bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical outcomes of bridge-to-bridge therapy with extracorporeal left ventricular assist device for acute myocardial infarction in cardiogenic shock
Authors: Tokunaga Chiho , Iguchi Atsushi , Nakajima Hiroyuki , Chubachi Fumiya , Hori Yuto , Takazawa Akitoshi , Hayashi Jun , Asakura Toshihisa , Yoshitake Akihiro
Published: February 2022

Background

Extracorporeal left ventricular assist device is often required for acute myocardial infarction patients in cardiogenic shock when temporary mechanical circulatory support fails to provide hemodynamic stabilization. This study aimed to evaluate the clinical outcomes of acute myocardial infarction patients in cardiogenic shock supported by an extracorporeal left ventricular assist device.

Methods

This retrospective study enrolled 13 acute myocardial infarction patients in cardiogenic shock treated with an extracorporeal left ventricular assist device from April 2011 to July 2020.

Results

Twelve (92.3%) and eleven (84.6%) patients were supported using venoarterial extracorporeal membrane oxygenation and intra-aortic balloon pumping before implantation, respectively. The median duration from acute myocardial infarction to extracorporeal left ventricular assist device implantation was 7 (3.5–24.5) days. The overall in-hospital mortality rate was 30.8% (n = 4). Extracorporeal left ventricular assist device was explanted in one patient for cardiac recovery; eight (61.5%) patients were approved as heart transplant candidates in whom the extracorporeal left ventricular assist device was exchanged for a durable left ventricular assist device; two (15.4%) expired while waiting for a heart transplant, and two (15.4%) received a successful transplant. The 1- and 3-year overall survival rates after extracorporeal left ventricular assist device implantation were 68.3% and 49.9%, respectively.

Conclusions

The operative mortality after extracorporeal left ventricular assist device implantation in acute myocardial infarction patients in cardiogenic shock was favorable. Our strategy of early hemodynamic stabilization with extracorporeal left ventricular assist device implantation in these patients as a bridge-to-bridge therapy was effective in achieving better survival.
The best QT correction formula in a non-hospitalized population: the Fasa PERSIAN cohort study
Authors: Yazdanpanah Mohammad Hosein , Naghizadeh Mohammad Mehdi , Sayyadipoor Sepideh , Farjam Mojtaba
Published: February 2022

Background

QT interval as an indicator of ventricular repolarization is a clinically important parameter on an electrocardiogram (ECG). QT prolongation predisposes individuals to different ventricular arrhythmias and sudden cardiac death. The current study aimed to identify the best heart rate corrected QT interval for a non-hospitalized Iranian population based on cardiovascular mortality.

Methods

Using Fasa PERSIAN cohort study data, this study enrolled 7071 subjects aged 35–70 years. Corrected QT intervals (QTc) were calculated by the QT interval measured by Cardiax® software from ECGs and 6 different correction formulas (Bazett, Fridericia, Dmitrienko, Framingham, Hodges, and Rautaharju). Mortality status was checked using an annual telephone-based follow-up and a minimum 3-year follow-up for each participant. Bland–Altman, QTc/RR regression, sensitivity analysis, and Cox regression were performed in IBM SPSS Statistics v23 to find the best QT. Also, for calculating the upper and lower limits of normal of different QT correction formulas, 3952 healthy subjects were selected.

Results

In this study, 56.4% of participants were female, and the mean age was 48.60 ± 9.35 years. Age, heart rate in females, and QT interval in males were significantly higher. The smallest slopes of QTc/RR analysis were related to Fridericia in males and Rautaharju followed by Fridericia in females. Thus, Fridericia’s formula was identified as the best mathematical formula and Bazett’s as the worst in males. In the sensitivity analysis, however, Bazett’s formula had the highest sensitivity (23.07%) among all others in cardiac mortality. Also, in the Cox regression analysis, Bazett’s formula was better than Fridericia’s and was identified as the best significant cardiac mortality predictor (Hazard ratio: 4.31, 95% CI 1.73–10.74,pvalue = 0.002).

