bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucagon-like peptide-1 (GLP-1) receptor agonists and cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of double-blind, randomized, placebo-controlled clinical trials
Authors: Qin Jing , Song Li
Published: May 2022

Background

The cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.

Methods

PubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.

Results

We included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).

Conclusion

We concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.
Late initiation of antenatal care and associated factors among pregnant women in Jimma Zone Public Hospitals, Southwest Ethiopia, 2020
Authors: Tadele Fetlework , Getachew Nigusu , Fentie Kelemu , Amdisa Demuma
Published: May 2022

Background

Late antenatal care initiation is linked to a higher risk of maternal death. Women who do not start ANC at an early stage may experience the effects of pregnancy-related health difficulties, as well as long-term health issues and pregnancy complications. Therefore, our study aimed to determine the prevalence of late initiation of antenatal care and associated factors among pregnant women in Jimma Zone public Hospitals.

Methods

A facility-based cross-sectional study design was employed in Jimma zone public hospitals from February 1 up to 30 March 2020 and 409 pregnant women were participated in the study by using a systematic random sampling method. Structured questionnaire was used to collect data that contain socio demographic variables, socio cultural variables, pregnancy related factors and predisposing factor related variables. The data was entered into EPI data version 3.1 and exported to SPSS version 20 for statistical analysis. Binary and multivariable logistic regression analysis were performed by using 95%CI and significance was declared at P < 0.05.

Result

Forty-eight percent of pregnant women were initiated their first ANC late. Primary education (AOR = 0.242; 95% CI, 0.071–0.828) and college diploma and above was (AOR = 0.142; 95% CI, 0.040- 0.511), mothers with an unplanned pregnancy (AOR = 11.290; 95%CI, 4.109–31.023), time taken to arrive the health facility greater than sixty (60) minutes (AOR = 8.285; 95% CI, 2.794–24.564) and inadequate knowledge about ANC service (AOR = 4.181; 95%CI, 1.693–10.348) were associated with late first Antenatal care initiating.

Conclusion

The prevalence of late initiation of ANC still remains a major public health concern in the study area. Level of education, unplanned pregnancy, distance from house to health facility, and lack of understanding about ANC services were all found to be significant variables in late ANC starting. As a result, healthcare workers can provide ongoing health education on the need of starting antenatal care visits early to avoid unfavorable pregnancy outcomes by considering all identified factors.
Decreasing dorsal cochlear nucleus activity ameliorates noise-induced tinnitus perception in mice
Authors: Malfatti Thawann , Ciralli Barbara , Hilscher Markus M. , Leao Richardson N. , Leao Katarina E.
Published: May 2022

Background

The dorsal cochlear nucleus (DCN) is a region known to integrate somatosensory and auditory inputs and is identified as a potential key structure in the generation of phantom sound perception, especially noise-induced tinnitus. Yet, how altered homeostatic plasticity of the DCN induces and maintains the sensation of tinnitus is not clear. Here, we chemogenetically decrease activity of a subgroup of DCN neurons, Ca2+/Calmodulin kinase 2 α (CaMKII α)-positive DCN neurons, using Gi-coupled human M4 Designer Receptors Exclusively Activated by Designer Drugs (hM4Di DREADDs), to investigate their role in noise-induced tinnitus.

Results

Mice were exposed to loud noise (9–11kHz, 90dBSPL, 1h, followed by 2h of silence), and auditory brainstem responses (ABRs) and gap prepulse inhibition of acoustic startle (GPIAS) were recorded 2 days before and 2 weeks after noise exposure to identify animals with a significantly decreased inhibition of startle, indicating tinnitus but without permanent hearing loss. Neuronal activity of CaMKII α+ neurons expressing hM4Di in the DCN was lowered by administration of clozapine-N-oxide (CNO). We found that acutely decreasing firing rate of CaMKII α+ DCN units decrease tinnitus-like responses (p = 3e −3, n = 11 mice), compared to the control group that showed no improvement in GPIAS (control virus; CaMKII α-YFP + CNO, p = 0.696, n = 7 mice). Extracellular recordings confirmed CNO to decrease unit firing frequency of CaMKII α-hM4Di+ mice and alter best frequency and tuning width of response to sound. However, these effects were not seen if CNO had been previously administered during the noise exposure (n = 6 experimental and 6 control mice).

Conclusion

We found that lowering DCN activity in mice displaying tinnitus-related behavior reduces tinnitus, but lowering DCN activity during noise exposure does not prevent noise-induced tinnitus. Our results suggest that CaMKII α-positive cells in the DCN are not crucial for tinnitus induction but play a significant role in maintaining tinnitus perception in mice.
Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs
Authors: Lorzadeh A. , Hammond C. , Wang F. , Knapp D. J. H. F. , Wong J. CH. , Zhu J. Y. A. , Cao Q. , Heravi-Moussavi A. , Carles A. , Wong M. , Sharafian Z. , Steif J. , Moksa M. , Bilenky M. , Lavoie P. M. , Eaves C. J. , Hirst M.
Published: May 2022

Background

Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription factor activity, epigenetic modifications, and changes in gene expression involved are thus complex and still poorly understood. To address this gap, we generated comprehensive reference epigenomes of 8 phenotypically defined subsets of normal human cord blood.

