bluuebunny/crossref_metadata_2025 huggingface dataset:
Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML
Authors: Mulet-Lazaro Roger , van Herk Stanley , Erpelinck Claudia , Bindels Eric , Sanders Mathijs A. , Vermeulen Carlo , Renkens Ivo , Valk Peter , Melnick Ari M. , de Ridder Jeroen , Rehli Michael , Gebhard Claudia , Delwel Ruud , Wouters Bas J.
Published: April 2021

Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid- or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (DMs), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE was a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of 1 allele via promoter methylation and concurrent overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission along with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DMs. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.
Acquired platelet GPVI receptor dysfunction in critically ill patients with sepsis
Authors: Weiss Lukas J. , Manukjan Georgi , Pflug Annerose , Winter Nadine , Weigel Mathis , Nagler Nils , Kredel Markus , Lâm Thiên-Trí , Nieswandt Bernhard , Weismann Dirk , Schulze Harald
Published: April 2021

Glycoprotein VI (GPVI), the platelet immunoreceptor tyrosine activating motif (ITAM) receptor for collagen, plays a striking role on vascular integrity in animal models of inflammation and sepsis. Understanding ITAM-receptor signaling defects in humans suffering from sepsis may improve our understanding of the pathophysiology, especially during disease onset. In a pilot study, platelets from 15 patients with sepsis were assessed consecutively at day of admission, day 5 to 7, and the day of intensive care unit (ICU) discharge and subjected to comprehensive analyses by flow cytometry, aggregometry, and immunoblotting. Platelet function was markedly reduced in all patients. The defect was most prominent after GPVI stimulation with collagen-related peptide. In 14 of 15 patients, GPVI dysfunction was already present at time of ICU admission, considerably before the critical drop in platelet counts. Sepsis platelets failed to transduce the GPVI-mediated signal to trigger tyrosine phosphorylation of Syk kinase or LAT. GPVI deficiency was partially inducible in platelets of healthy donors through coincubation in whole blood, but not in plasma from patients with sepsis. Platelet aggregation upon GPVI stimulation increased only in those patients whose condition ameliorated. As blunted GPVI signaling occurred early at sepsis onset, this defect could be exploited as an indicator for early sepsis diagnosis, which needs to be confirmed in prospective studies.
The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL
Authors: Di Grande Alessandra , Peirs Sofie , Donovan Paul D. , Van Trimpont Maaike , Morscio Julie , Lintermans Beatrice , Reunes Lindy , Vandamme Niels , Goossens Steven , Nguyen Hien Anh , Lavie Arnon , Lock Richard B. , Prehn Jochen H. M. , Van Vlierberghe Pieter , Ní Chonghaile Triona
Published: April 2021

B-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response of luciferase-positive LOUCY cells to ABT-199 monotherapy and observed specific residual disease in the splenic microenvironment. Of note, these results were confirmed by using a primary ETP-ALL patient-derived xenograft. Splenomegaly has previously been associated with poor prognosis in diverse types of leukemia. However, the exact mechanism by which the splenic microenvironment alters responses to specific targeted therapies remains largely unexplored. We show that residual LOUCY cells isolated from the spleen microenvironment displayed reduced BCL-2 dependence, which was accompanied by decreased BCL-2 expression levels. Notably, this phenotype of reduced BCL-2 dependence could be recapitulated by using human splenic fibroblast coculture experiments and was confirmed in an in vitro chronic ABT-199 resistance model of LOUCY. Finally, single-cell RNA-sequencing was used to show that ABT-199 triggers transcriptional changes in T-cell differentiation genes in leukemic cells obtained from the spleen microenvironment. Of note, increased expression of CD1a and sCD3 was also observed in ABT199-resistant LOUCY clones, further reinforcing the idea that a more differentiated leukemic population might display decreased sensitivity toward BCL-2 inhibition. Overall, our data reveal the spleen as a site of residual disease for ABT-199 treatment in ETP-ALL and provide evidence for plasticity in T-cell differentiation as a mechanism of therapy resistance.
Electroencephalographic dynamics of etomidate‐induced loss of consciousness
Authors: Zhang Lei , Fan Shunqin , Zhang Jiawei , Fang Kun , Wang Lei , Cao Yuanyuan , Chen Lijian , Liu Xuesheng , Gu Erwei
Published: April 2021

Background

Highly structured electroencephalography (EEG) oscillations can occur in adults during etomidate-induced general anesthesia, but the link between these two phenomena is poorly understood. Therefore, in the present study, we investigated the electroencephalogram dynamics of etomidate-induced loss of consciousness (LOC) in order to understand the neurological mechanism of etomidate-induced LOC.

Methods

This study is a prospective observational study. Etomidate-induced anesthesia was performed on eligible patients undergoing elective surgery. We analyzed EEG data from 20 patients who received etomidate for the induction of general anesthesia. We used power spectra and coherence methods to process and analyze the EEG data. Our study was based on 4-channel EEG recordings.