Conclusion

Fridericia was the best correction formula based on mathematical methods. Bazett’s formula despite its poorest performance in mathematical methods, was the best one for cardiac mortality prediction. Practically, it is suggested that physicians use QTcB for a better evaluation of cardiac mortality risk. However, in population-based studies, QTcFri might be the one to be used by researchers.
Implantable device measured objective daily physical activity as a predictor of long-term all-cause mortality and cardiac death in patients with age > 75 years and high risk of sudden cardiac death: a cohort study
Authors: Li Xiaoyao , Chen Keping , Hua Wei , Su Yangang , Yang Jiefu , Liang Zhaoguang , Xu Wei , Zhao Shuang , Li Zeyi , Zhang Shu
Published: February 2022

Background

To study the relationship between objective daily physical activity (PA), as measured by implantable cardioverter defibrillators (ICDs)/cardiac resynchronization therapy defibrillators (CRTDs), and long-term prognoses in patients with age > 75 years at high risk of sudden cardiac death (SCD).

Methods

In total, 133 patients with age > 75 years old (age 79.52 ± 3.68 years) in the SUMMIT study were retrospectively analysed. The major endpoint was all-cause mortality, and the minor endpoint was cardiac death.

Results

The mean follow-up time was 57.1 ± 24.2 months (range: from 4 to 96 months). In total, 46 all-cause mortality and 23 cardiac death events occurred. The receiver operating characteristic curve indicated a baseline PA cut-off value of 6.47% (93 min/day) can predict all-cause mortality in patients with age > 75 years, with an area under the curve of 0.670 (95% confidence interval (CI): 0.573–0.767, P = 0.001). The sensitivity was 67.4%, and the specificity was 66.7%. Patients with baseline PA ≤ 6.47% had higher rates of all-cause mortality (51.7% vs 20.5%, P < 0.001) and cardiac death (25.0% vs 11.0%, P = 0.040). The estimated Kaplan-Meier survival curves showed that patients with PA ≤ 6.47% had an increased cumulative incidence of all-cause mortality (Log-rank P < 0.0001) and cardiac death (Log-rank P = 0.0067). Multivariate Cox regression analysis showed that PA ≤ 6.47% was an independent predictor of all-cause mortality (hazard ratio (HR) 3.137, 95% CI: 1.667–5.904, P < 0.001) and cardiac death (HR value 3.345, 95% CI: 1.394–8.028, P = 0.007).

Conclusions

Daily PA of about 1.5 h was associated with lower all-cause mortality and cardiac death risk in patients with age > 75 years and high risk of SCD with ICDs/CRTDs. PA monitoring may aid in long-term management of older patients at high risk of SCD.
Efficacy and safety of Androgen Deprivation Therapy (ADT) combined with modified docetaxel chemotherapy versus ADT combined with standard docetaxel chemotherapy in patients with metastatic castration-resistant prostate cancer: study protocol for a multicentre prospective randomized controlled trial
Authors: Yang Xiangwei , Chen Hong , Xu Duanya , Chen Xianju , Li Yamei , Tian Jun , Wang Dongwen , Pang Jun
Published: February 2022

Background

Androgen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen.

Methods

This is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life.

Discussion

The expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance.

Trial registration

chictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study.
Bilateral blindness after uneventful brolucizumab injection for macular degeneration
Authors: Barchichat Ilan , Thiel Michael , Job Oliver , Schmid Martin
Published: February 2022

Background

We report a very severe case of bilateral panuveitis and ischemic vasculitis with possible perineural inflammation, which followed bilateral intravitreal brolucizumab administration in a patient with neovascular age-related macular degeneration (nAMD).

Case presentation

On December 11, 2020, a 81-year-old woman presented with severe bilateral loss of vision. Eight days earlier, she had received uneventful bilateral injection of brolucizumab, a novel anti-vascular endothelial growth factor (VEGF) single-chain variable region (scFv) recombinant protein drug, for treatment of neovascular age-related macular degeneration (nAMD).

Slit-lamp examination revealed signs of a bilateral panocular vasculitis with ischemia. Scanning laser ophthalmoscopy of her left eye revealed marked vascular sheathing.