Results

We describe a striking contraction of H3K27me3 density in differentiated myelo-erythroid cells that resembles a punctate pattern previously ascribed to pluripotent embryonic stem cells. Phenotypically distinct progenitor cell types display a nearly identical repressive H3K27me3 signature characterized by large organized chromatin K27-modification domains that are retained by mature lymphoid cells but lost in terminally differentiated monocytes and erythroblasts. We demonstrate that inhibition of polycomb group members predicted to control large organized chromatin K27-modification domains influences lymphoid and myeloid fate decisions of primary neonatal hematopoietic progenitors in vitro. We further show that a majority of active enhancers appear in early progenitors, a subset of which are DNA hypermethylated and become hypomethylated and induced during terminal differentiation.

Conclusion

Primitive human hematopoietic cells display a unique repressive H3K27me3 signature that is retained by mature lymphoid cells but is lost in monocytes and erythroblasts. Intervention data implicate that control of this chromatin state change is a requisite part of the process whereby normal human hematopoietic progenitor cells make lymphoid and myeloid fate decisions.
Spatiotemporal analysis of highly pathogenic avian influenza (H5N1) outbreaks in poultry in Egypt (2006 to 2017)
Authors: Elsobky Yumna , El Afandi Gamal , Salama Akram , Byomi Ahmed , Omar Muhammad , Eltholth Mahmoud
Published: May 2022

Background

In Egypt, the highly pathogenic avian influenza (HPAI) subtype H5N1 is endemic and possesses a severe impact on the poultry. To provide a better understanding of the distributional characteristics of HPAI H5N1 outbreaks in Egypt, this study aimed to explore the spatiotemporal pattern and identify clusters of HPAI H5N1 outbreaks in Egypt from 2006 to 2017.

Results

The Epidemic curve (EC) was constructed through time series analysis; in which six epidemic waves (EWs) were revealed. Outbreaks mainly started in winter peaked in March and ended in summer. However, newly emerged thermostable clades (2.2.1.1 and 2.2.1.2) during the 4th EW enabled the virus to survive and cause infection in warmer months with a clear alteration in the seasonality of the epidemic cycle in the 5th EW. The endemic situation became more complicated by the emergence of new serotypes. As a result, the EC ended up without any specific pattern since the 6th EW to now. The spatial analysis showed that the highest outbreak density was recorded in the Nile Delta considering it as the ‘Hot spot’ region. By the 6th EW, the outbreak extended to include the Nile valley. From spatiotemporal cluster epidemics, clustering in the Delta was a common feature in all EWs with primary clusters consistently detected in the hot-spot region, but the location and size varied with each EW. The highest Relative Risk (RR) regions in an EW were noticed to contain the primary clusters of the next EW and were found to include stopover sites for migratory wild birds. They were in Fayoum, Dakahlia, Qalyobiya, Sharkia, Kafr_Elsheikh, Giza, Behera, Menia, and BeniSuef governorates. Transmission of HPAI H5N1 occurred from one location to another directly resulted in a series of outbreaks forming neighboring secondary clusters. The absence of geographical borders between the governorates in addition to non-restricted movements of poultry and low vaccination and surveillance coverage contributed to the wider spread of infection all over Egypt and to look like one epidemiological unit.

Conclusion

Our findings can help in better understanding of the characteristics of HPAI H5N1 outbreaks and the distribution of outbreak risk, which can be used for effective disease control strategies.

Graphical abstract
Comparative craniometric measurements of two Canid species in Egypt: the Egyptian red fox and the Egyptian Baladi dog
Authors: Mahdy Mohamed A. A. , Mohamed Walid Fathy
Published: May 2022

The Egyptian red fox (Vulpes vulpes aegyptiaca) and Egyptian Baladi dog (Canis familiaris) are two members of the Family Canidae that are widely distributed in Egypt. The skulls of different Canid species vary greatly in their size and shape; therefore, they can be used as a tool to study the evolution and evolutionary history of these animals. The craniometric measurements are crucial for species identification and determination of the specific sites for nerve blocks. The present study compared the craniometric measurements of the red fox and Baladi dog skulls by measuring 47 parameters on each skull and calculation of 8 indices. The red fox skull had significantly lower values of 41 craniometric measurements (approximately 87% of the measurements done), including skull length, width, and height, cranial length and width, palatal and mandibular length, and dental measurements. In contrast, the red fox had significantly higher values of only 3 measurements (approximately 6% of the measurements done) including the tympanic bulla measurement. While only three skull measurements did not differ significantly between the red fox and dog. Statistics revealed that domestic dog had significantly higher values of foramen magnum and palatine indices, and significantly lower value of nasal index than those of red fox. The present work reported variations in the gross and craniometric measurements of skull between the red fox and dog. The measured cranial parameters of both adult animals provide valuable information that can be used in ecological studies, comparative anatomy, and clinical veterinary sciences.
Identifying key genes and functionally enriched pathways in Th2-high asthma by weighted gene co-expression network analysis
Authors: Cao Yao , Wu Yi , Lin Li , Yang Lin , Peng Xin , Chen Lina
Published: May 2022

Background

Asthma is a chronic lung disease characterized by reversible inflammation of the airways. The imbalance of Th1/Th2 cells plays a significant role in the mechanisms of asthma. The aim of this study was to identify asthma-related key genes and functionally enriched pathways in a Th2-high group by using weighted gene coexpression network analysis (WGCNA).

