastasis and poor prognosis in patients with cervical cancer
Authors: Li Guoqing , Wu Qiulei , Gong Lanqing , Xu Xiaohan , Cai Jing , Xu Linjuan , Zeng Ya , He Xiaoqi , Wang Zehua
Published: October 2021

Background

Pelvic lymph node metastasis (LNM) is a crucial independent prognostic factor in cervical cancer (CCa) and serves as an indicator for radiation therapy as the primary or an adjuvant treatment option. However, preoperative diagnosis of LNM remains challenging. Thus, we aimed to identify biomarkers of LNM in patients with presumed early-stage CCa.

Methods

The differentially expressed genes (DEGs) between tumours with different lymph node statuses were identified by using The Cancer Genome Atlas database. Then, univariate Cox regression analysis and Kaplan–Meier analyses were utilized to screen overall survival (OS)-associated genes. Multivariate Cox analysis and logistical analysis were utilized to evaluate independent risk factors for OS and LNM, respectively. Subsequently, the protein level of fatty acid binding protein 4 (FABP4) was detected in normal cervical and CCa tissues by immunohistochemistry assays. EdU assays were performed to determine whether FABP4 altered the proliferation of cervical cancer cells. Wound healing and Transwell assays were conducted to explore the effects of FABP4 depletion on migratory and invasive abilities of cervical cancer cells. F-actin fluorescence staining were performed to investigate morphological change and Western blotting analyses were performed to determine epithelial mesenchymal transition-related marker expression and downstream signalling pathways.

Results

A total of 243 DEGs, including 55 upregulated and 188 downregulated DEGs, were found in CCa patients with LNM versus those without LNM. Among these, FABP4 was found to be closely associated with poor OS. Multivariate analysis uncovered that FABP4 was an independent risk factor for OS and LNM in patients with CCa. The immunohistochemical results verified dramatically increased FABP4 expression in CCa tissues compared to normal cervical epithelia and its association with poor OS and LNM. In vitro, The proliferation, migration and invasion of cervical cancer cells were significantly inhibited after knocking down of FABP4, which was accompanied by elevated expression of E-cadherin and downregulated expression of N-cadherin, Vimentin and p-AKT.

Conclusions

FABP4 might be a promising biomarker of LNM and survival in patients with early-stage CCa and therefore could significantly contribute to the development of personalized prognosis prediction and therapy optimization.
Expression and prognostic potential of ribosome 18S RNA m6A methyltransferase METTL5 in gastric cancer
Authors: Wang Zhenshuang , Liu Jingwei , Yang Yi , Xing Chenzhong , Jing Jingjing , Yuan Yuan
Published: October 2021

Background

Ribosomal RNA N6-methyltransferase METTL5 was reported to catalyze m6A in 18S rRNA. We aimed to investigate the expression and prognostic features of METTL5 in gastric cancer (GC).

Methods

In this study, 168 GC patients and their corresponding adjacent tissues were collected. Immunohistochemical staining was used to detect the expression of METTL5 protein. Univariate and multivariate Cox analysis were used to dertermine the prognostic role of METTL5 protein in GC, and a nomogram was constructed to evaluate GC patients’ prognosis based on METTL5 expression. Data from TCGA and GEO database were also used to validate the prognostic value of METTL5 in GC patients on mRNA level. We further performed GSEA enrichment analysis to explore the possible function and related pathways related to METTL5.

Results

METTL5 protein in gastric cancer tissues (GCTs) was significantly decreased compared with adjacent normal tissues (ANTs) and adjacent intestinal metaplasia tissues (AIMTs) (P < 0.001, respectively). Meanwhile, METTL5 expression was negatively correlated with clinicopathologic stage. According to multivariate Cox proportional hazards model analysis, METTL5 protein expression was a good independent predictor of GC prognosis (p < 0.05). Patients with high METTL5 expression had better prognosis. The nomogram constructed based on METTL5 expression could predict the prognosis of GC patients well. GSEA analysis showed that genes of METTL5 low expression group were enriched in some oncogenic signaling pathways such as ERBB, MAPK, JAK-STAT, Wnt, and mTOR, as well as some immune pathways, including Fc-gamma R mediated phagocytosis, Fc-epsilon Ri, chemokine, T cell receptor and B cell receptor signaling pathway. While the high expression group of METTL5 was mainly related to oxidative phosphorylation, nucleotide excision repair and mismatch repair.