Results

Compared with the baseline (awake period), etomidate induced an increase in power in delta, theta, alpha and beta waves during LOC. Compared with the awake period, the delta-wave (1–4 Hz), alpha-wave(8–13 Hz), and theta-wave(4–8 Hz) coherence increased significantly during LOC, while the slow-wave (< 1 Hz) coherence decreased. However, the delta wave (1.0–4.0 Hz) during etomidate-induced LOC was more coherent than during the awake period (1.86–3.17 Hz, two-group test for coherence,p < 0.001).

Conclusions

The neural circuit mechanism of etomidate-induced LOC is closely related to the induction of oscillation in delta, theta, alpha and beta waves and the enhancement of delta-wave coherence.

Trial registration

ChiCTR1800017110
Co-infection of HIV in patients with Buruli ulcer disease in Central Ghana
Authors: Amoako Yaw Ampem , Loglo Aloysius Dzigbordi , Frimpong Michael , Agbavor Bernadette , Abass Mohammed Kabiru , Amofa George , Ofori Elizabeth , Ampadu Edwin , Asiedu Kingsley , Stienstra Ymkje , Wansbrough-Jones Mark , van der Werf Tjip , Phillips Richard Odame
Published: April 2021

Background

Previous studies have reported that presence and severity of Buruli ulcer (BU) may reflect the underlying immunosuppression in HIV infected individuals by causing increased incidence of multiple, larger and ulcerated lesions. We report cases of BU-HIV coinfection and the accompanying programmatic challenges encountered in central Ghana.

Methods

Patients with PCR confirmed BU in central Ghana who were HIV positive were identified and their BU01 forms were retrieved and reviewed in further detail. A combined 16S rRNA reverse transcriptase / IS2404 qPCR assay was used to assess the Mycobacterium ulcerans load. The characteristics of coinfected patients (BU+HIV+) were compared with a group of matched controls.

Results

The prevalence of HIV in this BU cohort was 2.4% (compared to national HIV prevalence of 1.7%). Eight of 9 BU+HIV+ patients had a single lesion and ulcers were the most common lesion type. The lesions presented were predominantly category II (5/9) followed by category I lesions. The median (IQR) time to healing was 14 (8–28) weeks in the BU+HIV+ compared to 28 (12–33) weeks in the control BU+HIV− group (p = 0.360). Only one BU+HIV+ developed a paradoxical reaction at week 16 but the lesion healed completely at week 20. The median bacterial load (16SrRNA) of BU+HIV+ patients was 750 copies /ml (95% CI 0–398,000) versus 500 copies/ml (95% CI 0–126,855,500) in BU+HIV− group. Similarly, the median count using the IS2404 assay was 500 copies/ml (95% CI 0–500) for BU+HIV+ patients versus 500 copies/ml (95% CI 500–31,000) for BU+HIV− patients. BU+HIV− patients mounted a significantly higher interferon-γ response compared to the BU+HIV+ co-infected patients with respective median (range) responses of [1687(81.11–4399) pg/ml] versus [137.5(4.436–1406) pg/ml, p = 0.03]. There were challenges with the integration of HIV and BU care in this cohort.

Conclusion

The prevalence of HIV in the BU+ infected population was not significantly increased when compared to the prevalence of HIV in the general population. There was no clear relationship between BU lesion severity and HIV viral load or CD4 counts. Efforts should be made to encourage the integration of care of patients with BU-HIV coinfection.
Molecular characterization of multidrug-resistant tuberculosis against levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, and delamanid in southwest of China
Authors: Zheng Huiwen , He Wencong , Jiao Weiwei , Xia Hui , Sun Lin , Wang Shengfen , Xiao Jing , Ou Xichao , Zhao Yanlin , Shen Adong
Published: April 2021

Objectives

To explore the drug susceptibility of levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), linezolid (LZD), clofazimine (CFZ) and delamanid (DLM) against multidrug resistant tuberculosis (MDR-TB) isolates from drug resistance survey of southwest China, and to illustrate the genetic characteristics of MDR-TB isolates with acquired drug resistance.

Methods

A total of 339 strains were collected from smear-positive TB patients in the drug resistance survey of southwest China between January 2014 and December 2016. The MICs for the above mentioned drugs were determined for MDR-TB by conventional drug susceptibility testing. Genes related to drug resistance were amplified with their corresponding pairs of primers.

Results

MDR was observed in 88 (26.0%; 88/339) isolates. LFX had the highest resistance rate (50.0%; 44/88), followed by MFX (38.6%; 34/88). The resistance rate to LZD, CFZ, and DLM was 4.5% (4/88), 3.4% (3/88), and 4.5% (4/88), respectively, and the lowest resistance rate was observed in BDQ (2.3%; 2/88). Of the 45 isolates resistant to LFX and MFX, the most prevalent resistance mutation was found in gyrA with the substitution of codon 94 (34/45, 75.6%). Two strains with CFZ - BDQ cross resistance had a mutation in the Rv0678 gene. Of the four LZD resistant isolates, two carried mutations in rplC gene. For the four isolates resistant to DLM, one isolate had mutations in codon 318 of fbiC gene, and two isolates were with mutations in codon 81 of ddn gene.

