bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of Posterior Tibial Slope in Turkish Population Groups with Magnetic Resonance İmaging
Authors: Karakanlı Musab Ümeyir , Deniz Ferdanur , Celilov İlkin , Sofulu Ömer , Küçükdurmaz Fatih
Published: August 2020

Background

The posterior tibial slope (PTS) has great importance on the balance and the stability of the knee and has to be taken into account during the reconstruction and replacement procedure. However, the anthropometric measurements are not universal and show population-based variations. The purpose of this study is to find features of PTS in the Turkish population in regards to the medial and lateral compartment.
Methods

Magnetic resonance images (MRIs) were retrieved from the Picture Archiving and Communication System (PACS). Subjects from 25 to 45 years old were included from the MRIs taken between July 2015 to July 2017. Any MRI with radiological signs of osteoarthritis, chondral and meniscus (grade 3 & 4) lesions was excluded as well as a deformity in the lower extremity, patients with a history of fracture and/or history of knee surgery. The measurements were made using T1-weighted coronal and sagittal MRI planes with a slice thickness of 4 mm. The PTS of the medial, lateral plateau were recorded with gender and age of the subjects. Non-parametric Spearman's Correlation tests and Student T tests were used to calculate the relationship between medial-lateral PTS and ages and also to evaluate PTS differences between genders.
Results

Two-hundred thirty-two subjects (122 female, 110 male) were included in the study. The mean medial and lateral PTS were 7.7°±1.3° and 7.5°±1.3° respectively, and there was a significant correlation (p < 0.001). However, no significant difference was found in the mean medial PTS (p = 0.45) and lateral PTS (p = 0.73) between genders and matched age groups.
Conclusions

Our results showed that there is no gender-based variation in the Turkish population. Although we do not make a systematic comparison, the measurements of PTS in the Turkish population were different from other populations.
Loss of MiR-192 Initiates a Hyperglycolysis and Stemness Positive Feedback in Hepatocellular Carcinoma
Authors: Gu Yuanzhuo , Ji Fubo , Liu Niya , Zhao Yongzhi , Wei Xiyang , Hu Shiyuan , Jia Wei , Wang Xin Wei , Budhu Anuradha , Ji Juling , Zhao Bin , Roessler Stephanie , Zheng Xin , Ji Junfang
Published: August 2020

Background: Emerging studies revealed that cancer stem cells (CSCs) possessed peculiar metabolic properties, which however remained largely unknown in hepatocellular carcinoma (HCC). Genetic silencing of liver-abundant miR-192 was a key feature for multiple groups of CSC-positive primary HCCs. We thus aimed to investigate essential metabolic features of hepatic CSCs via using HCCs with miR-192 silencing as a model. Methods: Data integration analyses of miR-192 with metabolome and mRNA transcriptome in HCC cohort 1 were performed to investigate miR-192 related metabolic features. Cellular and molecular assays were performed to examine whether and how miR-192 regulated the identified metabolic feature. Co-culture systems consisting of HCC and non-HCC cells were established to explore effects of the metabolomic property on stemness features in HCC cells via interacting with non-HCC cells. Results: High expression of glycolysis-related metabolites and genes presented in HCCs with low miR-192 and CSC-positive HCCs in two independent HCC cohorts. miR-192 knock-out cells displayed CSC features and miR-192 loss led to an enhanced glycolytic phenotype via targeting three glycolysis regulators, i.e., Glut1, Pfkfb3, and c-Myc. Meanwhile, c-Myc suppressed miR-192 transcription, ensuring a low-miR-192/high-c-Myc loop to maintain hyperglycolysis. Moreover, over-produced lactic acid from hyperglycolytic HCC cells stimulated the Erk phosphorylation of co-cultured non-HCC cells partially via NDRG3 and MCT1, which in turn promoted cell malignancy and stemness of HCC cells. Conclusions: In CSC-positive HCCs, miR-192 loss enhanced glycolysis via a c-Myc/miR-192/glycolysis regulators signal loop, allowing HCC cells to actively coordinate with their environment non-HCC cells for further increased stemness and malignancy.
Prophylactic Use of Glucocorticoids and Postoperative Delirium/Cognitive Dysfunction in Adults After Major Surgery: a Meta-Analysis of Randomized Controlled Trials
Authors: Xie Yan , Liu Yang , Liu Yi
Published: August 2020

Objectives. To investigate whether prophylactic use of glucocorticoids (GCs) would affect the incidence of postoperative delirium (POD)/cognitive dysfunction (POCD) after major surgeries. Methods. A systemic review of randomized controlled trials (RCTs) searched from the Pubmed, Cochrane Library, Embase, and Clinical Trials.gov was conducted. Effect of GCs on the incidence of POD/POCD and several secondary outcomes, including s100-β, mechanical ventilation time, length of ICU stay, length of postoperative hospital stay, postoperative cardiac arrhythmia, and adverse outcomes, were analyzed. The Cochrane Collaboration’s risk of bias tool and the GRADE system were used to assess the risk of bias of included studies and the evidence quality of combined results, respectively. Results. There were 726 records detected and only 11 studies were included at last. Six of the 11 RCT studies were categorized as low risk of bias, 3 studies as unclear, and 2 as high. Prophylactic use of GCs didn’t show any significant effect on the incidence of POD/POCD after major surgeries, but the evidence quality of this result was very low. For the secondary outcome, GCs can significantly decrease the level of s100-β, length of ICU stay, length of postoperative hospital stay, and ventilation time, with the evidence quality varied from very low to moderate. For the rest of the secondary outcomes, no significant effect was observed. Conclusion. Prophylactic use of GCs didn’t have a significant effect on the incidence of POD and POCD. However, this result was very uncertain, and more relevant high-quality RCTs are needed.
Chronic care models and opportunities for improving health care practice and outcomes in Sub-Saharan Africa: Protocol for systematic review
Authors: Otieno Peter , Agyemang Charles , Gyasi Razak M. , Ngugi Anthony K. , Kyobutungi Catherine , Asiki Gershim
Published: August 2020