Conclusions

METTL5 protein was decreased in GCTs compared with AIMTs and ANTs, and it may be a potential prognostic biomarker in GC.
Temperature-dependent tensile properties of polyamide 12 for the use in percutaneous transluminal coronary angioplasty balloon catheters
Authors: Amstutz C. , Weisse B. , Valet S. , Haeberlin A. , Burger J. , Zurbuchen A.
Published: October 2021

Background

Percutaneous transluminal coronary angioplasty (PTCA) balloon catheters must withstand high pressures required for the lesion treatment, pushing loads during insertion, and pulling loads during withdrawal. These loads pose a challenge especially for polymeric tubular shafts with small cross sections. In order to enable new design innovations and to better understand the mechanics of current catheter technologies, the tensile properties of polyamide (PA) 12 were investigated. PA 12 dog bone specimens and medical PA 12 tubes were either stored at ambient temperature and humidity or conditioned in water, and subjected to tensile loads at different temperatures. In addition, the effect on the tensile properties of the necking process, a forming process to reduce the wall thickness of the tubes, was determined.

Results

The tested tubes showed a reduction in both Young’s Modulus (− 41.5%) and yield stress (− 29.2%) compared to standardized specimens. Furthermore, an increase in temperature and water absorption softens the material and reduces the mechanical properties like the Young’s Modulus and the yield stress. It was found that the material strengthens during the necking process. Likely due to the orientation of the polymers chain molecules in load direction (Rösler et al., 2007), the Young’s Modulus of the material could be increased by 43.5%. Furthermore, the absence of a yield point after necking allows for a greater loading capacity of the material without unstable neck growth. Besides the strengthening, the ultimate strain is reduced by 50%. This indicates that the necking process induces plastic deformation.

Conclusion

The investigation showed that the environmental conditions like temperature and humidity can influence mechanical properties. It could also be shown that pre-forming processes such as necking can enhance the mechanical properties, such as the Young’s Modulus, while reducing the wall thickness. These findings suggest possible further development of catheters with a small cross section and higher mechanical strength and highlight the importance to account for the targeted operating temperature during the design process.
Identification and validation of an immune-associated RNA-binding proteins signature to predict clinical outcomes and therapeutic responses in colon cancer patients
Authors: Sun Di , Yang Kui-Sheng , Chen Jian-Liang , Wang Zheng-bing
Published: October 2021

Background

The immune infiltration of patients with colon cancer (CC) is closely associated with RNA-binding proteins (RBPs). However, immune-associated RBPs (IARBPs) in CC remain unexplored.

Methods

The data were downloaded from The Cancer Genome Atlas (TCGA) and the patients were divided into four immune subgroups by single sample gene set enrichment analysis (ssGSEA), in which weighted gene correlation network analysis (WGCNA) identified modules of co-expressed genes correlated with immune infiltration. Univariate (UCR) and multivariate Cox regression (MCR) analyses were applied to screen survival-associated IARBPs. Then, a prognostic signature was performed on TCGA dataset. Risk model was constructed based on the TCGA dataset. Based on the median risk score, CC patients were subdivided into low- and high-risk groups. Furthermore, the accuracy and prognostic value of this signature were validated by using Kaplan-Meier (K-M) curve, receiver operating characteristic (ROC). We further validated the findings in Gene Expression Omnibus (GEO) database. Finally, we evaluated the association between gene expression level and drug sensitivity.

Results

Based on the infiltration of immune cells, the TCGA patients were divided into four subgroups. In total, we identified 25 IARBPs, after differential expression and WGCNA analysis. Subsequently, two IARBP signatures (FBXO17 and PPARGC1A) were identified to be significantly associated with the overall survival (OS) of CC patients. K-M survival analysis revealed that the low-risk group correlated with prolonged OS. The prognostic signature was an independent prognostic factor and reflects the immune status of CC patients. Finally, FBXO17 was related with drug sensitivity of bleomycin, gemcitabine, and lenvatinib. PPARGC1A was related to drug sensitivity of dabrafenib, vemurafenib, and trametinib.