T1 fat-saturated post-contrast images of the orbit revealed a higher-than-normal signal of the choroid, with localized choroidal detachment. Additionally, pathologic enhancement was visible around the optic nerve in the orbit, which was interpreted as vasculitis. Due to the severe bilateral panuveitis with vasculitis, an additional vitreous tap was obtained, which revealed elevated levels of interleukin six and interleukin ten.

Conclusions

To our knowledge, this is the first documented case showing both panuveitis and ischemic vasculitis with possible perineural inflammation. We do not recommend performing bilateral brolucizumab injections until more data is available regarding the mechanism of brolucizumab-induced vasculitis. From a clinical point of view, we find it difficult to justify the use of brolucizumab when there are other well-known agents, such as ranibizumab and aflibercept, which have better safety profiles and comparable efficacy.
Stillbirth trends by maternal sociodemographic characteristics among a large internal migrant population in Shenzhen, China, over a 10-year period: a retrospective study
Authors: Ma Rui , Zou Lingyun
Published: February 2022

Background

Cities such as Shenzhen in southern China have large immigrant populations, and the reproductive health issues of pregnant women in these populations have not received sufficient attention. Stillbirth seriously threatens their health and is becoming a social issue worthy of attention. We conducted this study to estimate the trend in stillbirths at 28 or more gestational weeks and the related sociodemographic characteristics of pregnant women among a large internal migrant population in South China.

Methods

A stillbirth is defined as a baby born with no signs of life after a given threshold, and are restricted to births of 28 weeks of gestation or longer, with a birth weight of at least 1000 g for international comparison. A population-based retrospective cohort of all births from January 2010 to December 2019 in Baoan, Shenzhen, was conducted using the Shenzhen Birth Registry Database. The overall stillbirth rate and year-specific stillbirth rate were calculated as the number of foetal deaths ≥28 gestational weeks or a birth weight ≥ 1000 g divided by the number of births over the last decade or in each year, respectively. The associations between the risk of stillbirth and maternal sociodemographic status were assessed using logistic regression. Spearman’s rank correlation was calculated to evaluate the correlation between the economic status of the maternal birthplace and the stillbirth.

Results

An overall stillbirth rate of 4.5 per 1000 births was estimated in a total of 492,184 births in our final analysis. Migrant women accounted for 87% of the total population but had a higher stillbirth rate (4.8 per 1000 births) than the permanent population (2.8 per 1000 births). The stillbirth rate varied by region of maternal birthplace, from 4.1 per 1000 births in women from East China to 5.7 per 1000 births in women from West China. The GDP per capita of the maternal birthplace was strongly correlated with the stillbirth rate.

Conclusions

Large disparities in the stillbirth rate exist between migrant and permanent populations and among regions of maternal birthplace in China. Strategies targeting migrant women based on their maternal birthplace are needed to further reduce the burden of stillbirth.
Exploring the potential of a school-based online health and wellbeing screening tool: professional stakeholders’ perspectives and experiences
Authors: Woodrow Nicholas , Fairbrother Hannah , Breheny Katie , d’Apice Katrina , Albers Patricia N , Mills Clare , Curtis Matthew , Hopkins Lisa , Tebbett Sarah , Campbell Rona , De Vocht Frank
Published: February 2022

Background

Supporting children and young people’s (CYP) mental and physical health is a global policy priority but detecting need and facilitating access to health services and support is challenging. This paper explores professional stakeholders’ perspectives of the acceptability, utility and effectiveness of a school-based online health and wellbeing screening tool, the Digital Health Contact (DHC). The DHC, delivered by Public Health School Nurses (PHSN), aims to identify, and put in place strategies to support, unmet health needs among CYP.

Methods

We employed a qualitative study design, using semi-structured interviews. Fourteen key stakeholders involved in the design and implementation of the DHC (commissioners, providers, PHSN and healthcare staff, school leaders) were purposively sampled. Data were analysed thematically.