Conclusion

This study provided evidence of the usefulness of new anti-TB drugs in the treatment of MDR-TB in China.
Saccharated ferric oxide attenuates haematopoietic response induced by epoetin beta pegol in patients undergoing haemodialysis
Authors: Iwasaki Takahide , Fujimori Akira , Nakanishi Takeshi , Okada Shioko , Hanawa Nobuto , Hasuike Yukiko , Kuragano Takahiro
Published: April 2021

Background

Decreased erythropoietin levels and impaired iron metabolism due to excessive hepcidin levels are responsible for renal anaemia in patients undergoing haemodialysis. Recently, erythroferrone (ERFE) has been identified as a factor that regulates hepcidin. In addition, fibroblast growth factor 23 (FGF23), which has been recognized as a phosphorus-regulating hormone, appears to be involved in haematopoietic regulation. Clarification of the detailed mechanism of haematopoiesis could lead to the improvement of renal anaemia treatment.

Methods

Epoetin beta pegol (CERA) was administered to patients undergoing haemodialysis at week 0, and the same amount of CERA with saccharated ferric oxide (SFO) was administered at week 4. The changes in haematopoiesis-related biomarkers, including ERFE, intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), and inflammatory markers, were examined.

Results

Administration of CERA increased ERFE levels, decreased hepcidin levels, and stimulated iron usage for haematopoiesis, leading to an increase in reticulocytes (Ret) and haemoglobin (Hb). Simultaneous administration of SFO with CERA (CERA + SFO) significantly attenuated the responses of ERFE, Ret, and Hb compared with CERA alone. Although iFGF23 levels were not affected by either CERA or CERA + SFO, cFGF23 was significantly elevated from baseline after CERA. Since cFGF23 levels were not affected by CERA + SFO, cFGF23 levels after CERA + SFO were significantly lower than those after CERA alone. The ratio of iFGF23 to cFGF23 (i/cFGF23 ratio) was significantly higher after CERA + SFO than that after CERA alone. In addition, high-sensitivity C-reactive protein (hsCRP) levels were significantly higher after CERA + SFO than after CERA alone.

Conclusion

Administration of SFO suppressed haematopoietic responses induced by CERA. Elevation of i/cFGF23 ratio and hsCRP could account for the inhibitory effects of SFO on haematopoiesis.

Trial registration

This study was registered with the University Hospital Medical Information Network (ID UMIN000016552).
C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival
Authors: Chu Chang , Elitok Saban , Zeng Shufei , Xiong Yingquan , Hocher Carl-Friedrich , Hasan Ahmed A. , Krämer Bernhard K. , Hocher Berthold
Published: April 2021

Background

Increased fibroblast growth factor 23 (FGF23) is a risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease. Limited data exist comparing the association of either c-terminal FGF23 (cFGF23) or intact FGF23 (iFGF23) in kidney transplant recipients (KTRs) with overall (all-cause) graft loss.

Methods

We conducted a prospective observational cohort study in 562 stable kidney transplant recipients. Patients were followed for graft loss and all-cause mortality for a median follow-up of 48 months.

Results

During a median follow-up of 48 months, 94 patients had overall graft loss (primary graft loss or death with functioning graft). Both cFGF23 and iFGF23 concentrations were significantly higher in patients with overall graft loss than those without (24.59 [11.43–87.82] versus 10.67 [5.99–22.73] pg/ml;p < 0.0001 and 45.24 [18.63–159.00] versus 29.04 [15.23–60.65] pg/ml;p = 0.002 for cFGF23 and iFGF23, respectively). Time-dependent ROC analysis showed that cFGF23 concentrations had a better discriminatory ability than iFGF23 concentrations in predicting overall (all-cause) graft loss. Cox regression analyses adjusted for risk factors showed that cFGF23 (HR for one unit increase of log transformed cFGF23: 1.35; 95% CI, 1.01–1.79;p = 0.043) but not iFGF23 (HR for one unit increase of log transformed iFGF23: 0.97; 95% CI, 0.75–1.25;p = 0.794) was associated with the overall graft loss.

Conclusion

Elevated cFGF23 concentrations at baseline are independently associated with an increased risk of overall graft loss. iFGF23 measurements were not independently associated with overall graft loss. The cFGF23 ELISA might detect bioactive FGF23 fragments that are not detected by the iFGF23 ELISA.
Increasing false positive diagnoses may lead to overestimation of stroke incidence, particularly in the young: a cross-sectional study
Authors: Appukutty Abhinav J. , Skolarus Lesli E. , Springer Mellanie V. , Meurer William J. , Burke James F.
Published: April 2021

Background

Stroke incidence is reportedly increasing in younger populations, although the reasons for this are not clear. We explored possible reasons by quantifying trends in neurologically focused emergency department (ED) visits, classification of stroke vs. TIA, and imaging use.

Methods

We performed a retrospective, serial, cross-sectional study using the National Hospital Ambulatory Medical Care Survey to examine time trends in age-stratified primary reasons for visit, stroke/TIA diagnoses, and MRI utilization from 1995 to 2000 and 2005–2015.