Methods

The gene expression profiles of GSE4302, which included 42 asthma patients and 28 controls, were selected from the Gene Expression Omnibus (GEO). A gene network was constructed, and genes were classified into different modules using WGCNA. Gene ontology (GO) was performed to further explore the potential function of the genes in the most related module. In addition, the expression profile and diagnostic capacity (ROC curve) of hub genes of interest were verified by dataset GSE67472.

Results

In dataset GSE4302, subjects with asthma were divided into Th2-high and Th2-low groups according to the expression of the SERPINB2, POSTN and CLCA1 genes. A weighted gene coexpression network was constructed, and genes were classified into 7 modules. Among them, the red module was most closely associated with Th2-high asthma, which contained 60 genes. These genes were significantly enriched in different biological processes and molecular functions. A total of 8 hub genes (TPSB2, CPA3, ITLN1, CST1, SERPINB10, CEACAM5, CHD26 and P2RY14) were identified, and the expression levels of these genes (except TPSB2) were confirmed in dataset GSE67472. ROC curve analysis validated that the expression of these 8 genes exhibited excellent diagnostic efficiency for Th2-high asthma and Th2-low asthma.

Conclusions

The study provides a novel perspective on Th2-high asthma by WGCNA, and the hub genes and potential pathways involved may be beneficial for the diagnosis and management of Th2-high asthma.
Influence of exercise duration on respiratory function and systemic immunity among healthy, endurance-trained participants exercising in sub-zero conditions
Authors: Gavrielatos Angelos , Ratkevica Iluta , Stenfors Nikolai , Hanstock Helen G.
Published: May 2022

Background

Strenuous endurance exercise in sub-zero temperatures can cause airway damage that may lead to EIB. Prolonged exercise can also elicit greater immune perturbations than short-duration exercise. However, the influence of exercise duration on lung function and systemic immunity in sub-zero temperatures has not been established. Additionally, it is currently unknown whether atopic disposition, which is risk factor for EIB, influences respiratory responses in a sub-zero climate. The aim of this study was to compare respiratory and systemic immune responses to two cold air running trials of short and long duration, as well as to examine whether the responses differed between atopic and non-atopic subjects.

Methods

Eighteen healthy, endurance-trained subjects (males/females: 14/4; age: 29.4 ± 5.9 years old; BMI: 23.1 ± 1.7; atopic/non-atopic: 10/8) completed two moderate-intensity climate chamber running trials at − 15 °C, lasting 30 and 90 min, in a randomized, cross-over design. Lung function (spirometry and impulse oscillometry), serum CC16, respiratory symptoms, and blood leukocyte counts were examined before and after the trials.

Results

Lung function was not significantly affected by exercise or exercise duration. CC16 concentration increased after both trials (p = 0.027), but the response did not differ between trials. Respiratory symptom intensity was similar after each trial. There was a greater increase in neutrophils (p < 0.001), and a decrease in eosinophils (p < 0.001) after the 90-min bout. The 90-min protocol increased X5 compared to the 30-min protocol only in atopic subjects (p = 0.015) while atopy increased lower airway symptoms immediately after the 90-min session (p = 0.004).

Conclusions

Our results suggest that a 90-min bout of moderate-intensity exercise at − 15 °C does not cause substantial lung function decrements, airway epithelial damage or respiratory symptoms compared to 30 min running in the same environment, despite a heightened redistribution of white blood cells. However, exercise at − 15 °C may cause airway injury and evoke respiratory symptoms, even at moderate intensity. Atopic status may lead to greater peripheral bronchodilation and higher frequency of respiratory symptoms after long-duration exercise in cold.

Trial registration:01/02/2022 ISRCTN13977758. This trial was retrospectively registered upon submission to satisfy journal guidelines. The authors had not initially registered the study, as the intervention was considered to be a controlled simulation of exercise in a naturally occurring environment (i.e. sub-zero air) for healthy volunteers.
Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease
Authors: Zhan Yuan , Chen Jinkun , Wu Jixing , Gu Yiya , Huang Qian , Deng Zhesong , Chen Shanshan , Wu Xiaojie , Lv Yongman , Zeng Zhilin , Xie Jungang
Published: May 2022

Background

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by chronic inflammation and airway remodeling. Human epididymis protein 4 (HE4) plays a critical role in various inflammatory or fibrotic diseases. However, the role of HE4 in COPD remains unidentified.

Methods

HE4 expression was determined in the lung tissues from COPD patients and cigarette smoke (CS)-exposed mice using immunohistochemical staining, qPCR, or western blot. The plasma level of HE4 was detected by ELISA. The regulations of HE4 in the expressions of CS extract (CSE)-induced inflammatory cytokines in human bronchial epithelial cells (HBE) were investigated through knockdown or overexpression of HE4. The role of secretory HE4 (sHE4) in the differentiation and proliferation in human pulmonary fibroblast cells (HPF) was explored via qPCR, western blot, CCK8 assay or 5-ethynyl-2′-deoxyuridine (EdU) staining. The probe of related mechanism in CSE-induced HE4 increase in HBE was conducted by administrating N-acetylcysteine (NAC).