Results

Our analysis generated two key themes: the perceived benefits of the DHC; and challenges in delivering the DHC. Stakeholders perceived the universal application of the DHC with linked follow-up intervention as an effective means of identifying and supporting CYP with unmet needs, and an efficient way to target limited service resources. There were barriers around enabling school engagement in the DHC, typically in terms of logistics, school infrastructure, and perspectives of fit with schools. These barriers were seen as being negated through developing effective working relationships between schools and PHSN. Effective relationships could highlight the potential benefits of participation. Overall, the DHC was seen as a valuable and effective use of resources, with a low burden on school staff.

Conclusions

The DHC, as a universal school-based health and wellbeing screening tool with linked follow-up intervention, has great potential in identifying and supporting unmet health needs among CYP. The perspectives and experiences of those involved in delivering the DHC highlight important considerations which may enable effective implementation and delivery of school screening programmes across other areas.
Comparison of retention and fracture load of endocrowns made from zirconia and zirconium lithium silicate after aging: an in vitro study
Authors: Sahebi Majid , Ghodsi Safoura , Berahman Parsia , Amini Amirhesam , Zeighami Somayeh
Published: February 2022

Background

This study aimed to compare retention and fracture load in endocrowns made from translucent zirconia and zirconium lithium silicate.

Methods

Fifty-six intact human maxillary molars after being mounted in acrylic resin, were scanned to acquire biogeneric copies. Specimens underwent standard endodontic treatment and were prepared for endocrown up to 2 mm above the cementoenamel junction. The specimens were randomly divided into two groups of 28, and endocrowns were designed using biogeneric copies and milled from high-translucent zirconia disks (Zr) and zirconium lithium silicate blocks (ZLS). After cementation with dual-cure resin cement, all the specimens underwent thermomechanical aging, and pull-out retention test and compressive test were conducted (14 specimens were used for each test in each group, n = 14), and failure modes in both tests were evaluated.

Results

Independent samples t-test showed significant difference between the retention of Zr (271.5 N ± 114.31) and ZLS (654.67 N ± 223.17) groups (p value = 0.012). Compressive test results were also significantly different between Zr (7395.07 N ± 1947.42) and ZLS (1618.3 N ± 585) (p = 0.002). Failure mode of retention test was primarily adhesive failure at the cement-restoration interface in Zr group and cement-tooth interface in ZLS group. Failure modes of fracture test for Zr group were 7 non-restorable fractures and one restorable fracture while 6 specimens resisted compressive loads up to 8500 N without fracture. ZLS group showed 7 restorable and 7 non-restorable failures.

Conclusions

Zr endocrowns showed significantly lower retention and higher fracture strength. Both materials seem to be suitable for fabrication of endocrown in clinical setup.
A care coordinator screening strategy to address health harming legal needs
Authors: Berg Daniel , Setrini Alice , Chan Kathy , Cibulskis Ann , Ameji Kulsum , Hinami Keiki
Published: February 2022

Background

Medical legal partnerships provide an opportunity to help address various social determinants of health; however, the traditional practice of screening patients during clinical encounters is limited by the capacity of busy clinicians. Our medical legal partnership utilized care coordinators trained by the legal service attorneys to screen patients outside of clinical encounters for health harming legal needs. The goal of our study was to demonstrate that our novel model could successfully identify and refer patients of a safety-net healthcare system to appropriate legal services.

Methods

We conducted a mixed methods evaluation of the program. Data was collected during the implementation period of the program from March 2017 to August 2018. Operational data collected included number of patients screened, number of referrals to the legal partner, source and reason for referrals. Return on investment was calculated by subtracting program costs from the total reimbursement to the health system from clients’ insurance benefits secured through legal services.

Results

During the 18-month study, 29,268 patients were screened by care coordinators for health harming legal needs, with 492 patients (1.7%) referred for legal assistance. Of the 133 cases closed in 2017, all clients were invited to participate in a telephone interview; 63 pre-consented to contact, 33 were successfully contacted and 23 completed the interview. The majority (57%) reported a satisfactory resolution of their legal barrier to health. This was accompanied by an improvement in self-reported health with a decrease of patients reporting less than optimal health from 16 (89%) prior to intervention to 8 (44%) after intervention [risk ratio (95% confidence interval): 0.20 (0.04, 0.91)]. Patients also reported improvements in general well-being for themselves and their family. The healthcare system recorded a 263% return on investment.