Conclusion

A novel two immune-associated RBPs that was established that may be useful in predicting survival and individualized treatment.
Improving outcomes of liver resection for hepatocellular carcinoma associated with portal vein tumor thrombosis over the evolving eras of treatment
Authors: Wang Yu-Chao , Lee Jin-Chiao , Wu Tsung-Han , Cheng Chih-Hsien , Lee Chen-Fang , Wu Ting-Jung , Chou Hong-Shiue , Chan Kun-Ming , Lee Wei-Chen
Published: October 2021

Background

The outcomes and management of hepatocellular carcinoma (HCC) have undergone several evolutionary changes. This study aimed to analyze the outcomes of patients who had undergone liver resection for HCC with portal vein tumor thrombosis (PVTT) in terms of the evolving era of treatment.

Materials and methods

A retrospective analysis of 157 patients who had undergone liver resection for HCC associated with PVTT was performed. The outcomes and prognostic factors related to different eras were further examined.

Results

Overall, 129 (82.1%) patients encountered HCC recurrence after liver resection, and the median time of recurrence was 4.1 months. Maximum tumor size ≥ 5 cm and PVTT in the main portal trunk were identified as the major prognostic factors influencing HCC recurrence after liver resection. Although the recurrence-free survival had no statistical difference between the two eras, the overall survival of patients in the second era was significantly better than that of the patients in the first era (p = 0.004). The 1-, 2-, and 3-year overall survival rates of patients in the second era were 60.0%, 45.7%, and 35.8%, respectively, with a median survival time of 19.6 months.

Conclusion

The outcomes of HCC associated with PVTT remain unsatisfactory because of a high incidence of tumor recurrence even after curative resection. Although the management and outcomes of patients with HCC and PVTT have greatly improved over the years, surgical resection remains an option to achieve a potential cure of HCC in well-selected patients.
How to measure premature mortality? A proposal combining “relative” and “absolute” approaches
Authors: Mazzuco Stefano , Suhrcke Marc , Zanotto Lucia
Published: October 2021

Background

The concept of “premature mortality” is at the heart of many national and global health measurement and benchmarking efforts. However, despite the intuitive appeal of its underlying concept, it is far from obvious how to best operationalise it. The previous work offers at least two basic approaches: an absolute and a relative one. The former—and far more widely used— approach sets a unique age threshold (e.g. 65 years), below which deaths are defined as premature. The relative approach derives the share of premature deaths from the country-specific age distribution of deaths in the country of interest. The biggest disadvantage of the absolute approach is that of using a unique, arbitrary threshold for different mortality patterns, while the main disadvantage of the relative approach is that its estimate of premature mortality strongly depends on how the senescent deaths distribution is defined in each country.

Method

We propose to overcome some of the downsides of the existing approaches, by combining features of both, using a hierarchical model, in which senescent deaths distribution is held constant for each country as a pivotal quantity and the premature mortality distribution is allowed to vary across countries. In this way, premature mortality estimates become more comparable across countries with similar characteristics.

Results

The proposed hierarchical models provide results, which appear to align with related evidence from  specific countries. In particular, we find a relatively high premature mortality for the United States and Denmark.

Conclusions

While our hybrid approach overcomes some of the problems of previous measures, some issues require further research, in particular the choice of the group of countries that a given country is assigned to and the choice of the benchmarks within the groups. Hence, our proposed method, combined with further study addressing these issues, could provide a valid alternative way to measure and compare premature mortality across countries.
The role of PDGFRA as a therapeutic target in young colorectal cancer patients
Authors: Kim Tae Won , Hong Hye Kyung , Lee Chung , Kim Sunmin , Lee Woo Yong , Yun Seong Hyeon , Kim Hee Cheol , Huh Jung Wook , Park Yoon Ah , Joung Je-Gun , Park Woong-Yang , Cho Yong Beom
Published: October 2021

Background

Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear.

Methods

We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation.

Results

Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = − 0.526). Moreover,PDGFRAshowed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression ofPDGFRAcompared to old PDCs and a reduced proliferation rate by knockdown ofPDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients.

Conclusions

Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.
Cytotoxic lymphocytes-related gene ITK from a systematic CRISPR screen could predict prognosis of ovarian cancer patients with distant metastasis
Authors: Xu Mengyao , Huang Shan , Chen Jiahui , Xu Wanxue , Xiang Rong , Piao Yongjun , Zhao Shuangtao
Published: October 2021

Background

Ovarian cancer, a highly metastatic malignancy, has benefited tremendously from advances in modern human genomics. However, the genomic variations related to the metastasis remains unclear.

Methods

We filtered various significant genes (n = 6722) associated with metastasis within a large-scale functional genomic CRISPR/Cas9 knock-out library including 122,756 single guide RNAs, and identified ITK (IL2 Inducible T Cell Kinase) as a potential cancer suppressor gene for ovarian cancer metastasis. Downstream bioinformatic analysis was performed for ITK using public databases.