Background: The rising burden of chronic diseases in sub-Saharan Africa (SSA) where health care systems are least developed has led to recent calls for increased investment in chronic care models (CCM) appropriate for low-resource settings. In SSA, limited resources are often allocated to treating acute diseases thus management of chronic conditions is a major challenge for health care systems. A large diversity of CCM exist in the literature but evidence supporting their use has been derived from high income settings. This is the motivation for conducting a systematic review to identify the existing CCM and their relevance and applicability in SSA.Methods and analysis: All peer-reviewed published and grey literature on CCM will be included. PubMed/MEDLINE, Embase, Scopus, Web of Science and Global Health Cinahl, African Journals Online, Informit Online, and PsycINFO will be searched to identify relevant articles. OpenSIGLE will be reviewed for grey literature. The articles retrieved will be independently screened for inclusion by two independent investigators while a third reviewer will arbitrate the disagreements. An independent critical appraisal of retrieved studies will be performed using standardized critical appraisal checklists. The data will be extracted from the key elements of CCM. Outcome measures for the effectiveness of the models in the context of SSA will include any reported improvement to the health care service delivery or changes in the health outcomes of patients with chronic illnesses. The study findings will be reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA).Discussion: This systematic review is expected to generate crucial evidence on the applicability of CCM in SSA and unearth the CCM components that are suitable for different levels of health care delivery systems and the emerging needs of the people living with comorbidities and multimorbidities in SSA.Systematic review registration: This review is registered in PROSPERO International Prospective Register of Systematic reviews CRD42020187756.
Circular RNA hsa_circ_0001829 Promotes Gastric Cancer Progression through miR-155-5p/SMAD2 Axis
Authors: Niu Qiuling , Dong Zhijie , Liang Min , Luo Yuanwei , Lin Hai , Lin Mingzhen , Zhong Xiu , Yao Wenxia , Weng Jinsheng , Zhou Xinke
Published: August 2020

Background: Accumulating evidences have shown that circular RNAs (circRNAs) play important roles in regulating the pathogenesis of cancer. However, the role of circRNAs in gastric cancer (GC) remains largely unclear. Methods: In this study, we identified a novel upregulated circRNA, hsa_circ_0001829, in chemically induced malignant transformed human gastric epithelial cells using RNA-seq. Subsequent qRT-PCR was performed to detect the expression level of hsa_circ_0001829 in GC cell lines and tissues. Functional roles of hsa_circ_0001829 in GC were then explored by loss- and gain-of- function assays. Bioinformatic prediction and luciferase assay were used to investigate potential mechanisms of hsa_circ_0001829. Finally, the mice xenograft models were constructed to assess the function of hsa_circ_0001829 in vivo.Results: We found that hsa_circ_0001829 was significantly upregulated in GC tissues and cell lines. Loss- and gain-of- function assays showed that hsa_circ_0001829 promotes GC cells proliferation, migration and invasion, and the affected cell cycle progression and apoptosis rates may account for the effect of hsa_circ_0001829 on GC proliferation. In addition, bioinformatic prediction and luciferase assay showed that hsa_circ_0001829 acts as a molecular sponge for miR-155-5p and that SMAD2 was a target gene of miR-155-5p; moreover, hsa_circ_0001829 sponges miR-155-5p to regulate SMAD2 expression and hsa_circ_0001829 promotes GC progression through the miR-155-5p–SMAD2 pathway. Finally, suppression of hsa_circ_0001829 expression inhibited subcutaneous tumor growth in vivo. Conclusion: Taken together, our findings firstly demonstrated a novel oncogenic role of hsa_circ_0001829 in GC progression, which is through miR-155-5p–SMAD2 axis, and our study may offer novel biomarkers and therapeutic targets for GC.
De Novo Assembly and Analysis of Transcriptome of the Dermacentor Marginatus Genes Differentially Expressed After Blood Feeding and Long-term Starvation
Authors: Hu Ercha , Meng Yuan , Ma Ying , Song Ruiqi , Hu Zhengxiang , Li Min , Hao Yunwei , Fan Xinli , Wei Liting Wei , Fan Shilong , Chen Songqin , Zhai Xuejie , Li Yongchang , Wei Zhang , Zhang Yang , Guo Qingyong , Bayin Chahan
Published: August 2020