Conclusions

In our medical legal partnership, screening for health harming legal needs by care coordinators outside of a clinical encounter allowed for efficient screening in a high risk population. The legal services intervention was associated with improvements in self-reported health and family well-being when compared to previous models. The return on investment was substantial.
Drug therapy-related problem management in Nigeria community pharmacy – process evaluation with simulated patient
Authors: Segun Showande Johnson , Damilola Lawal Sodiq
Published: February 2022

Background

Unresolved drug therapy-related problems (DTRPs) have economic and clinical consequences and are common causes of patients’ morbidity and mortality. This study evaluated the ability of community pharmacists to identify and resolve DTRPs and assessed the perceived barriers to DTRP identification and resolution.

Methods

A cross-sectional study which employed the use of three simulated patients (SPs) visit to 36 selected community pharmacies in 11 local government areas in Ibadan, Nigeria. The SPs played the role of a patient with prescription for multiple ailments (23-year-old male), type 2 diabetes and hypertensive patient with medication packs (45-year-old male) and hypertensive patient with gastric ulcer with a prescription (37-year-old female). They re-enacted three rehearsed vignettes when they spoke with the pharmacists. A five-member panel of experts predetermined the DTRPs present in the vignettes (n = 11), actions to take to investigate the DTRPs (n = 9) and recommendations to resolve the DTRPs (n = 9). Pharmacists’ perceived barriers to the identification and resolution of DTRPs were assessed with a self-administered questionnaire. The percentage ability to detect and resolve DTRPs was determined and classified as poor ability (≤30%), fair ability (> 30 - ≤50%), moderate ability (> 50 - ≤70%) and high ability (> 70%).

Results

One hundred and eight visits were made by the three SPs to the pharmacies. In total, 4.42/11 (40.2%) DTRPs were identified, 3.50/9 (38.9%) actions were taken, and 3.94/9 (43.8%) recommendations were made to resolve the identified DTRPs. The percentage ability of the community pharmacists to detect and resolve DTRPs varied slightly from one vignette to another (vignette 1–49.3%, vignette 2–39.1%, vignette 3–38.8%). But overall, it was fair (40.9%). Pharmacists’ perceived barriers to DTRP detection and resolution included lack of access to patient’s/client’s medical history and lack of software for DTRP detection.

Conclusions

The community pharmacists displayed fair ability in detecting and resolving DTRPs. Several barriers preventing the optimal performance of pharmacist in DTRP identification and resolution were identified including inaccessibility of patient’s/client’s medical history. The regulatory authority of pharmacy education and practice in Nigeria need to mount Continuing Education Program to address this deficit among community pharmacists.
Functional genomics elucidates regulatory mechanisms of Parkinson’s disease-associated variants
Authors: Chen Rui , Liu Jiewei , Li Shiwu , Li Xiaoyan , Huo Yongxia , Yao Yong-Gang , Xiao Xiao , Li Ming , Luo Xiong-Jian
Published: February 2022

Background

Genome-wide association studies (GWASs) have identified multiple risk loci for Parkinson’s disease (PD). However, identifying the functional (or potential causal) variants in the reported risk loci and elucidating their roles in PD pathogenesis remain major challenges. To identify the potential causal (or functional) variants in the reported PD risk loci and to elucidate their regulatory mechanisms, we report a functional genomics study of PD.

Methods

We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) (from neuronal cells and human brain tissues) data and GWAS-identified single-nucleotide polymorphisms (SNPs) in PD risk loci. We then conducted a series of experiments and analyses to validate the regulatory effects of these (i.e., functional) SNPs, including reporter gene assays, allele-specific expression (ASE), transcription factor (TF) knockdown, CRISPR-Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis.

Results

We identified 44 SNPs (from 11 risk loci) affecting the binding of 12 TFs and we validated the regulatory effects of 15 TF binding-disrupting SNPs. In addition, we also identified the potential target genes regulated by these TF binding-disrupting SNPs through eQTL analysis. Finally, we showed that 4 eQTL genes of these TF binding-disrupting SNPs were dysregulated in PD cases compared with controls.