Results

HE4 was up-regulated in both the lung tissue and plasma of COPD patients relative to controls, and the plasma HE4 was negatively associated with lung function in COPD patients. The same enhanced HE4 expression was verified in CS-exposed mice and CSE-induced HBE, but CSE failed to increase HE4 expression in HPF. In vitro experiments showed that reducing HE4 expression in HBE alleviated CSE-induced IL-6 release while overexpressing HE4 facilitated IL-6 expression, mechanistically through affecting phosphorylation of NFκB-p65, whereas intervening HE4 expression had no distinctive influence on IL-8 secretion. Furthermore, we confirmed that sHE4 promoted fibroblast-myofibroblast transition, as indicated by promoting the expression of fibronectin, collagen I and α-SMA via phosphorylation of Smad2. EdU staining and CCK-8 assay demonstrated the pro-proliferative role of sHE4 in HPF, which was further confirmed by enhanced expression of survivin and PCNA. Pretreatment of NAC in CSE or H2O2-induced HBE mitigated HE4 expression.

Conclusions

Our study indicates that HE4 may participate in airway inflammation and remodeling of COPD. Cigarette smoke enhances HE4 expression and secretion in bronchial epithelium mediated by oxidative stress. Increased HE4 promotes IL-6 release in HBE via phosphorylation of NFκB-p65, and sHE4 promotes fibroblastic differentiation and proliferation.
Multi-omics analysis revealed TEK and AXIN2 are potential biomarkers in multifocal papillary thyroid cancer
Authors: Kim Ga Hyun , Heo Hye Jin , Kang Ji Wan , Kim Eun-Kyung , Baek Seung Eun , Kim Keunyoung , Kim In Joo , Suh Sunghwan , Lee Byung-Joo , Kim Yun Hak , Pak Kyoungjune
Published: May 2022

Background

Papillary thyroid carcinoma (PTC), the most common endocrine cancer, accounts for 80–85% of all malignant thyroid tumors. This study focused on identifying targets that affect the multifocality of PTC. In a previous study, we determined 158 mRNAs related to multifocality in BRAF-mutated PTC using The Cancer Genome Atlas.

Methods

We used multi-omics data (miRNAs and mRNAs) to identify the regulatory mechanisms of the investigated mRNAs. miRNA inhibitors were used to determine the relationship between mRNAs and miRNAs. We analyzed the target protein levels in patient sera using ELISA and immunohistochemical staining of patients’ tissues.

Results

We identified 44 miRNAs that showed a negative correlation with mRNA expression. Using in vitro experiments, we identified four miRNAs that inhibit TEK and/or AXIN2 among the target mRNAs. We also showed that the downregulation of TEK and AXIN2 decreased the proliferation and migration of BRAF ( +) PTC cells. To evaluate the diagnostic ability of multifocal PTC, we examined serum TEK or AXIN2 in unifocal and multifocal PTC patients using ELISA, and showed that the serum TEK in multifocal PTC patients was higher than that in the unifocal PTC patients. The immunohistochemical study showed higher TEK and AXIN2 expression in multifocal PTC than unifocal PTC.

Conclusions

Both TEK and AXIN2 play a potential role in the multifocality of PTC, and serum TEK may be a diagnostic marker for multifocal PTC.
Residential greenness, asthma, and lung function among children at high risk of allergic sensitization: a prospective cohort study
Authors: Hartley Kim , Ryan Patrick H. , Gillespie Gordon L. , Perazzo Joseph , Wright J. Michael , Rice Glenn E. , Donovan Geoffrey H. , Gernes Rebecca , Hershey Gurjit K. Khurana , LeMasters Grace , Brokamp Cole
Published: May 2022

Background

While benefits of greenness to health have been reported, findings specific to child respiratory health are inconsistent.

Methods

We utilized a prospective birth cohort followed from birth to age 7 years (n = 617). Residential surrounding greenness was quantified via Normalized Difference Vegetation Index (NDVI) within 200, 400, and 800 m distances from geocoded home addresses at birth, age 7 years, and across childhood. Respiratory health outcomes were assessed at age 7 years, including asthma and lung function [percent predicted forced expiratory volume in the first second (%FEV1), percent predicted forced vital capacity (%FVC), and percent predicted ratio of forced expiratory volume in the first second to forced vital capacity (%FEV1/FVC)]. We assessed associations using linear and logistic regression models adjusted for community deprivation, household income, and traffic-related air pollution. We tested for effect measure modification by atopic status.

Results

We noted evidence of positive confounding as inverse associations were attenuated upon adjustment in the multivariable models. We found evidence of effect measure modification of NDVI and asthma within 400 m at age 7 years by atopic status (p = 0.04), whereby children sensitized to common allergens were more likely to develop asthma as exposure to greenness increased (OR = 1.3, 95% CI: 0.9, 2.0) versus children not sensitized to common allergens (OR = 0.8, 95% CI: 0.5, 1.2). We found consistently positive associations between NDVI and %FEV1and %FVC which similarly evidenced positive confounding upon adjustment. In the adjusted regression models, NDVI at 7 years of age was associated with %FEV1(200 m: β = 2.1, 95% CI: 0.1, 3.3; 400 m: β = 1.6, 95% CI: 0.3, 2.9) and %FVC (200 m: β = 1.8, 95% CI: 0.7, 3.0; 400 m: β = 1.6, 95% CI: 0.3, 2.8; 800 m: β = 1.5, 95% CI: 0.1, 2.8). Adjusted results for %FEV1/FVC were non-significant except exposure at birth in the 400 m buffer (β = 0.81, 95% CI: 0.1, 1.5). We found no evidence of effect measure modification of NDVI by atopic status for objective measures of lung function.