Background
The Ixodid tick Dermacentor marginatus is a vector of many pathogens wide spread in Eurasia. Study of gene targets of the tick species provides insight to find novel tick protective antigen for drug development and vaccine targets.
Methods
To obtain a broader picture of gene sequences and changes in expression level, the RNA-seq was performed to obtain the whole-body transcriptome data of D. marginatus adult female ticks after engorgement and long-term starvation. Subsequently, the real-time quantitative PCR (RT-qPCR) was applied to validate the RNA-seq data.
Results
The RNA-seq produced 30251 unigenes, of which 32% were annotated using Trinity. Gene expression was compared among groups differed by status as newly molted, starved and engorged female adult ticks. Nearly 1/3 of the unigenes in each group were differentially expressed compared to the other two group, and the most numerous were genes encoding proteins involved in catalytic and binding activities and apoptosis. Selected up-regulated differentially expressed genes in each group associated to protein, lipids, carbohydrate and chitin metabolism. Blood feeding and long-term starvation also caused genes differentially expressed in the defense response and antioxidant response. RT-qPCR results indicated 6 differentially expressed transcripts showed similar trends in expression changes with RNA-seq results confirming that the gene expression profiles in transcriptome data is in consistent with RT-qPCR validation.
Conclusions
Obtaining the sequence information of D. marginatus and characterizing the expression pattern of the genes involved in blood feeding and during starvation would be helpful in understanding molecular physiology of D. marginatus and provides data for anti-tick vaccine and drug development for controlling the tick.
Interpersonal Counselling for Adolescent Depression Delivered by Youth Mental Health Workers Without Core Professional Training: A Feasibility Randomised Controlled Trialstudy Protocol
Authors: Abotsie Gabriel , Cestaro Viktoria , Gee Brioney , Murdoch Jamie , Katangwe Thando , Meiser-Stedman Richard Richard , Shepstone Lee , Turner David , Tulk Susie , Jarret Sharon , Wilson Jon , Clarke Timothy , Bonnie Teague , Wilkinson Paul
Published: August 2020

Background: Depression is a common health problem during adolescence and is associated with adverse academic, social and health outcomes. To meet demand for treatment for adolescent depression, there is a need for evidence-based interventions suitable for delivery outside of specialist Child and Adolescent Mental Health Services (CAMHS). Interpersonal Counselling for Adolescents (IPC-A), is a brief manualised intervention for adolescent depression suitable for delivery by staff who are not qualified health professionals following participation in a brief training course. While initial piloting within Local Authority services has generated promising results, the effectiveness and cost-effectiveness of IPC-A has yet to be established. This study aims to assess the feasibility of a randomised controlled trial (RCT), evaluating the effectiveness and cost-effectiveness of IPC-A delivered by staff without core professional training in comparison to current provision.Method: Feasibility RCT with process evaluation using ethnographic methodology. Eligible young people (n=60) will be randomised in a 1:1 ratio to receive either IPC-A or treatment as usual (TAU). Participants will be assessed pre-randomisation (baseline) and followed up at 5, 10 and 23 weeks post-randomisation. A parallel process evaluation will generate understanding of intervention implementation across services and explore the acceptability of the intervention from the perspective of young people and other key stakeholders.Participants: Young people aged 12-18 years presenting to non-specialist services with symptoms of depression. Youth workers, young people and stakeholders will participate in the process evaluation.Discussion: The need for effective and accessible interventions for young people with mild/sub-threshold depression who in most cases, do not meet the threshold for mainstream mental health services is long overdue. The primary output of this feasibility trial will be the design of the subsequent full-scale trial. If the results of the current study indicate that this would be feasible, we intend to progress to a multi-site, assessor-blind, superiority RCT of the effectiveness and cost-effectiveness of IPC-A in comparison to TAU for adolescents presenting to non-specialist services with depressive symptoms. If satisfactory solutions to any problems encountered cannot be identified, alternative research designs will be considered. If proven effective, an IPC-A training programme could be implemented.Trial registry: ISRCTN registry, ISRCTN82180413. Registered 31 December 2019, https://doi.org/10.1186/ISRCTN82180413
Wip1 regulates the immunomodulatory effects of murine mesenchymal stem cells in type 1 diabetes mellitus via targeting IFN-α/BST2
Authors: Zhou Na , Liu Weijiang , Liu Yuanlin , Li Xue , Wang Yang , Zheng Rongxiu , Zhang Yi
Published: August 2020

Background: Mesenchymal stem cells (MSCs) shows significant therapeutic effects in type 1 diabetes mellitus (T1DM) as they could regulate the inflammatory processes. However, little is known about the process of MSCs immunosuppression in T1DM. In this study, we investigated the effects of wild type p53-induce phosphatase 1 (Wip1) on regulating MSCs immunosuppressive capacities in T1DM mice.Methods: Primary wild type (Wip1+/+) MSCs and Wip1 knockout (Wip1−/−) MSCs were cultured in vitro. T1DM mouse model was induced with streptozotocin and then was treated with Wip1+/+ MSCs (5 × 105) or Wip1−/− MSCs (5 × 105) by tail vein injection. The general physiological states of T1DM mice were measured every week. Moreover, the pathological changes in the pancreatic tissue were observed. Enzyme-linked immunosorbent assay (ELISA) and flow cytometry were used to detect the expressions of inflammatory cytokines in mice.Results: Wip1 −/− MSCs had lower therapeutic effects in T1DM mice. Moreover, we screened and confirmed bone marrow stromal cell antigen2 (BST2) gene that showed the target gene for Wip1 through gene chips, quantitative polymerase chain reaction and Western blot. Wip1−/− MSCs exhibited lower immunosuppressive capacity, as evidenced by enhanced expression of BST2, with concurrent increased expression of interferon-α (IFN-α). In vivo distribution analysis results indicated that Wip1−/− MSCs homed to the damaged pancreatic tissue. Wip1−/− MSCs influenced the expression of immune factors by remarkably increasing the expression of tumor necrosis factor-α (TNF-α), interleukin-17A (IL-17A), IFN-α, IFN-β, and IFN-γ and decreasing the expression of IL-4 and IL-10.Conclusions: Wip1 affects MSCs immunomodulation by regulating the expression of IFN-α/BST2. These findings suggest that Wip1 is required to regulate the therapeutic effects of MSCs on T1DM treatment, indicating a novel role of Wip1 in immunoregulation.
The Urgent Need to Empower Rare Disease Organizations in China: An Interview-Based Study
Authors: Li Xuefeng , Lu Zijuan , Zhang Jianyong , Zhang Xiangyu , Zhang Shu , Zhou Jincheng , Li Bingzhe , Ou Li
Published: August 2020