Results

We found that patients in low-ITK group had poor prognosis and more distant metastasis than those in high-ITK group in TCGA and GEO databases. We also demonstrated that ITK combined with the clinical factors could accurately predict prognosis through multiple Cox regression analysis and ROC analysis. Moreover, alterations correlated with distant metastasis emereged with significantly increased expression in SAMRCD1 in low-ITK group, but CD244 and SOCS1 in high-ITK group. Integrated analysis revealed dysregulated molecular processes including predominantly oncogenic signaling pathways in low-ITK group but immune related pathways in high-ITK group, which suggested ITK might inhibit distant metastasis in ovarian cancer. Furtherly, deconvolution of the cellular composition of all samples validated the close correlation between ITK and immune related function especially for cytotoxic lymphocytes.

Conclusions

Together, these data provide insights into the potential role of ITK, with implications for the future development of tansformative ovarian cancer therapeutics.
Ribonuclease zymogen induces cytotoxicity upon HIV-1 infection
Authors: Windsor Ian W. , Dudley Dawn M. , O’Connor David H. , Raines Ronald T.
Published: October 2021

Background

Targeting RNA is a promising yet underdeveloped modality for the selective killing of cells infected with HIV-1. The secretory ribonucleases (RNases) found in vertebrates have cytotoxic ribonucleolytic activity that is kept in check by a cytosolic ribonuclease inhibitor protein, RI.

Methods

We engineered amino acid substitutions that enable human RNase 1 to evade RI upon its cyclization into a zymogen that is activated by the HIV-1 protease. In effect, the zymogen has an HIV-1 protease cleavage site between the termini of the wild-type enzyme, thereby positioning a cleavable linker over the active site that blocks access to a substrate.

Results

The amino acid substitutions in RNase 1 diminish its affinity for RI by 106-fold and confer high toxicity for T-cell leukemia cells. Pretreating these cells with the zymogen leads to a substantial drop in their viability upon HIV-1 infection, indicating specific toxicity toward infected cells.

Conclusions

These data demonstrate the utility of ribonuclease zymogens as biologic prodrugs.
Smoothness metrics for reaching performance after stroke. Part 1: which one to choose?
Authors: Mohamed Refai Mohamed Irfan , Saes Mique , Scheltinga Bouke L. , van Kordelaar Joost , Bussmann Johannes B. J. , Veltink Peter H. , Buurke Jaap H. , Meskers Carel G. M. , van Wegen Erwin E. H. , Kwakkel Gert , van Beijnum Bert-Jan F.
Published: October 2021

Background

Smoothness is commonly used for measuring movement quality of the upper paretic limb during reaching tasks after stroke. Many different smoothness metrics have been used in stroke research, but a ‘valid’ metric has not been identified. A systematic review and subsequent rigorous analysis of smoothness metrics used in stroke research, in terms of their mathematical definitions and response to simulated perturbations, is needed to conclude whether they are valid for measuring smoothness. Our objective was to provide a recommendation for metrics that reflect smoothness after stroke based on: (1) a systematic review of smoothness metrics for reaching used in stroke research, (2) the mathematical description of the metrics, and (3) the response of metrics to simulated changes associated with smoothness deficits in the reaching profile.

Methods

The systematic review was performed by screening electronic databases using combined keyword groupsStroke,ReachingandSmoothness. Subsequently, each metric identified was assessed with mathematical criteria regarding smoothness: (a) being dimensionless, (b) being reproducible, (c) being based on rate of change of position, and (d) not being a linear transform of other smoothness metrics. The resulting metrics were tested for their response to simulated changes in reaching using models of velocity profiles with varying reaching distances and durations, harmonic disturbances, noise, and sub-movements. Two reaching tasks were simulated; reach-to-point and reach-to-grasp. The metrics that responded as expected in all simulation analyses were considered to be valid.

Results

The systematic review identified 32 different smoothness metrics, 17 of which were excluded based on mathematical criteria, and 13 more as they did not respond as expected in all simulation analyses. Eventually, we found that, for reach-to-point and reach-to-grasp movements, onlySpectral Arc Length(SPARC) was found to be a valid metric.