Conclusion

Sensitivity to allergens may modify the effect of greenness on risk for asthma in children but greenness is likely beneficial for concurrent lung function regardless of allergic status.
Key early proinflammatory signaling molecules encapsulated within circulating exosomes following traumatic injury
Authors: Walsh Sarah A. , Davis Thomas A.
Published: May 2022

Background

Assessment of immune status in critically ill patients is often based on serial tracking of systemic cytokine levels and clinical laboratory values. Exosomes are extracellular vesicles that can be secreted and internalized by cells to transport important cellular cargo in the regulation of numerous physiological and pathological processes. Here, we characterize the early compartmentalization profile of key proinflammatory mediators in serum exosomes in the steady state and following trauma. Adult male Sprague-Dawley rats (91 including naïve) were divided into one of four traumatic injury model groups incorporating whole-body blast, fracture, soft-tissue crush injury, tourniquet-induced ischemia, and limb amputation. Serum was collected at 1, 3, 6, and 24 h, and 3- and 7-day post-injury. Electrochemiluminescence-based immunoassays for 9 key proinflammatory mediators in whole serum, isolated serum exosomes, and exosome depleted serum were analyzed and compared between naïve and injured rats. Serum clinical chemistry analysis was performed to determine pathological changes.

Results

In naïve animals, substantial amounts of IL-1β, IL-10, and TNF-α were encapsulated, IL-6 was completely encapsulated, and CXCL1 freely circulating. One hour after blast injury alone, levels of exosome encapsulated IFN-γ, IL-10, IL-6, IL-13, IL-4, and TNF-α increased, whereas freely circulating and membrane-associated levels remained undetectable or low. Rats with the most severe polytraumatic injuries with end organ complications had the earliest rise and most pronounced concentration of IL-1β, IL-10, TNF-α, and IL-6 across all serum compartments. Moreover, CXCL1 levels increased in relation to injury severity, but remained almost entirely freely circulating at all timepoints.

Conclusion

These findings highlight that conventional ELISA-based assessments, which detect only free circulating and exosome membrane-bound mediators, underestimate the full immunoinflammatory response to trauma. Inclusion of exosome encapsulated mediators may be a better, more accurate and clinically useful early strategy to identify, diagnose, and monitor patients at highest risk for post-traumatic inflammation-associated complications.
Tumor microenvironment-responsive BSA nanocarriers for combined chemo/chemodynamic cancer therapy
Authors: Zhang Ruiyi , Liu Teng , Li Wanzhen , Ma Zhiyuan , Pei Pei , Zhang Weiwei , Yang Kai , Tao Yugui
Published: May 2022

Tumor microenvironment (TME), characterized by high glutathione (GSH), high hydrogen peroxide (H2O2) and acidic pH levels, is favorable for the growth, invasion and metastasis of cancer cells. Taking advantage of the specific characteristics of tumors, TME-responsive GCBD NPs are designed to deliver nanoscale coordination polymers (NCPs, GA-Cu) and chemotherapy drugs (doxorubicin, DOX) based on bovine serum albumin (BSA) nanocarriers into cancer cells for combined chemodynamic therapy (CDT) and chemotherapy. In an acidic environment, GCBD NPs could release approximately 90% copper ions, which can not only consume overexpressed GSH to modulate the TME but can also react with endogenous H2O2in a Fenton-like reaction to achieve the CDT effect. Meanwhile, the released DOX could enter the nucleus of tumor cells and affect their proliferation to achieve efficient chemotherapy. Both in vitro and in vivo experiments showed that GCBD NPs had good biosafety and could effectively inhibit the growth of cancer cells. GCBD NPs are promising as a biocompatible nanoplatform to exploit TME characteristics for combined chemo and chemodynamic therapy, providing a novel strategy to eradicate tumors with high efficiency and specificity.

Graphical Abstract
Evaluation of the first two Frontline cohorts of the field epidemiology training program in Guinea, West Africa
Authors: Collins Doreen , Diallo Boubacar Ibrahima , Bah Mariama Boubacar , Bah Marlyatou , Standley Claire J. , Corvil Salomon , Martel Lise D. , MacDonald Pia D. M.
Published: May 2022

Background

The 2014–2016 Ebola virus disease outbreak in West Africa revealed weaknesses in the health systems of the three most heavily affected countries, including a shortage of public health professionals at the local level trained in surveillance and outbreak investigation. In response, the Frontline Field Epidemiology Training Program (FETP) was created by CDC in 2015 as a 3-month, accelerated training program in field epidemiology that specifically targets the district level. In Guinea, the first two FETP-Frontline cohorts were held from January to May, and from June to September 2017. Here, we report the results of a cross-sectional evaluation of these first two cohorts of FETP-Frontline in Guinea.