Background: Each rare disease affects a small number of population, and thus is neglected. However, a total of 7,000 rare diseases may affect 10% of the population. Due to the severity and lack of rare disease awareness, rare disease represents a huge challenge for the healthcare system. In Western countries, patient organizations have been playing an integral role in raising awareness, advocating legislation, and supporting drug development. This study aims to assess the unmet needs of rare disease patient organizations in China, and identify their unmet needs, providing essential information for the government and legislators. Results: A total of 28 individuals representing 28 patient organizations in China were interviewed. Most organizations do not have official registration, employees, written standard operation protocol, or reliable financial resources. Misdiagnosis or delayed diagnosis is common, and treatment is often lacking. Due to the lack of financial resources, no organizations have been able to sponsor academic research, unlike their counterparts in Western countries. As to challenges, 71.4% of interviewees listed lack of rare disease awareness among the general public, while 67.9% selected lack of financial resources. Further, only 7.3% of these organizations received support from the government, and 28.6% received support from the general public. As to recommendations to the government, 82.1% of interviewees selected special insurance programs for rare diseases because rare diseases have been generally excluded from the national medical insurance programs. In addition, 78.6% of interviewees recommended to stimulate rare disease research, 75% recommended to import orphan drugs, and 71.4% recommended legislation of an orphan drug act, highlighting the urgent need of therapies. Conclusions: Due to lack of support and rare disease awareness, patient organizations in China are still in the early phase. To empower these patient organizations, recommendations from these patient organizations should be considered by the government and legislators.
Association of sickle cell disease with nutritional status among under-five children and mediating role of hemoglobin level: secondary analysis of data from 2018 Nigeria Demographic and Health Survey
Authors: Islam Mohammad Redwanul , Moinuddin Md. , Ahmed Ayeda , Rahman Syed Moshfiqur
Published: August 2020

Background: Malnutrition continues to affect under-five children in Africa to an overwhelming proportion. The situation is further compounded by the burden of sickle cell disease (SCD). However, association of SCD with stunting, wasting, and underweight in a nationally representative sample of under-five children remains unexplored. We aimed to describe prevalence of undernutrition by sickle cell status, to evaluate its association with growth faltering ascertained with anthropometric indices, and to explore mediating role of hemoglobin.Methods: We availed data from the 2018 Nigeria Demographic and Health Survey (DHS) and the sample comprised 11233 children aged 6–59 months who were successfully genotyped for SCD. The DHS employed a two-stage stratified sampling strategy. SickleSCAN rapid diagnostic test was used for SCD genotyping. Z-scores of length/height-for-age (HAZ), weight-for-height (WHZ), and weight-for-age (WAZ) were computed against the 2006 World Health Organization Child Growth Standards. We fitted logistic regression models to evaluate association of SCD with stunting, wasting, and underweight. Mediation analysis was performed to capture the indirect effect of, and proportion of total effect mediated through hemoglobin level in SCD-anthropometric indices association.Results: Prevalences of stunting, wasting, and underweight among children with SCD were 55.4% (54.5–56.4), 9.1% (8.6–9.7), and 38.9% (38.0-39.8), respectively. The odds of stunting were 2.39 times higher (adjusted odds ratio (aOR) 2.39, 95% CI: 1.26–4.54) among sickle children than those with normal hemoglobin. SCD was also significantly associated with underweight (aOR 2.64, 95% CI: 1.25–5.98), but not with wasting (aOR 1.60, 95% CI: 0.85–3.02). Hemoglobin level significantly mediated SCD-HAZ (adjusted indirect effect (aIE) -0.328, 95% CI: -0.387, -0.270), SCD-WHZ (aIE − 0.080, 95% CI: -0.114, -0.050), and WAZ (aIE − 0.245, 95% CI: -0.291, -0.200) associations. The extent of mediation was highest for SCD-HAZ association (adjusted proportion mediated 0.928, 95% CI: 0.535–2.770).Conclusion: We presented compelling evidence of the negative impact of SCD on nutritional status of under-five children. Integration of a nutrition-oriented approach into a definitive SCD care package and its nation-wide implementation could bring promising results by mitigating the nutritional vulnerability of children with SCD.
Dietary protein is the strong predictor of coronary artery disease; a data mining approach
Authors: Soflaei Sara Saffar , Shamsara Elham , Sahranavard Toktam , Esmaily Habibollah , Moohebati Mohsen , Shabani Niloofar , Asadi Zahra , Tajfard Mohammad , Ferns Gordon A , Mobarhan Majid Ghayour
Published: August 2020