Conclusions

Based on this systematic review and simulation analyses, we recommend the use of SPARC as a valid smoothness metric in both reach-to-point and reach-to-grasp tasks of the upper limb after stroke. However, further research is needed to understand the time course of smoothness measured with SPARC for the upper limb early post stroke, preferably in longitudinal studies.
Insights into motor performance deficits after stroke: an automated and refined analysis of the lower-extremity motor coordination test (LEMOCOT)
Authors: Handelzalts Shirley , Koren Yogev , Goldhamer Noy , Yeshurun-Tayer Adi , Parmet Yisrael , Shmuelof Lior , Bar-Haim Simona
Published: October 2021

Background

The lower-extremity motor coordination test (LEMOCOT) is a performance-based measure used to assess motor coordination deficits after stroke. We aimed to automatically quantify performance on the LEMOCOT and to extract additional performance parameters based on error analysis in persons with stroke (PwS) and healthy controls. We also aimed to explore whether these parameters provide additional information regarding motor control deficit that is not captured by the traditional LEMOCOT score. In addition, the associations between the LEMOCOT score, parameters of error and performance-based measures of lower-extremity impairment and gait were tested.

Methods

Twenty PwS (age: 62 ± 11.8 years, time after stroke onset: 84 ± 83 days; lower extremity Fugl-Meyer: 30.2 ± 3.7) and 20 healthy controls (age: 42 ± 15.8 years) participated in this cross-sectional exploratory study. Participants were instructed to move their big toe as fast and accurately as possible between targets marked on an electronic mat equipped with force sensors (Zebris FDM-T, 60 Hz). We extracted the contact surface area of each touch, from which the endpoint location, the center of pressure (COP), and the distance between them were computed. In addition, the absolute and variable error were calculated.

Results

PwS touched the targets with greater foot surface and demonstrated a greater distance between the endpoint location and the location of the COP. After controlling for the number of in-target touches, greater absolute and variable errors of the endpoint were observed in the paretic leg than in the non-paretic leg and the legs of controls. Also, the COP variable error differentiated between the paretic, non-paretic, and control legs and this parameter was independent of in-target counts. Negative correlations with moderate effect size were found between the Fugl Meyer assessment and the error parameters.

Conclusions

PwS demonstrated lower performance in all outcome measures than did controls. Several parameters of error indicated differences between legs (paretic leg, non-paretic leg and controls) and were independent of in-target touch counts, suggesting they may reflect motor deficits that are not identified by the traditional LEMOCOT score.
Postoperative acute kidney injury requiring continuous renal replacement therapy and outcomes after coronary artery bypass grafting: a nationwide cohort study
Authors: Oh Tak Kyu , Song In-Ae
Published: October 2021

Background

Previous studies reported that patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) after cardiac surgery were at a higher risk of postoperative mortality. However, the impact of AKI and CRRT on long-term mortality has not yet been identified. Therefore, we investigated whether postoperative AKI requiring CRRT was associated with one-year all-cause mortality after coronary artery bypass grafting (CABG).

Methods

For this population-based cohort study, we analyzed data from the National Health Insurance Service database in South Korea. The cohort included all adult patients diagnosed with ischemic heart disease who underwent isolated CABG between January 2012 and December 2017.

Results

A total of 15,115 patients were included in the analysis, and 214 patients (1.4%) required CRRT for AKI after CABG during hospitalization. They received CRRT at 3.1 ± 8.5 days after CABG, for 3.1 ± 7.8 days. On multivariable Cox regression, the risk of 1-year all-cause mortality in patients who underwent CRRT was 7.69-fold higher. Additionally, on multivariable Cox regression, the 30-day and 90-day mortality after CABG in patients who underwent CRRT were 18.20-fold and 20.21-fold higher than the normal value, respectively. Newly diagnosed chronic kidney disease (CKD) requiring renal replacement therapy (RRT) 1 year after CABG in patients who underwent CRRT was 2.50-fold higher. In the generalized log-linear Poisson model, the length of hospital stay (LOS) in patients who underwent CRRT was 5% longer.