Methods

The evaluation was conducted in April 2018 and consisted of interviews with graduates, their supervisors, and directors of nearby health facilities, as well as direct observation of data reports and surveillance tools at health facilities. Interviews and site visits were conducted using standardized questionnaires and checklists. Qualitative data were coded under common themes and analyzed using descriptive statistics.

Results

The evaluation revealed a significant perception of improvement in all assessed skills by the graduates, as well as high levels of self-reported involvement in key activities related to data collection, analysis, and reporting. Supervisors highlighted improvements to systematic and quality case and summary reporting as key benefits of the FETP-Frontline program. At the health facility level, staff reported the training had resulted in improvements to information sharing and case notifications. Reported barriers included lack of transportation, available support personnel, and other resources. Graduates and supervisors both emphasized the importance of continued and additional training to solidify and retain skills.

Conclusions

The evaluation demonstrated a strongly positive perceived benefit of the FETP-Frontline training on the professional activities of graduates as well as the overall surveillance system. However, efforts are needed to ensure greater gender equity and to recruit more junior trainee candidates for future cohorts. Moreover, although improvements to the surveillance system were observed concurrent with the completion of the two cohorts, the evaluation was not designed to directly measure impact on surveillance or response functions. Combined with the rapid implementation of FETP-Frontline around the world, this suggests an opportunity to develop standardized evaluation toolkits, which could incorporate metrics that would directly assess the impact of equitable field epidemiology workforce development on countries’ abilities to prevent, detect, and respond to public health threats.
A systems thinking approach to understanding youth active recreation
Authors: Koorts Harriet , Salmon Paul M. , Swain Christopher T. V. , Cassar Samuel , Strickland David , Salmon Jo
Published: May 2022

Background

Active recreation contributes to child and adolescent physical activity, however, factors affecting uptake are poorly understood at the systems level. The aims of this study were: (1) to use systems analysis methods to understand youth active recreation in Victoria, Australia, (ii) identify potential system leverage points to enhance active recreation, and (iii) explore stakeholder views of systems analysis methods for informing practice and policy decision-making.

Methods

Phase 1: Umbrella review of systematic reviews (2013–2018), synthesising evidence for correlates, determinants and intervention evidence for promoting active recreation.Phase 2: Development of three systems models (ActorMap and two ActivMaps), depicting active recreation actors/organisations, correlates, determinants and intervention evidence.Phase 3: Development of causal loop diagrams (CLDs) and identification of leverage points based on the Action Scales Model.Phase 4: Model feedback via stakeholder interviews (n = 23; 16 organisations).

Results

From the literature, 93 correlates and determinants, and 49 intervention strategies were associated with child and adolescent active recreation; the majority located at a social or individual level. Ten potential system leverage points were identified in the CLDs, which differed for pre-schoolers versus children and adolescents. Only time outdoors (an event leverage point) emerged for all age groups. Changes to the built and natural environment (i.e., land use planning, urban design) as a complete domain was a key structural leverage point for influencing active recreation in children and adolescents. Subject matter experts and stakeholder interviews identified 125 actors operating across seven hierarchical active recreation system levels in Victoria. Stakeholder interviews identified 12 areas for future consideration and recommendations for practice/policy influence.

Conclusions

Our findings underscore the need for dynamic models of system behaviour in active recreation, and to capture stakeholder influence as more than a transactional role in evidence generation and use. Effective responses to youth inactivity require a network of interventions that target specific leverage points across the system. Our models illustrate areas that may have the greatest system-level impact, such as changes to the built and natural environment, and they provide a tool for policy, appraisal, advocacy, and decision-making within and outside of government.
Geographical hotspots and correlates of early sexual debut among women in Ghana
Authors: Amoako Johnson Fiifi
Published: May 2022

Objectives

Generalisation of sexual behaviour, including early sexual initiation, does not provide comprehensive knowledge of young people’s sexual attitudes, behaviours and challenges, given the high sociocultural diversity and economic inequalities within countries. This study examines geographical hotspots of early sexual initiation, at the district level in Ghana and the factors associated with the observed spatial patterns.

Methods

Data was derived from the 2017 Ghana Maternal Health Survey, covering 21,392 women aged 15–49 years. Early sexual debut denotes first sexual intercourse before attaining the legal age of sexual consent, which in Ghana, is 16 years. The Bayesian geoadditive semiparametric regression technique was used to examine geographical hotspots and correlates of the observed spatial patterns, classified into demographic, socioeconomic and pregnancy outcome factors.

Results

The results show that 26.7% (95% CI = 26.1–27.3) of women had their first sexual intercourse before attaining the age of 16 years. Hotspots of early sexual debut was observed predominantly among districts along the mainstream of the Volta Lake, which are also reported hotspots of child trafficking, labour and slavery. Demographic, socioeconomic and pregnancy related factors were identified to be correlated with the observed spatial clustering.