Backgrounds and aims: Coronary artery disease (CAD) is the major cause of mortality and morbidity globally. Diet is known to contribute to CAD risk, and the dietary intake of specific macro- or micro-nutrients might be potential predictors of CAD risk. Machine learning methods may be helpful in the analysis of the contribution of several parameters in dietary including macro- and micro-nutrients to CAD risk. Here we aimed to determine the most important dietary factors for predicting CAD.Methods: Total 273 cases with more than 50% obstruction in at least one coronary artery and 443 healthy controls who completed a food frequency questionnaire (FFQ) were entered into the study. All dietary intakes were adjusted for energy intake. QUEST method was applied to determine the diagnosis pattern of CAD.Results: Total 34 dietary variables obtained from FFQ were entered the study that 23 of these variables were significantly associated with CAD according to t-test. Out of 23 dietary input variables adjusted protein, manganese, biotin, zinc and cholesterol remained in the model. According to our tree, only protein intake could identify the patients with coronary artery stenosis according to angiography from healthy participant up to 80%. Manganese dietary intake was the second important variable after protein. The accuracy of the tree was 84.36% for training dataset and 82.94% for testing dataset.Conclusion: Among different macro- and micro-nutrients in the dietary, a combination of protein, manganese, biotin, zinc and cholesterol could predict the presence of CAD.
Outcomes of proximal femoral locking-plate fixation for pathological fractures of the proximal femur
Authors: Riansuwan Kongkhet , Jivasomboonkul Somkiat , Phimolsarnti Rapin , Chandhanayingyong Chandhanarat , Asavamongkolkul Apichat
Published: August 2020

Background

Intramedullary nailing of long bones is a common technique for management of existing or impending pathological fracture of the proximal femur. This fixation has been shown to be biomechanically superior to the locking-plate system. However, serious complications, including pulmonary embolism, have been reported in patients treated with intramedullary nailing with or without reaming. The purpose of this report was to study the treatment outcomes of proximal femoral locking-plate fixation of pathological fractures of the proximal femur relative to clinical results, implant failure, and surgical complications.
Methods

From 2007 to 2018, 17 patients (18 femurs) with a diagnosis of impending or existing pathological fracture of the proximal femur were treated with proximal femoral locking-plate fixation. Data collected included operative duration, estimated blood loss, ambulatory status, hardware failure events, and postoperative complications.
Results

Of the 18 femurs that were included, 13 were existing pathological fractures and 5 were impending fractures. The mean age of patients was 53.7 years (range: 28–89), and 12 of them were female. The mean follow-up was 11.3 months (range: 1–67). Ten of 17 patients (62.5%) had progressive lung disease from pulmonary metastasis or from lung primary. No patient developed oxygen desaturation or cardiac arrest during the intraoperative or postoperative period. Thirteen of 17 patients (76.5%) could walk with or without an assistive device at the time of final follow-up. Two patients required close postoperative monitoring in the ICU due to poor preoperative status, and both of those patients died within one month after surgery from other medical problems. No hardware failure occurred.
Conclusion

For pathological fracture of the proximal femur, proximal femoral locking-plate fixation is a treatment option that results in fewer perioperative and postoperative cardiopulmonary events and surgical complications. Most patients can ambulate with or without an assistive device at the final follow-up.
Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells
Authors: Larrue Clément , Guiraud Nathan , Dubois Marine , Mouchel Pierre-Luc , Farge Thomas , Gotanègre Mathilde , Bosc Claudie , Saland Estelle , Nicolau-Travers Marie-Laure , Sabatier Marie , Serhan Nizar , Sahal Ambrine , Boet Emeline , Mouche Sarah , Heydt Quentin , Aroua Nesrine , Stuani Lucille , Kaoma Tony , Angenendt Linus , Mikesch Jan-Henrik , Schliemann Christoph , Vergez Francois , Tamburini Jerome , Récher Christian , Sarry Jean-Emmanuel
Published: August 2020

Drug tolerant leukemic cell subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these Relapse-Initiating Cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncovered that the G-protein coupled receptor CALCRL is expressed in leukemic stem cells (LSCs) and RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM) correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency and sensitizes to cytarabine in patient-derived xenograft (PDX) models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA integrity and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.
Host-Response Subphenotypic Classification with A Parsimonious Model Offers Prognostic Information in Patients with Acute Respiratory Failure: A Prospective Cohort Study.
Authors: Drohan Callie M. , Nouraie S. Mehdi , Bain William , Shah Faraaz A. , Evankovich John , Zhang Yingze , Morris Alison , McVerry Bryan J. , Kitsios Georgios D.
Published: August 2020

Background: Recent research in patients with ARDS has consistently shown the presence of two distinct subphenotypes of host-responses (hyper- and hypo-inflammatory) with markedly different outcomes and responses to therapies. However, inherent uncertainty in reaching the diagnosis of ARDS creates considerable biological and clinical overlap with other broadly-defined syndromes of acute respiratory failure, such as patients with risk factors (e.g. sepsis or pneumonia) for ARDS (at-risk for ARDS [ARFA]) or patients with decompensated congestive heart failure (CHF). Limited data are available for the presence of subphenotypes in such broader critically-ill populations. Methods: We enrolled mechanically-ventilated patients with acute respiratory failure (ARDS, ARFA, and CHF) and measured 11 plasma biomarkers at baseline. We applied latent class analysis (LCA) methods to determine optimal subphenotypic classifications in this inclusive patient cohort by considering clinical variables and biomarkers. We then derived a parsimonious logistic regression model for subphenotype predictions and compared clinical outcomes between subphenotypes.Results: We included 334 patients (123 [37%] ARDS, 177 [53%] ARFA, 34 [10%] CHF) in a derivation cohort and 36 patients in a temporally-independent validation cohort. A two-class LCA model was found to be optimal, classifying 29% of patients in the hyper-inflammatory subphenotype, consistent with prior findings. A 4-variable parsimonious model (angiopoietin-2, soluble tumor necrosis factor receptor-1, procalcitonin and bicarbonate) for subphenotype prediction offered excellent classification (area under the curve = 0.98) compared to LCA classifications. For both LCA- and regression model classifications, hyper-inflammatory patients had higher severity of illness by Sequential Organ Failure Assessment scores, fewer ventilator-free days and higher 30- and 90-day mortality (all p<0.01) compared to the hypo-inflammatory group. Subphenotype predictions in the validation cohort revealed consistent trends for clinical outcomes and higher levels of inflammatory biomarkers in the hyper-inflammatory group (22%). Conclusions: Host-response subphenotypes are observable in broader and heterogeneous patient populations beyond just patients with ARDS, and subphenotypic classifications offer prognostic information on clinical outcomes. Accurate subphenotyping is possible with the use of a simple predictive model to improve clinical applicability.
Acute Skeletal Muscle Wasting and Dysfunction Predict Physical Disability at Hospital Discharge in Patients With Critical Illness
Authors: Mayer Kirby P. , Bastin Melissa L. Thompson , Montgomery-Yates Ashley A. , Pastva Amy M. , Dupont-Versteegden Esther E. , Parry Selina M. , Morris Peter E
Published: August 2020