Results

Five million eight hundred thousand ED visits with a primary diagnosis of stroke (CI 5.3 M–6.4 M) were represented in the data. The incidence of neurologically focused reason for visits (Neuro RFVs) increased over time in both the young and in older adults (young: + 111 Neuro RFVs/100,000 population/year, CI + 94 − + 130; older adults: + 70 Neuro RFVs/100,000 population/year, CI + 34 − + 108). The proportion of combined stroke and TIA diagnoses decreased over time amongst older adults with a Neuro RFV (OR 0.95 per year, p < 0.01, CI 0.94–0.96) but did not change in the young (OR 1.00 per year, p = 0.88, CI 0.95–1.04). Within the stroke/TIA population, no changes in the proportion of stroke or TIA were identified. MRI utilization rates amongst patients with a Neuro RFV increased for both age groups.

Conclusions

We found, but did not anticipate, increased incidence of neurologically focused ED visits in both age groups. Given the lower pre-test probability of a stroke in younger adults, this suggests that false positive stroke diagnoses may be increasing and may be increasing more rapidly in the young than in older adults.
KLF5-mediated Eppk1 expression promotes cell proliferation in cervical cancer via the p38 signaling pathway
Authors: Ma Dong , Pan Zhe , Chang Quan , Zhang Jin-jin , Liu Xiao , Hua Na , Li Guo-Hua
Published: April 2021

Background

Epiplakin1 (Eppk1) is part of epidermal growth factor (EGF) signal and takes part in reorganization of cytoskeleton and cell proliferation. However, the role of Eppk1 in cervical cancer (CC) remains unknown.

Methods

To express Eppk1 and KLF5 and their correlation, we used RNA-sequence, RT-qPCR, TCGA database and immunofluorescence staining in vitro and in different pathological cervical tissues. In CC cell lines, we tested adenovirus-mediated over expression or knockdown of KLF5 and siRNA-mediated knockdown of Eppk1 and a suiting assessment of cell proliferation and cell signaling by western blot and CCK8 tests. We studied the mechanism by which KLF5 regulates Eppk1 expression by reporter gene test and chromatin immunoprecipitation test.

Results

Eppk1 expression promoted in CC tissues and cell lines compared with increased KLF5 expression. The results of immunofluorescence staining further showed the increased co-expression of Eppk1 and KLF5 correlated substantially with tumorigenesis in cervical tissues. Overexpression of KLF5 significantly increased Eppk1 expression at transcription and translation levels. Conversely, the knockdown of KLF5 by siRNA against KLF5 decreased Eppk1 expression. Mechanically, KLF5 activated Eppk1 transcription by direct binding to the Eppk1 promoter. Gain- and loss-of-function experiments reported that KLF5 promoted cell proliferation in Hela partly dependent on Eppk1 upregulation. Besides, KLF5-mediated activation of p38 signaling significantly decreased after Eppk1 knockdown compared with decline of proliferation, suggesting that Eppk1 lies upstream of p38 signaling affecting cell proliferation. Finally, Eppk1 expression is positively correlated with tumor size in clinicopathological features of CC.

Conclusions

Eppk1 may be an effective therapeutic target for affecting p38 signaling pathway and cell proliferation in cervical cancer.
POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1
Authors: Luo Ronggang , Zhuo Yi , Du Quan , Xiao Rendong
Published: April 2021

Background

To detect and investigate the expression of POU domain class 2 transcription factor 2 (POU2F2) in human lung cancer tissues, its role in lung cancer progression, and the potential mechanisms.

Methods

Immunohistochemical (IHC) assays were conducted to assess the expression of POU2F2 in human lung cancer tissues. Immunoblot assays were performed to assess the expression levels of POU2F2 in human lung cancer tissues and cell lines. CCK-8, colony formation, and transwell-migration/invasion assays were conducted to detect the effects of POU2F2 and AGO1 on the proliferaion and motility of A549 and H1299 cells in vitro. CHIP and luciferase assays were performed for the mechanism study. A tumor xenotransplantation model was used to detect the effects of POU2F2 on tumor growth in vivo.

Results

We found POU2F2 was highly expressed in human lung cancer tissues and cell lines, and associated with the lung cancer patients’ prognosis and clinical features. POU2F2 promoted the proliferation, and motility of lung cancer cells via targeting AGO1 in vitro. Additionally, POU2F2 promoted tumor growth of lung cancer cells via AGO1 in vivo.

Conclusion

We found POU2F2 was highly expressed in lung cancer cells and confirmed the involvement of POU2F2 in lung cancer progression, and thought POU2F2 could act as a potential therapeutic target for lung cancer.
Modified team-based and blended learning perception: a cohort study among medical students at King Saud University
Authors: Albarrak Ahmed I. , Zakaria Nasriah , Almulhem Jwaher , Khan Samina A. , Karim Norshahriza Abdul
Published: April 2021

Background & Objective

Medical schools have evolved toward competency-based education and active learner-centered strategies. Medical informatics course was introduced in 2011 in the 3rd year at the College of Medicine (CoM), King Saud University (KSU), to enhance future medical graduates with technological and information competencies. Modified team-based learning and blended learning were emphasized using face-to-face lectures, various e-learning technologies, workshop and seminars. The current study’s main objective was to assess students’ perceptions towards blended and modified team-based learning at the CoM in KSU.