Conclusion

Policies and interventions such as sexual and reproductive health education should target at-risk population, simultaneously addressing other child abuses perpetuating the practice.
Effects of acute and chronic oxidative stress on the blood–brain barrier in 2D and 3D in vitro models
Authors: Chung Tracy D. , Linville Raleigh M. , Guo Zhaobin , Ye Robert , Jha Ria , Grifno Gabrielle N. , Searson Peter C.
Published: May 2022

Oxidative stress is a shared pathology of neurodegenerative disease and brain injuries, and is derived from perturbations to normal cell processes by aging or environmental factors such as UV exposure and air pollution. As oxidative cues are often present in systemic circulation, the blood–brain barrier (BBB) plays a key role in mediating the effect of these cues on brain dysfunction. Therefore, oxidative damage and disruption of the BBB is an emergent focus of neurodegenerative disease etiology and progression. We assessed barrier dysfunction in response to chronic and acute oxidative stress in 2D and 3D in vitro models of the BBB with human iPSC-derived brain microvascular endothelial-like cells (iBMECs). We first established doses of hydrogen peroxide to induce chronic damage (modeling aging and neurodegenerative disease) and acute damage (modeling the response to traumatic brain injury) by assessing barrier function via transendothelial electrical resistance in 2D iBMEC monolayers and permeability and monolayer integrity in 3D tissue-engineered iBMEC microvessels. Following application of these chronic and acute doses in our in vitro models, we found local, discrete structural changes were the most prevalent responses (rather than global barrier loss). Additionally, we validated unique functional changes in response to oxidative stress, including dysfunctional cell turnover dynamics and immune cell adhesion that were consistent with changes in gene expression.
Overexpressing Arabidopsis thaliana ACBP6 in transgenic rapid-cycling Brassica napus confers cold tolerance
Authors: Alahakoon Aruni Y. , Tongson Eden , Meng Wei , Ye Zi-Wei , Russell Derek A. , Chye Mee-Len , Golz John F. , Taylor Paul W. J.
Published: May 2022

Background

Rapid-cycling Brassica napus (B. napus-RC) has potential as a rapid trait testing system for canola (B. napus) because its life cycle is completed within 2 months while canola usually takes 4 months, and it is susceptible to the same range of diseases and abiotic stress as canola. However, a rapid trait testing system for canola requires the development of an efficient transformation and tissue culture system for B. napus-RC. Furthermore, effectiveness of this system needs to be demonstrated by showing that a particular trait can be rapidly introduced into B. napus-RC plants.

Results

An in-vitro regeneration protocol was developed for B. napus-RC using 4-day-old cotyledons as the explant. High regeneration percentages, exceeding 70%, were achieved when 1-naphthaleneacetic acid (0.10 mg/L), 6-benzylaminopurine (1.0 mg/L), gibberellic acid (0.01 mg/L) and the ethylene antagonist silver nitrate (5 mg/L) were included in the regeneration medium. An average transformation efficiency of 16.4% was obtained using Agrobacterium-mediated transformation of B. napus-RC cotyledons using Agrobacterium strain GV3101 harbouring a plasmid with an NPTII (kanamycin-selectable) marker gene and the Arabidopsis thaliana cDNA encoding ACYL-COA-BINDING PROTEIN6 (AtACBP6). Transgenic B. napus-RC overexpressing AtACBP6 displayed better tolerance to freezing/frost than the wild type, with enhanced recovery from cellular membrane damage at both vegetative and flowering stages. AtACBP6-overexpressing B. napus-RC plants also exhibited lower electrolyte leakage and improved recovery following frost treatment, resulting in higher yields than the wild type. Ovules from transgenic AtACBP6 lines were better protected from frost than those of the wild type, while the developing embryos of frost-treated AtACBP6-overexpressing plants showed less freezing injury than the wild type.

Conclusions

This study demonstrates that B. napus-RC can be successfully regenerated and transformed from cotyledon explants and has the potential to be an effective trait testing platform for canola. Additionally, AtACBP6 shows potential for enhancing cold tolerance in canola however, larger scale studies will be required to further confirm this outcome.
Barriers and facilitators of implementing interventions to improve appropriate antibiotic use in low- and middle-income countries: a systematic review based on the Consolidated Framework for Implementation Research
Authors: Wu Shishi , Tannous Elias , Haldane Victoria , Ellen Moriah E. , Wei Xiaolin
Published: May 2022

Background

Behavior change interventions that aim to improve rational antibiotic use in prescribers and users have been widely conducted in both high- and LMICs. However, currently, no review has systematically examined challenges unique to LMICs and offered insights into the underlying contextual factors that influence these interventions. We adopted an implementation research perspective to systematically synthesize the implementation barriers and facilitators in LMICs.

Methods

We conducted literature searches in five electronic databases and identified studies that involved the implementation of behavior change interventions to improve appropriate antibiotic use in prescribers and users in LMICs and reported implementation barriers and facilitators. Behavior change interventions were defined using the behavior change wheel, and the coding and synthesis of barriers and facilitators were guided by the Consolidated Framework for Implementation Research (CFIR).

Results

We identified 52 eligible studies, with the majority targeting prescribers practicing at tertiary facilities (N=39, 75%). The most commonly reported factors influencing implementation were found in the inner setting domain of the CFIR framework, particularly related to constraints in resources and the infrastructure of the facilities where interventions were implemented. Barriers related to the external policy environment (e.g., lack of national initiatives and policies on antibiotic use), and individual characteristics of target populations (e.g., reluctance to change prescribing behaviors) were also common, as well as facilitators related to intervention characteristics (e.g., embedding interventions in routine practice) and process (e.g., stakeholder engagement). We also provided insights into the interrelationships between these factors and the underlying causes contributing to the implementation challenges in LMICs.