Background: Patients surviving critical illness develop muscle weakness and impairments in physical function, however, the relationship between early skeletal muscle dysfunction and physical function at hospital discharge remains unclear. The primary purpose of this study was to determine if changes in muscle size, strength and power assessed in the intensive care unit (ICU) predict physical function at hospital discharge. Methods: Study design is a single-center, prospective, observational study in patients admitted to the medicine or cardiothoracic ICU with diagnosis of sepsis or acute respiratory failure. Rectus femoris (RF) and tibialis anterior (TA) muscle ultrasound images were obtained day one of ICU admission, repeated serially and assessed for muscle cross-sectional area (CSA), layer thickness (mT), and echointensity (EI). Muscle strength, as measured by Medical Research Council-sum score, and muscle power (lower-extremity leg-press) were assessed prior to ICU discharge. Physical function was assessed with performance on 5-times sit-to-stand (5STS) at hospital discharge.Results: Forty-one patients with median age of 61 years (IQR 55-68), 56% male, and sequential organ failure assessment score of 8.1 ± 4.8 were enrolled. RF muscle CSA decreased significantly a median percent change of 18.5% from day 1 to 7 (F = 26.6, p = 0.0253). RF EI increased at a mean percent change of 10.5 ± 21% in the first 7 days (F = 3.28, p = 0.081). At hospital discharge 25.7% of patients (9/35) met criteria for ICU-acquired weakness. Change in RF EI in first 7 days of ICU admission and muscle power measured prior to ICU were strong predictors of ICU-AW at hospital discharge (AUC = 0.912). Muscle power at ICU discharge, age and ICU length of stay were predictive of performance on 5STS at hospital discharge.Conclusion: ICU-assessed muscle dysfunction is a predictor of physical disability at hospital discharge in patients surviving critical illness.
Ca2+-Activated Mitochondrial Biogenesis and Functions Improve Stem Cell Fate in Rg3-Treated Human Mesenchymal Stem Cells
Authors: Hong Taeui , Kim Moon Young , Ly Dat Da , Park Su Jung , Eom Young Woo , Park Kyu-Sang , Baik Soon Koo
Published: August 2020

Although mitochondrial functions are essential for cell survival, their critical roles in stem cell fate, including proliferation, differentiation, and senescence, remain elusive. Ginsenoside Rg3 exhibits various biological activities and reportedly increases mitochondrial biogenesis and respiration. Herein, we observed that Rg3 increased proliferation and suppressed senescence of human bone marrow-derived mesenchymal stem cells. Osteogenic, but not adipogenic, differentiation was facilitated by Rg3 treatment. Rg3 suppressed reactive oxygen species production and upregulated mitochondrial biogenesis and antioxidant enzymes, including superoxide dismutase. Consistently, Rg3 strongly augmented basal and ATP synthesis-linked respiration with high spare respiratory capacity. Rg3 treatment elevated cytosolic Ca2+ concentration contributing to mitochondrial activation. Reduction of intracellular or extracellular Ca2+ levels strongly inhibited Rg3-induced activation of mitochondrial respiration and biogenesis. Taken together, Rg3 enhances capabilities of mitochondrial and antioxidant functions mainly through a Ca2+-dependent pathway, which improves the proliferation and differentiation potentials and prevents the senescence of human mesenchymal stem cells.
Prevalence and Risk Factors of Burden Among Caregivers of Older Patients in the Emergency Department The Caregiver Burden of Acutely Presenting Older Patients
Authors: Zaalberg Tessel , Barten Dennis , Heugten Caroline van , Klijnsma Petra , Knarren Lieve , Hiemstra Ytje , Kurvers Roel , Lekx Anita , Mooijaart Simon , Janssen-Heijnen Maryska
Published: August 2020

BACKGROUND

The number of older individuals that live independently at home is rising. These older individuals often rely on caregivers who typically have a similar age and health status. Therefore, caregivers may experience a high burden. We determined the prevalence and risk factors of burden among caregivers of older patients in the emergency department (ED).
Methods

a prospective observational cohort study of primary caregivers of patients aged ≥ 70 years visiting the ED of a Dutch teaching hospital. Structured interviews were conducted with patients and their caregivers. Caregiver burden was measured using the caregiver strain index (CSI). Additionally, data from medical records were extracted to determine potential risk factors. Univariate and multivariate regression analyses were conducted to identify independent determinants for burden.
RESULTS