Methods

A survey was distributed to medical students in three consecutive years: 2017–2019. The survey contains items regarding student perception of various types of blended learning techniques applied in the course. The survey was administered using i-Clicker; an interactive device that enables students to answer survey questions. Descriptive statistics were used to examine the perception of students on these blended learning dimensions investigated.

Results

Seven-hundred and one student responded to the questionnaire (male; 69.5%, female 30.5%). Out of which, 59.1% of students found team interactions positively supported discussions and asked questions freely, and 48.1% expressed that working in groups facilitated their learning process. However, 56.0% of students chose face-to-face lectures as the most preferred class activities followed by discussion 23.8%. More than 78% of participants agree that online quizzes are good experience and enjoyable. Grade center where students can check for marks and attendance also received high perception (66.3%).

Conclusion

Introducing modified team-based and blended-learning are considered challenging, and therefore, investigating their perceptions can provide useful insights into how these methods could be used more effectively. The blended-learning technique is highly essential in teaching medical informatics to overcome challenges faced due to a large number of students and the need for various exposures to reach the course’s learning goals. Moreover, it is noticed that students were engaged in face-to-face and online activities, furthermore, modified team-based learning reported facilitating learning and asking questions without embarrassment.
Stacked LSTM based deep recurrent neural network with kalman smoothing for blood glucose prediction
Authors: Rabby Md Fazle , Tu Yazhou , Hossen Md Imran , Lee Insup , Maida Anthony S. , Hei Xiali
Published: April 2021

Background

Blood glucose (BG) management is crucial for type-1 diabetes patients resulting in the necessity of reliable artificial pancreas or insulin infusion systems. In recent years, deep learning techniques have been utilized for a more accurate BG level prediction system. However, continuous glucose monitoring (CGM) readings are susceptible to sensor errors. As a result, inaccurate CGM readings would affect BG prediction and make it unreliable, even if the most optimal machine learning model is used.

Methods

In this work, we propose a novel approach to predicting blood glucose level with a stacked Long short-term memory (LSTM) based deep recurrent neural network (RNN) model considering sensor fault. We use the Kalman smoothing technique for the correction of the inaccurate CGM readings due to sensor error.

Results

For the OhioT1DM (2018) dataset, containing eight weeks’ data from six different patients, we achieve an average RMSE of 6.45 and 17.24 mg/dl for 30 min and 60 min of prediction horizon (PH), respectively.

Conclusions

To the best of our knowledge, this is the leading average prediction accuracy for the ohioT1DM dataset. Different physiological information, e.g., Kalman smoothed CGM data, carbohydrates from the meal, bolus insulin, and cumulative step counts in a fixed time interval, are crafted to represent meaningful features used as input to the model. The goal of our approach is to lower the difference between the predicted CGM values and the fingerstick blood glucose readings—the ground truth. Our results indicate that the proposed approach is feasible for more reliable BG forecasting that might improve the performance of the artificial pancreas and insulin infusion system for T1D diabetes management.
Protocol for a mixed methods exploratory investigation into the role and contribution of the healthcare assistant in out-of-hours palliative care
Authors: Hasson Felicity , McIlfatrick Sonja , Payne Sheila , Slater Paul , Finlay Dori-Anne , McConnell Tracey , Fee Anne
Published: April 2021

Background

Most people spend their last year of life at home, with many wishing to die there, but patients may need access to care after hours. Out-of-hours palliative care is delivered by multi-disciplinary teams including Health Care Assistants (HCA). However, little is known about the role, contribution and impact Health Care Assistants have on out-of-hours palliative care services. The aim of this study is to examine the Health Care Assistant role, contribution and impact on service delivery and patient care in out-of-hours community palliative care provided by hospice organisations.

Methods and analysis

A mixed methods exploratory study consisting of four phases. Phase one involves a scoping review to systematically map and identify gaps in policy and literature on the HCA role in out-of-hours palliative care. In phase two, all United Kingdom hospices will be invited to participate in an online census to enable the development of a typology of out-of-hours services and the contribution of the Health Care Assistant. During phase three organisational case studies representing different service types will collect information from Health Care Assistants, patients, caregivers and service managers to gather qualitative and quantitative data about out-of-hours service provision and the Health Care Assistant role. Finally, phase four will synthesize and refine results through online focus groups.

Ethics and dissemination

Ethical approval has been obtained for phase two through Ulster University Research Governance Filter Committee, Nursing and Health Research. Findings will be disseminated through practitioner and/or research journals, conferences, and social media.
The cost-effectiveness of Cochlear implants in Swedish adults
Authors: Gumbie Mutsa , Olin Emma , Parkinson Bonny , Bowman Ross , Cutler Henry
Published: April 2021

Background

Research has shown unilateral cochlear implants (CIs) significantly improve clinical outcomes and quality of life in adults. However, only 13% of eligible Swedish adults currently use a unilateral CI. The objective was to estimate the cost-effectiveness of unilateral CIs compared to a hearing aid for Swedish adults with severe to profound hearing loss.

Methods

A Markov model with a lifetime horizon and six-month cycle length was developed to estimate the benefits and costs of unilateral CIs from the Swedish health system perspective. A treatment pathway was developed through consultation with clinical experts to estimate resource use and costs. Unit costs were derived from the Swedish National Board of Health and Welfare and the Swedish Association of Local Authorities and Regions. Health outcomes were reported in terms of Quality Adjusted Life Years (QALYs).