Conclusion

We presented a comprehensive overview of the barriers and facilitators of implementing behavior change interventions to promote rational antibiotic use in LMICs. Our findings suggest that facilitating the implementation of interventions to improve rational antibiotic use needs comprehensive efforts to address challenges at policy, organizational, and implementation levels. Specific strategies include (1) strengthening political commitment to prompt mobilization of domestic resources and formulation of a sustainable national strategy on AMR, (2) improving the infrastructure of health facilities that allow prescribers to make evidence-based clinical decisions, and (3) engaging local stakeholders to improve their buy-in and facilitate contextualizing interventions.

Trial registration

PROSPERO: CRD42021252715.
30-day mortality in patients treated for brain metastases: extracranial causes dominate
Authors: Nieder Carsten , Stanisavljevic Luka , Aanes Siv Gyda , Mannsåker Bård , Haukland Ellinor Christin
Published: May 2022

Background

Established prognostic models, such as the diagnosis-specific graded prognostic assessment, were not designed to specifically address very short survival. Therefore, a brain metastases-specific 30-day mortality model may be relevant. We hypothesized that in-depth evaluation of a carefully defined cohort with short survival, arbitrarily defined as a maximum of 3 months, may provide signals and insights, which facilitate the development of a 30-day mortality model.

Methods

Retrospective analysis (2011–2021) of patients treated for brain metastases with different approaches. Risk factors for 30-day mortality from radiosurgery or other primary treatment were evaluated.

Results

The cause of death was unrelated to brain metastases in 61%. Treatment-related death (grade 5 toxicity) did not occur. Completely unexpected death was not observed, e.g. accident, suicide or sudden cardiac death. Logistic regression analysis showed 9 factors associated with 30-day mortality (each assigned 3–6 points) and a point sum was calculated for each patient. The point sum ranged from 0 (no risk factors for death within 30 days present) to 30. The results can be grouped into 3 or 4 risk categories. Eighty-three percent of patients in the highest risk group (> 16 points) died within 30 days, and none survived for more than 2 months. However, many cases of 30-day mortality (more than half) occurred in intermediate risk categories.

Conclusion

Extracranial tumor progression was the prevailing cause of 30-day mortality and few, if any deaths could be considered relatively unexpected when looking at the complete oncological picture. We were able to develop a multifactorial prediction model. However, the model’s performance was not fully satisfactory and it is not routinely applicable at this point in time, because external validation is needed to confirm our hypothesis-generating findings.
The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy
Authors: Cheng Yuan-Kai , Kuo Shih-Hsun , Yen Heng-Hsuan , Wu Jing-Hu , Chen Yu-Chieh , Huang Ming-Yii
Published: May 2022

Background

To analyze the prognostic factors associated with stage IB-IVA cervical cancer in patients who underwent concurrent chemoradiation therapy (CCRT) and to compare the clinical toxicities and dosimetric parameters of organs at risk between the different radiotherapy techniques.

Methods

This retrospective study enrolled 93 patients with stage IB-IVA cervical cancer who underwent definitive CCRT between April 2009 and December 2017. Nine patients (9.7%) received 3DCRT, 43 patients (46.2%) underwent VMAT, and 41 patients (44.1%) received tomotherapy, and all of them followed by brachytherapy using a 2D planning technique. The treatment outcomes and related prognostic factors were analyzed. We also compared the clinical toxicities and dosimetric parameters between the different techniques used for the last 30 patients.

Results

With a median follow-up of 52.0 months, the 5-year overall survival (OS), progression-free survival (PFS), locoregional recurrence–free survival (LRRFS), and distant metastases–free survival (DMFS) were analyzed. In a Cox proportional hazards regression model, pretreatment SCC Ag > 10 ng/mL was a significant prognostic factor for PFS (hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.03–4.70; P = 0.041), LRRFS (HR, 3.48; 95% CI 1.07–11.26; P = 0.038), and DMFS (HR 2.80; 95% CI 1.02–7.67; P = 0.045). Increasing the rectal volume receiving a radiation dose exceeding 30 Gy (V30 of rectum; odds ratio [OR] 1.15; 95% CI 1.10–1.30; P = 0.03) was associated with a higher possibility of ≥ Grade 2 acute radiation therapy (RT)-related diarrhea. The median rectal V30 values were 56.4%, 97.5%, and 86.5% for tomotherapy, 3-dimensional conformal radiation therapy (3DCRT), and volumetric modulated arc therapy (VMAT), respectively (P < 0.001). In addition, the chance of experiencing ≥ Grade 2 acute diarrhea were 10.0%, 66.7%, and 54.5% for tomotherapy, 3DCRT, and VMAT, respectively (P = 0.029).

Conclusions

Patients with pretreatment SCC Ag ≤ 10 ng/mL have better PFS, LRRFS, and DMFS than those with pretreatment SCC Ag > 10 ng/mL. The rectal V30 is a significant predictor of severe acute diarrhea. Tomotherapy significantly decreased the rectal V30, reducing the severity of acute RT-related diarrhea during external beam RT.

Trial registration This study was approved by the institutional review board at Kaohsiung Medical University Hospital. The registration number is KMUHIRB-E(I)-20190054 and retrospectively registered on 2019/3.