A primary caregiver was reported by 200 of 628 included ED patients. The mean age of patients with a caregiver was 82 (SD 6.7) years and the mean age of the caregivers was 66 (SD 12.4) years. Seventy-eight caregivers (39%) experienced a high burden. Multivariate analysis showed a significant association between high caregiver burden and patients with cognitive impairment or dependency for instrumental activities of daily living (IADL) and more self-reported hours of care per day.
CONCLUSION

Almost 40% of older patients in the ED have a caregiver who experiences a high burden. Formal assessment in the ED may help provide adequate care to the patients and their caregivers.
Stimulation-Induced Differential Redistributions of Clathrin and Clathrin-Coated Vesicles in Axons Compared to Soma/Dendrites
Authors: Tao-Cheng Jung-Hwa
Published: August 2020

Clathrin-mediated endocytosis plays an important role in the recycling of synaptic vesicle in presynaptic terminals, and in the recycling of transmitter receptors in neuronal soma/dendrites. The present study uses electron microscopy (EM) and immunogold EM to document the different categories of clathrin-coated vesicles (CCV) and pits (CCP) in axons compared to soma/dendrites, and the depolarization-induced redistribution of clathrin in these two polarized compartments of the neuron. The size of CCVs in presynaptic terminals (~40 nm; similar to the size of synaptic vesicles) is considerably smaller than the size of CCVs in soma/dendrites (~90 nm). Furthermore, neuronal stimulation induces an increase in the number of CCV/CCP in presynaptic terminals, but a decrease in soma/dendrites. Immunogold labeling of clathrin revealed that in presynaptic terminals under resting conditions, the majority of clathrin molecules are unassembled and concentrated outside of synaptic vesicle clusters. Upon depolarization with high K+, label for clathrin became scattered among de-clustered synaptic vesicles and moved closer to the presynaptic active zone. In contrast to axons, clathrin-labeled CCVs and CCPs were prominent in soma/dendrites under resting conditions, and became inconspicuous upon depolarization with high K+. Thus, EM examination suggests that the regulation and mechanism of clathrin-mediated endocytosis differ between axon and dendrite, and that clathrrin redistributes differently in these two neuronal compartments upon depolarization.
Health Surveillance Indicators: What is Available in European Data Sets for Policy Evaluation?
Authors: Stanley Isobel , Neumann-Podczaska Agnieszka , Wieczorowska-Tobis Katarzyna , Mensink Gert B.M. , Rosas Lina Garnica , Do Stefanie , Omar Karim Abu , Woods Catherine , Ahrens Wolfgang , Hebestreit Antje , Murrin Celine
Published: August 2020

Background: Policies targeting diets and physical activity have been proposed as mechanisms for the prevention and control non communicable diseases in Europe. While these actions have the potential to improve health at a population level, the impact of these policies in Europe is currently unknown. The aim of this study, as part of the wider Policy Evaluation Network, is to catalogue the data currently available for policy evaluation in Europe to inform the development of surveillance instruments. The catalogues will also provide an opportunity for key stakeholders to view the available EU indicators that can be employed to evaluate policies which influence diet, physical activity and sedentary behaviour. Methods: A suite of key indicators was agreed by PEN members and over 30 EU experts during a workshop in September 2019. Next, variables in existing EU monitoring systems were suggested by workshop participants for the measurement of each key indicator. The mapping process involved an evaluation of how suitable the suggested variables were as measures for the indicators. This was done using a Likert scale (matched, somewhat matched, less matched, not matched). Results: The suite of key indicators included both behaviour outcome indicators and upstream indicators relating to diet (n=72) and physical activity and sedentary behaviour (n=67). 72% of diet indicators and 86% of physical activity and sedentary behaviour indicators were matched to at least one variable in an existing EU monitoring system. The majority of indicator-measure pairs were categorised as ‘matched’ on the Likert scale. Conclusions: While there are gaps in the measurement of policy level indicators in domains such as inequality, funding and resources and governance, the majority of key policy indicators were mapped to measures in existing systems. Therefore, much of the data for evaluation of policies is readily available.
Day-to-Day Pattern of Work and Leisure Time Physical Behaviours: Are Low Socioeconomic Status Adults Couch Potatoes or Work Warriors?
Authors: Rasmussen Charlotte Lund , Dumuid Dorothea , Hron Karel , Gupta Nidhi , Jørgensen Marie Birk , Nabe-Nielsen Kirsten , Holtermann Andreas
Published: August 2020