Conclusion

Our study systematically reveals the gene regulatory mechanisms of PD risk variants (including widespread disruption of CTCF binding), generates the landscape of potential PD causal variants, and pinpoints promising candidate genes for further functional characterization and drug development.
Comprehensive pan-cancer analysis on CBX3 as a prognostic and immunological biomarker
Authors: Niu Hongjuan , Chen Peiqiong , Fan Lu , Sun Boyu
Published: February 2022

Background

Increased evidence supports the relationship between chromobox protein homolog 3 (CBX3) and tumorigenesis of some cancers. However, the role of CBX3 in pan-cancers remains poorly defined. In the research, we aimed to investigate the prognostic value and the immunological functions of CBX3.

Results

We explored the potential oncogenic roles of CBX3 in mRNA and protein levels based on the diverse databases, including the expression, the correlation with prognosis, tumor microenvironment (TME), DNA methylation, protein phosphorylation and enrichment analysis across all TCGA tumors. The results show that CBX3 is overexpressed in multiple cancers, and significant correlations exist between high expression and adverse prognosis in most tumor patients. We observed an enhanced phosphorylation level in uterine corpus endometrial carcinoma, colon cancer and lung adenocarcinoma. A distinct relationship was also found between CBX3 expression and TME, including immune infiltration of tumor-infiltrating lymphocytes and cancer-associated fibroblasts, immune score or matrix score, immune checkpoints. The correlative transcription factors and miRNAs of CBX3-binding hub genes were analyzed to investigate the molecular mechanism. Moreover, alcoholism and alteration of DNA cellular biology may be involved in the functional mechanisms of CBX3.

Conclusion

The first pan-cancer study offers a relatively comprehensive cognition on the oncogenic roles of CBX3 as a prognostic and immunological marker in various malignant tumors.
Nifuroxazide ameliorates pulmonary fibrosis by blocking myofibroblast genesis: a drug repurposing study
Authors: Gan Cailing , Zhang Qianyu , Liu Hongyao , Wang Guan , Wang Liqun , Li Yali , Tan Zui , Yin Wenya , Yao Yuqin , Xie Yongmei , Ouyang Liang , Yu Luoting , Ye Tinghong
Published: February 2022

Background

Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease with a complex pathogenesis and high mortality. The development of new drugs is time-consuming and laborious; therefore, research on the new use of old drugs can save time and clinical costs and even avoid serious side effects. Nifuroxazide (NIF) was originally used to treat diarrhoea, but more recently, it has been found to have additional pharmacological effects, such as anti-tumour effects and inhibition of inflammatory diseases related to diabetic nephropathy. However, there are no reports regarding its role in pulmonary fibrosis.

Methods

The therapeutic effect of NIF on pulmonary fibrosis in vivo was measured by ELISA, hydroxyproline content, H&E and Masson staining, immunohistochemistry (IHC) and western blot. Immune cell content in lung tissue was also analysed by flow cytometry. NIF cytotoxicity was evaluated in NIH/3T3 cells, human pulmonary fibroblasts (HPFs), A549 cells and rat primary lung fibroblasts (RPLFs) using the MTT assay. Finally, an in vitro cell model created by transforming growth factor-β1 (TGF-β1) stimulation was assessed using different experiments (immunofluorescence, western blot and wound migration assay) to evaluate the effects of NIF on the activation of NIH/3T3 and HPF cells and the epithelial-mesenchymal transition (EMT) and migration of A549 cells.

Results

In vivo, intraperitoneal injection of NIF relieved and reversed pulmonary fibrosis caused by bleomycin (BLM) bronchial instillation. In addition, NIF inhibited the expression of a variety of cellular inflammatory factors and immune cells. Furthermore, NIF suppressed the activation of fibroblasts and EMT of epithelial cells induced by TGF-β1. Most importantly, we used an analytical docking experiment and thermal shift assay to further verify that NIF functions in conjunction with signal transducer and activator of transcription 3 (Stat3). Moreover, NIF inhibited the TGF-β/Smad pathway in vitro and decreased the expression of phosphorylated Stat3 in vitro and in vivo.