Results

Unilateral CIs for Swedish adults with severe to profound hearing loss are likely to be deemed cost-effective when compared to a hearing aid (SEK 140,474 per QALY gained). The results were most sensitive to the age when patients are implanted with a CI and the proportion of patients eligible for CIs after triage.

Conclusions

An increase in the prevalence of Swedish adults with severe to profound hearing loss is expected as the population ages. Earlier implantation of unilateral CIs improves the cost-effectiveness among people eligible for CIs. Unilateral CIs are an efficacious and cost-effective option to improve hearing and quality of life in Swedish adults with severe to profound hearing loss.
Urgent care center wait times increase for COVID-19 results in August 2020, with rapid testing availability limited
Authors: Yousman Laurie C , Khunte Akshay , Hsiang Walter , Jain Siddharth , Forman Howard , Wiznia Daniel
Published: April 2021

Background

In a response to the pandemic, urgent care centers (UCCs) have gained a critical role as a common location for COVID-19 testing. We sought to characterize the changes in testing accessibility at UCCs between March and August 2020 on the basis of testing availability (including rapid antigen testing), wait time for test results, cost of visits, and cost of tests.

Methods

Data were collected using a secret shopper methodology. Researchers contacted 250 UCCs in 10 states. Investigators used a standardized script to survey centers on their COVID-19 testing availability and policies. UCCs were initially contacted in March and re-called in August. T-tests and chi-square tests were conducted to identify differences between March and August data and differences by center classification.

Results

Our results indicate that both polymerase chain reaction (PCR) tests to detect COVID-19 genetic material and rapid antigen COVID-19 tests have increased in availability. However, wait times for PCR test results have significantly increased to an average of 5.79 days. Additionally, a high proportion of UCCs continue to charge for tests and visits and no significant decrease was found in the proportion of UCCs that charge for COVID-19 testing from March to August. Further, no state reported a majority of UCCs with rapid testing available, indicating an overall lack of rapid testing.

Conclusions

From March to August, COVID-19 testing availability gradually improved. However, many barriers lie in access to COVID-19 testing, including testing costs, visit costs, and overall lack of availability of rapid testing in the majority of UCCs. Despite the passage of the CARES Act, these results suggest that there is room for additional policy to improve accessibility to testing, specifically rapid testing.
The effects of MEX3A knockdown on proliferation, apoptosis and migration of osteosarcoma cells
Authors: Wang Bangmin , Hong Zheping , Zhao Chen , Bi Qing , Yuan Junhui , Chen Jihang , Shen Yi
Published: April 2021

Background

Osteosarcoma is an aggressive malignant tumor which has attracted worldwide attention. MEX3A may be associated with tumors while has not yet seen its coverage on osteosarcoma. Herein, this study was to investigate the correlation between MEX3A and the progression of osteosarcoma.

Methods

Firstly, we determined that expression of MEX3A was significantly higher in osteosarcoma tissues than that in marginal bone by immunohistochemical staining. Additionally, MEX3A expression was downregulated by the RNAi‐mediated knockdown. The functions of MEX3A knockdown on proliferation, apoptosis, cell cycle, migration was assessed by MTT assay, flow cytometry, wound-healing assay and Transwell assay, respectively. Knockdown of MEX3A resulted in suppressing cell proliferation, increasing cell apoptosis, inducing the G2 phase cell cycle arrest, and attenuating cellular migration. Furthermore, mouse xenograft model confirmed inhibitory effects of MEX3A knockdown on osteosarcoma formation.

Results

The preliminary exploration on the molecular mechanism of MEX3A in osteosarcoma cells showed that the induction of apoptosis needs the participation of a series of apoptosis- associated factors, such as upregulation of Caspase 3, Caspase 8 and HSP60, downregulation of HSP27 and XIAP.

Conclusions

In summary, these findings predicated that therapy directed at decreasing MEX3A expression is a potential osteosarcoma treatment.
Corneal confocal microscopy differentiates inflammatory from diabetic neuropathy
Authors: Fleischer Michael , Lee Inn , Erdlenbruch Friedrich , Hinrichs Lena , Petropoulos Ioannis N. , Malik Rayaz A. , Hartung Hans-Peter , Kieseier Bernd C. , Kleinschnitz Christoph , Stettner Mark
Published: April 2021

Background

Immune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) are treatable neuropathies. Among individuals with diabetic neuropathy, it remains a challenge to identify those individuals who develop CIDP. Corneal confocal microscopy (CCM) has been shown to detect corneal nerve fiber loss and cellular infiltrates in the sub-basal layer of the cornea. The objective of the study was to determine whether CCM can distinguish diabetic neuropathy from CIDP and whether CCM can detect CIDP in persons with coexisting diabetes.

Methods

In this multicenter, case-control study, participants with CIDP (n = 55) with (n = 10) and without (n = 45) diabetes; participants with diabetes (n = 58) with (n = 28) and without (n = 30) diabetic neuropathy, and healthy controls (n = 58) underwent CCM. Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and dendritic and non-dendritic cell density, with or without nerve fiber contact were quantified.