Conclusions

This population-based cohort study showed that postoperative AKI requiring CRRT was associated with a higher 1-year all-cause mortality after CABG. Furthermore, it was associated with a higher rate of 30-day and 90-day mortality, longer LOS, and higher rate of CKD requiring RRT 1 year after CABG. Our results suggest that CRRT-associated AKI after CABG may be associated with an increased risk of mortality; hence, there should be interventions in these patients after hospital discharge.
Team approach to polypharmacy evaluation and reduction: study protocol for a randomized controlled trial
Authors: Mangin Dee , Lamarche Larkin , Agarwal Gina , Banh Hoan Linh , Dore Brown Naomi , Cassels Alan , Colwill Kiska , Dolovich Lisa , Farrell Barbara , Garrison Scott , Gillett James , Griffith Lauren E. , Holbrook Anne , Jurcic-Vrataric Jane , McCormack James , O’Reilly Daria , Raina Parminder , Richardson Julie , Risdon Cathy , Savelli Mat , Sherifali Diana , Siu Henry , Tarride Jean-Éric , Trimble Johanna , Ali Abbas , Freeman Karla , Langevin Jessica , Parascandalo Jenna , Templeton Jeffrey A. , Dragos Steven , Borhan Sayem , Thabane Lehana
Published: October 2021

Background

Polypharmacy in older adults can be associated with negative outcomes including falls, impaired cognition, reduced quality of life, and general and functional decline. It is not clear to what extent these are reversible if the number of medications is reduced. Primary care does not have a systematic approach for reducing inappropriate polypharmacy, and there are few, if any, approaches that account for the patient’s priorities and preferences. The primary objective of this study is to test the effect of TAPER (Team Approach to Polypharmacy Evaluation and Reduction), a structured operationalized clinical pathway focused on reducing inappropriate polypharmacy. TAPER integrates evidence tools for identifying potentially inappropriate medications, tapering, and monitoring guidance and explicit elicitation of patient priorities and preferences. We aim to determine the effect of TAPER on the number of medications (primary outcome) and health-related outcomes associated with polypharmacy in older adults.

Methods

We designed a multi-center randomized controlled trial, with the lead implementation site in Hamilton, Ontario. Older adults aged 70 years or older who are on five or more medications will be eligible to participate. A total of 360 participants will be recruited. Participants will be assigned to either the control or intervention arm. The intervention involves a comprehensive multidisciplinary medication review by pharmacists and physicians in partnership with patients. This review will be focused on reducing medication burden, with the assumption that this will reduce the risks and harms of polypharmacy. The control group is a wait list, and control patients will be given appointments for the TAPER intervention at a date after the final outcome assessment. All patients will be followed up and outcomes measured in both groups at baseline and 6 months.

Discussion

Our trial is unique in its design in that it aims to introduce an operationalized structured clinical pathway aimed to reduce polypharmacy in a primary care setting while at the same time recording patient’s goals and priorities for treatment.

Trial registration

ClinicalTrials.govNCT02942927. First registered on October 24, 2016.
Activation of the autophagy pathway decreases dengue virus infection in Aedes aegypti cells
Authors: Chen Tse-Yu , Smartt Chelsea T.
Published: October 2021

Background

Mosquito-borne dengue virus (DENV) causes major disease worldwide, impacting 50–100 million people every year, and is spread by the major mosquito vector Aedes aegypti. Understanding mosquito physiology, including antiviral mechanisms, and developing new control strategies have become an important step towards the elimination of DENV disease. In the study reported here, we focused on autophagy, a pathway suggested as having a positive influence on virus replication in humans, as a potential antiviral target in the mosquito.

Methods

To understand the role played by autophagy in Ae. aegypti, we examined the activation of this pathway in Aag-2 cells, an Ae. aegypti-derived cell line, infected with DENV. Rapamycin and 3-methyladenine, two small molecules that have been shown to affect the function of the autophagy pathway, were used to activate or suppress, respectively, the autophagy pathway.

Results

At 1-day post-DENV infection in Aag-2 cells, transcript levels of both the microtubule-associated protein light chain 3-phosphatidylethanolamine conjugate (LC3-II) and autophagy-related protein 1 (ATG1) increased. Rapamycin treatment activated the autophagy pathway as early as 1-h post-treatment, and the virus titer had decreased in the Aag-2 cells at 2 days post-infection; in contrast, the 3-methyladenine treatment did not significantly affect the DENV titer. Treatment with these small molecules also impacted the ATG12 transcript levels in DENV-infected cells.

Conclusions

Our studies revealed that activation of the autophagy pathway through rapamycin treatment altered DENV infection in the mosquito cells, suggesting that this pathway could be a possible antiviral mechanism in the mosquito system. Here we provide fundamental information needed to proceed with future experiments and to improve our understanding of the mosquito’s immune response against DENV.

Graphical Abstract