Conclusion

Taken together, we conclude that NIF inhibits and reverses pulmonary fibrosis, and these results support NIF as a viable therapeutic option for IPF treatment.

Graphic Abstract
Overexpression of CBS/H2S inhibits proliferation and metastasis of colon cancer cells through downregulation of CD44
Authors: Zhang Yuyang , Chen Shanwen , Zhu Jing , Guo Shihao , Yue Taohua , Xu Hao , Hu Jianwen , Huang Zhihao , Chen Zeyang , Wang Pengyuan , Liu Yucun
Published: February 2022

Background

The role of hydrogen sulfide (H2S) in cancer biology is controversial, including colorectal cancer. The bell-shaped effect of H2S refers to pro-cancer action at lower doses and anti-cancer effect at higher concentrations. We hypothesized that overexpression of cystathionine-beta-synthase (CBS)/H2S exerts an inhibitory effect on colon cancer cell proliferation and metastasis.

Methods

Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8), clone-formation and sphere formation assay. Cell migration was evaluated by transwell migration assay. Intracellular H2S was detected by H2S probe. Chromatin immunoprecipitation (ChIP) analysis was carried out to examine DNA–protein interaction. Cell experiments also included western blotting, flow cytometry, immunohistochemistry (IHC) and immunofluorescence analysis. We further conducted in vivo experiments to confirm our conclusions.

Results

Overexpression of CBS and exogenous H2S inhibited colon cancer cell proliferation and migration in vitro. In addition, overexpression of CBS attenuated tumor growth and liver metastasis in vivo. Furthermore, CD44 and the transcription factor SP-1 was probably involved in the inhibitory effect of CBS/H2S axis on colon cancer cells.

Conclusions

Overexpression of CBS and exogenous provision of H2S inhibited colon cancer cell proliferation and migration both in vivo and in vitro. Molecular mechanisms might involve the participation of CD44 and the transcription factor SP-1.
Similarly efficacious anti-malarial drugs SJ733 and pyronaridine differ in their ability to remove circulating parasites in mice
Authors: SheelaNair Arya , Romanczuk Aleksandra S. , Aogo Rosemary A. , Haldar Rohit Nemai , Lansink Lianne I. M. , Cromer Deborah , Salinas Yandira G. , Guy R. Kiplin , McCarthy James S. , Davenport Miles P. , Haque Ashraful , Khoury David S.
Published: February 2022

Background

Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the “parasite clearance curve”, has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation.

Methods

In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine were compared against sodium artesunate in mice infected with Plasmodium berghei (strain ANKA). To measure each compound’s capacity for pRBC removal in vivo, flow cytometric monitoring of a single cohort of fluorescently-labelled pRBC was employed, and combined with ex vivo parasite culture to assess parasite maturation and replication.

Results

These three compounds were found to be similarly efficacious in controlling established infection by reducing overall parasitaemia. While sodium artesunate acted relatively consistently across the life-stages, single-dose SJ733 elicited a biphasic effect, triggering rapid, partly phagocyte-dependent removal of trophozoites and schizonts, followed by arrest of residual ring-stages. In contrast, pyronaridine abrogated maturation of younger parasites, with less pronounced effects on mature parasites, while modestly increasing pRBC removal.

Conclusions

Anti-malarials SJ733 and pyronaridine, though similarly efficacious in reducing overall parasitaemia in mice, differed markedly in their capacity to arrest replication and remove pRBC from circulation. Thus, similar parasite clearance curves can result for anti-malarials with distinct capacities to inhibit, kill and clear parasites.
Correlation of cholesteryl ester metabolism to pathogenesis, progression and disparities in colorectal Cancer
Authors: Liu Zhirong , Gomez Christian R. , Espinoza Ingrid , Le Thuy Phuong T. , Shenoy Veena , Zhou Xinchun
Published: February 2022

Background

Colorectal cancer (CRC) is one of the most common cancers worldwide characterized by disparities in age, gender, race and anatomic sites. The mechanism underlying pathogenesis, progression and disparities of CRC remains unclear. This study aims to reveal the association of expression levels of enzymes related to cholesteryl ester (CE) metabolism with pathogenesis, progression and disparities of CRC.