Results

Dendritic cell density in proximity to corneal nerve fibers was significantly higher in participants with CIDP with and without diabetes compared to participants with diabetic neuropathy and controls. CNFD, CNFL, and CNBD were equally reduced in participants with CIDP, diabetic neuropathy, and CIDP with diabetes.

Conclusions

An increase in dendritic cell density identifies persons with CIDP. CCM may, therefore, be useful to differentiate inflammatory from non-inflammatory diabetic neuropathy.
Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer
Authors: Zhou Xiaoxiao , Liu Kun , Cui Jing , Xiong Jiongxin , Wu Heshui , Peng Tao , Guo Yao
Published: April 2021

Background

Pancreatic cancer is a malignant tumor and ranks the sixth in incidence among cancers. Circular RNA (circRNA) has been reported to regulate the progression of pancreatic cancer. However, the effects of circ-membrane bound O-acyltransferase domain containing 2 (circ-MBOAT2) on regulating pancreatic cancer process were unclear.

Methods

The expression levels of circ-MBOAT2, microRNA-433-3p (miR-433-3p) and glutamic-oxaloacetic transaminase 1 (GOT1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). GOT1 protein expression was determined by western blot analysis. Cell proliferation was illustrated by 3-(4,5)-dimethylthiahiazo (−z-y1)-3,5-di-phenytetrazoliumromide (MTT) and cell colony formation assay. Cell apoptosis was demonstrated by flow cytometry analysis. Cell invasion and migration were investigated by transwell invasion and wound-healing assays. Glutamine catabolism was explained by detecting glutamine consumption, alpha ketoglutarate (α-KG) production and glutamate production. In vivo assay was performed to illustrate the impacts of circ-MBOAT2 silencing on tumor formation in vivo. The binding relationship between miR-433-3p and circ-MBOAT2 or GOT1 was predicted by circinteractome or starbase online databases, and identified by dual-luciferase reporter assay.

Results

Circ-MBOAT2 and GOT1 expression were significantly upregulated, while miR-433-3p expression was downregulated in pancreatic cancer tissues and cells compared with normal pancreatic tissues or cells. Circ-MBOAT2 silencing repressed cell proliferation, migration, invasion and glutamine catabolism, whereas promoted cell apoptosis in pancreatic cancer. Additionally, circ-MBOAT2 acted as a sponge of miR-433-3p, which was found to be associate with GOT1. MiR-433-3p inhibitors hindered circ-MBOAT2 silencing-mediated impacts on pancreatic cancer progression and glutamine catabolism. Furthermore, circ-MBOAT2 silencing repressed tumor formation in vivo.

Conclusion

Circ-MBOAT2 modulated tumor development and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. This finding suggests that circ-MBOAT2 may be a therapeutic target for pancreatic cancer.
Hypoxia-dependent expression of MAP17 coordinates the Warburg effect to tumor growth in hepatocellular carcinoma
Authors: Dong Fangyuan , Li Rongkun , Wang Jiaofeng , Zhang Yan , Yao Jianfeng , Jiang Shu-Heng , Hu Xiaona , Feng Mingxuan , Bao Zhijun
Published: April 2021

Background

Reprogrammed glucose metabolism, also known as the Warburg effect, which is essential for tumor progression, is regarded as a hallmark of cancer. MAP17, a small 17-kDa non-glycosylated membrane protein, is frequently dysregulated in human cancers. However, its role in hepatocellular carcinoma (HCC) remains largely unknown.

Methods

Immunohistochemistry was used to analyze the expression pattern of MAP17 in HCC. Loss-of-function and gain-of-function studies were performed to investigate the oncogenic roles of MAP17 in vitro and in vivo. RNA sequencing, co-immunoprecipitation, immunofluorescence and western blotting were used to study the molecular mechanism of MAP17 affecting the tumor growth and glycolytic phenotype of HCC.

Results

An integrative analysis showed that MAP17, a small 17-kDa non-glycosylated membrane protein, is significantly related to the glycolytic phenotype of hepatocellular carcinoma (HCC). Firstly, we found that MAP17 expression is hypoxia-dependent and predicts a poor prognosis in HCC. Genetic silencing of MAP17 reduced the rate of glucose uptake, lactate release, extracellular acidification rate, and expression of glycolytic genes. Ectopic expression of wild type MAP17 but not its PDZ binding domain mutant MAP17-PDZm increased tumor glycolysis. Further research showed that MAP17 knockdown markedly retarded in vivo tumor growth in HCC. Importantly, attenuation of tumor glycolysis by galactose largely hijacked the growth-promoting role of MAP17 in HCC cells. RNA sequencing analysis revealed that MAP17 knockdown leads to transcriptional changes in the ROS metabolic process, cell surface receptor signaling, cell communication, mitotic cell cycle progression, and regulation of cell differentiation. Mechanistically, MAP17 exerted an increased tumoral phenotype associated with an increase in reactive oxygen species (ROS), which activates downstream effectors AKT and HIF1α to enhance the Warburg effect. In HCC clinical samples, there is a close correlation between MAP17 expression and HIF1α or phosphorated level of AKT.