BackgroundMost studies on day-to-day patterns of physical behaviours (i.e. physical activities and sedentary behaviour) are based on adult populations of high socioeconomic status (SES) and without differentiating between work and leisure time. Thus, we aimed to characterise the day-to-day leisure time physical behaviours patterns among low SES adults and investigate if a day of the week, workday, work duration, and work physical behaviours influence these leisure-time patterns.MethodsThis cross-sectional study included 1012 adults from typical low SES occupations (e.g. manufacturing, cleaning and transportation). The participants wore accelerometers for 1-7 days to measure daily physical behaviours during work and leisure time, expressed as 3-part time-use compositions consisting of time spent 1) sedentary, 2) standing or 3) being active (i.e. walking, running, stair climbing, or cycling). Multivariate multilevel log-ratio models were used to regress leisure time-use composition on day-of-week and the interaction between day-of-week and (1) type of day, (i.e., work/non-work), (3) work duration, and (4) work time-use composition. Models were adjusted for sex, age, BMI, and smoking-status. ResultsOver the course of a week, the workers were primarily sedentary during leisure time, while spending most work time standing or being active. Leisure time physical behaviours were associated with type of day (p < 0.005, more sedentary on workdays vs. non-workdays), day-of-week (p < 0.005, more sedentary on Friday, Saturday and Sunday), standing work (p < 0.005, more sedentary and less active leisure time on Sunday), active work (p < 0.005, less sedentary and more active leisure time on Sunday), and work duration (p < 0.005, less active leisure time on Friday). ConclusionsOur findings suggest that while low SES adults’ leisure time is mostly sedentary, their work time is predominantly standing or active. Leisure time was spent more sedentary on workdays compared to non-workdays, indicating that work factors influenced day-to-day leisure time behaviours. Accordingly, work physical behaviours and work duration were differently associated with leisure time physical behaviours. Our findings support the value of considering the influence of work factors when planning strategies aiming to increase health-enhancing leisure time activities among low SES adults.
Endochin-like quinolone-300 and ELQ-316 inhibit Babesia bovis, B. bigemina, B. caballi and Theileria equi
Authors: Suarez Carlos , Silva Marta G. , Bastos Reginaldo G. , Doggett J. Stone , Riscoe Michael K. , Pou Sovitj , Winter Rolf , Dodean Rozalia A. , Nilsen Aaron
Published: August 2020

Background: The most common apicomplexan parasites causing bovine babesiosis are Babesia bovis and B. bigemina, while B. caballi and Theileria equi are responsible for equine piroplasmosis. Treatment and control of these diseases are usually achieved using potentially toxic chemotherapeutics, such as imidocarb diproprionate, but drug-resistant parasites are emerging, and alternative effective and safer drugs are needed. Endochin-like quinolones (ELQ)-300 and ELQ-316 proved safe and efficacious against related apicomplexans, such as Plasmodium spp., and ELQ-316 was also effective against B. microti, without showing toxicity in mammals.Methods: Inhibitory effects of ELQ-300 and ELQ-316 were assessed on the growth of cultured B. bovis, B. bigemina, B. caballi and T. equi. Percentage of parasitized erythrocytes was measured by flow cytometry. Effect of the ELQ drugs on the viability of actively replicating horse and bovine peripheral blood mononuclear cells (PBMC) was assessed by ELISA. Results: We calculated IC50 ranging from 0.04 to 0.37 nM for ELQ-300, and from 0.002 to 0.1 nM for ELQ-316 at 72 hr among all cultured parasites tested. None of the parasites tested were able to replicate in cultures in the presence of the ELQs-300 and ELQ-316 at IC100, which range from 1.3 to 5.7 nM for ELQ-300 and from 1.0 to 6.0 nM for ELQ-316 at 72 hours. Neither ELQ-300 nor ELQ-316 altered the viability of equine and bovine PBMC at their IC100 in in vitro testing. Conclusions: ELQ-300 and ELQ-316 have a significant inhibitory activity on the main parasites responsible for bovine babesiosis and equine piroplasmosis at doses that are tolerable to host cells. These ELQ drugs may be viable candidates for developing alternative protocols for the treatment of bovine babesiosis and equine piroplasmosis.
First report on molecular identification of Eimeria sp. from captive forest musk deer
Authors: Ren Ziwei , Yu Dong , Zhao Wei , Luo Yan , Cheng Jianguo , Wang Yin , Yang Zexiao , Yao Xueping , Yang Wei , Wu Xi , Li Yimeng
Published: August 2020

Background: Forest musk deer (Moschus berezovskii) is a national first-level protected and endangered wild animals in China. The intestinal coccidiosis of captive forest musk deer is one of the most important diseases. However, few studies have been conducted to quantify Eimeria sp. infection and to identify its molecules. Thus, the objective of this study was to investigate the Eimeria sp. infection in the intestinal tract of forest musk deer in Sichuan and Shaanxi, China, and to identify the 18S rRNA gene fragment of Eimeria sp. , which provides scientific basic experimental data for the molecular epidemiological investigation and population genetic analysis of Eimeria sp. of captive forest musk deer in 7 regions.Methods: 328 faecal samples of forest musk deer were collected from 7 farms. The DNA of Eimeria sp. in the positive samples was extracted and used as template for nested PCR amplification. The 18S rRNA gene fragment was connected with the plasmid vector, and the products were introduced into Escherichia coli (DH5α). The culture bacterial solution was used as a PCR reaction template for identification.Results: In total, we collected 328 faecal samples from forest musk deer in Lixian (n=54), Maoxian (n=52), Ma’erkang (n=49), Dujiangyan (n=55), Hanyuan (n=41), Luding (n=36) and Weinan (n=41). 198 (60.37%) faecal samples were positive for Eimeria sp. We analyzed the 18S rRNA gene sequence of Eimeria sp, and determined 34 types with similarity of 90.5% ~ 100%. A phylogenetic tree constructed based on the 18S rRNA gene sequence of Eimeria sp., it was confirmed that Eimeria sp. parasitized in the intestinal tract of forest musk deer was closely related to Eimeria alabamensis from Bos taurus, Eimeria faurei from Ovis aries and Eimeria ahsata from Ovis aries.Conclusions: To our knowledge, this was the first molecular identification of Eimeria sp. in the intestinal tract of forest musk deer. The study suggested that Eimeria sp. parasitizes in the intestinal tract of forest musk deer, which is their carrier.