Conclusions

Our results show that MAP17 is a novel glycolytic regulator, and targeting MAP17/ROS pathway may be an alternative approach for the prevention and treatment of HCC.
Correction to: A conceptual framework for contemporary professional foot care practice: “The value based digital foot care”
Authors: Deschamps Kevin , Brabants Antoine , Nester Chris , Gijon‐Nogueron Gabriel , Simşek Engin , Newton Veronica
Published: April 2021

An amendment to this paper has been published and can be accessed via the original article.
Extinction and persistence of a stochastic SIRV epidemic model with nonlinear incidence rate
Authors: Rifhat Ramziya , Teng Zhidong , Wang Chunxia
Published: April 2021

In this paper, a stochastic SIRV epidemic model with general nonlinear incidence and vaccination is investigated. The value of our study lies in two aspects. Mathematically, with the help of Lyapunov function method and stochastic analysis theory, we obtain a stochastic threshold of the model that completely determines the extinction and persistence of the epidemic. Epidemiologically, we find that random fluctuations can suppress disease outbreak, which can provide us some useful control strategies to regulate disease dynamics. In other words, neglecting random perturbations overestimates the ability of the disease to spread. The numerical simulations are given to illustrate the main theoretical results.
Combining self-reported and objectively measured survey data to improve hypertension prevalence estimates: Portuguese experience
Authors: Kislaya Irina , Leite Andreia , Perelman Julian , Machado Ausenda , Torres Ana Rita , Tolonen Hanna , Nunes Baltazar
Published: April 2021

Background

Accurate data on hypertension is essential to inform decision-making. Hypertension prevalence may be underestimated by population-based surveys due to misclassification of health status by participants. Therefore, adjustment for misclassification bias is required when relying on self-reports. This study aims to quantify misclassification bias in self-reported hypertension prevalence and prevalence ratios in the Portuguese component of the European Health Interview Survey (INS2014), and illustrate application of multiple imputation (MIME) for bias correction using measured high blood pressure data from the first Portuguese health examination survey (INSEF).

Methods

We assumed that objectively measured hypertension status was missing for INS2014 participants (n = 13,937) and imputed it using INSEF (n = 4910) as auxiliary data. Self-reported, objectively measured and MIME-corrected hypertension prevalence and prevalence ratios (PR) by sex, age group and education were estimated. Bias in self-reported and MIME-corrected estimates were computed using objectively measured INSEF data as a gold-standard.

Results

Self-reported INS2014 data underestimated hypertension prevalence in all population subgroups, with misclassification bias ranging from 5.2 to 18.6 percentage points (pp). After MIME-correction, prevalence estimates increased and became closer to objectively measured ones, with bias reduction to 0 pp - 5.7 pp. Compared to objectively measured INSEF, self-reported INS2014 data considerably underestimated prevalence ratio by sex (PR = 0.8, 95CI = [0.7, 0.9] vs. PR = 1.2, 95CI = [1.1, 1.4]). MIME successfully corrected direction of association with sex in bivariate (PR = 1.1, 95CI = [1.0, 1.3]) and multivariate analyses (PR = 1.2, 95CI = [1.0, 1.3]). Misclassification bias in hypertension prevalence ratios by education and age group were less pronounced and did not require correction in multivariate analyses.

Conclusions

Our results highlight the importance of misclassification bias analysis in self-reported hypertension. Multiple imputation is a feasible approach to adjust for misclassification bias in prevalence estimates and exposure-outcomes associations in survey data.
Youth sport participation and physical activity in rural communities
Authors: Kellstedt Debra K. , Schenkelberg Michaela A. , Essay Ann M. , Von Seggern Mary J. , Rosenkranz Richard R. , Welk Gregory J. , High Robin , Dzewaltowski David A.
Published: April 2021

Background

Physical activity, a high-frequency health behavior, varies by where children live, learn, and play. Children accumulate physical activity in adult-led in-school and out-of-school settings. Youth sport is a potential setting for physical activity, but there are differences in youth sport participation based on age, sex, and socioeconomic status. There is a gap in understanding demographic influences on youth sport participation and how these factors interact to influence physical activity. This study examines influences of grade, sex, and family income on youth sport participation and these factors and youth sport participation on moderate-to-vigorous physical activity of children in rural communities.

Methods

Children (n = 418 3rd–6th graders) living in two rural communities completed the online Youth Activity Profile as part of Wellscapes, a type 3 hybrid implementation-effectiveness community randomized trial. Mixed models with community as a random effect examined main effects and interactions of grade, sex, and family income on youth sport participation and these factors and youth sport participation on moderate-to-vigorous physical activity.

Results

About 80% of children engaged in youth sport, and full-pay lunch students were almost four times more likely to have youth sport participation than students with free/reduced lunch (OR = 3.91, 95% CI = 1.95, 7.8). Females and 6th graders (p < 0.05) had lower physical activity than comparison groups. Males with higher family income had greater physical activity; females with higher family income had less physical activity. For 6th graders, high family income had less effect on physical activity than similar 3rd-5th graders (p < 0.01).

Conclusions

While a fairly high percentage of children participate in youth sports, there are disparities in rural communities on youth sport participation and physical activity outcomes based on age, sex, and family income.