Methods

The differences in gene expression levels were analyzed for enzymes in CE synthesis (acyl CoA: cholesterol acyltransferase 1 and 2, ACAT1, and ACAT2), and in CE hydrolysis (neutral cholesterol ester hydrolase, NCEH1 and lysosomal acid lipase, LAL) on TNMplot platform between CRC and normal colorectal tissues (NCT) in a large cohort. The differences in protein expression levels for these enzymes were determined by Immunochemistry (IHC) performed on tissue microarray containing 96 pairs of CRC and benign colorectal tissues (BCT) from different patient populations. The expression level represented as IHC score of each enzyme was compared between CRC and BCT in entire population and populations stratified by race, gender and anatomic sites. Student’s t-test, Fisher exact test and ANOVA were used for data analysis. Significant p value was set at P<0.05.

Results

The gene expression level of ACAT1 was significantly lower in CRC than in NCT (P = 2.15e-119). The gene expression level of ACAT2 was not statistically different between CRC and NCT. The gene expression level of LIPA (encoding LAL) was significantly higher in CRC than in NCT (P = 2.01e-14). No data was found for the gene expression level of NCEH1. The IHC score of ACAT1was significantly lower in CRC than in BCT in all studied populations and in sub site of colon, but not in that of rectum. The IHC score of ACAT2 was not statistically different between CRC and BCT. IHC score of NCEH1 was significantly higher in CRC than in BCT only in African American (AA) population. The IHC score of LAL was significantly higher in CRC than in BCT in all studied populations and in all sub sites. In addition, decreased ACAT1 in CRC significantly correlated to progression of CRC: the lower IHC score of ACAT1, the more advanced clinical stage of CRC will be.

Conclusions

This study revealed that altered expression levels in enzymes related to CE metabolism highly correlate to the pathogenesis, clinical progression and disparities of CRC. The results will add revenue in elucidating mechanisms underlying progression of CRC, and shed light on seeking biomarkers and exploring therapeutic targets for CRC in a new direction.
Assessing the psychometric properties of the Chinese return-to-work self-efficacy questionnaire using Rasch model analysis
Authors: Liu Feng , Zhang Zhenxiang , Lin Beilei , Ping Zhiguang , Mei Yongxia
Published: February 2022

Background

Self-efficacy is a significant predictor of return to work and affects the confidence of survivors to return to work after illness. The Return-to-work self-efficacy (RTW-SE) questionnaire is a self-report questionnaire to assess confidence in returning to work with good reliability and validity. The aim of this study was to translate and cross-culturally adapt the RTW-SE questionnaire into Chinese and examine the psychometric properties among young and middle-aged stroke survivors using Rasch model analysis.

Methods

The cross-cultural adaptation and translation procedures followed a dual-translation approach. The psychometric properties of the RTW-SE questionnaire were examined using Rasch model analysis by Winsteps software. The unidimensionality and local independence were analyzed by principal component analysis of the residuals (PCAR) and standardized residual correlations.Category diagnostics were performed for scale function, and the item fit, reliability, and separation were also validated. Item-person maps were used to examine the distribution and matching of item’s location and person ability. Finally, the differential item functioning (DIF) was used to measure gender-related group equivalence.

Results

A total of 366 participants aged 23–59 years were recruited from three communities in Zhengzhou. The RTW-SE questionnaire demonstrated unidimensionality and a 5-point Likert rating scale was more appropriate to investigate young and middle-aged stroke survivors’self-efficacy. There was a good fit for the items with both person and item reliabilities greater than 0.8 and separation indices of 3.75 and 3.94, respectively. The item location was identified from the item-person map as not covering person ability, but the scale did not have an age-related DIF.

Conclusions

The results confirm evidence of appropriate psychometric properties of the RTW-SE questionnaire and can be used as a reliable and validated instrument for measuring self-efficacy to return to work in young and middle-aged Chinese patients with stroke.
Health-related quality of life in individuals with genital herpes: a systematic review
Authors: Devine Angela , Xiong Xiuqin , Gottlieb Sami Lynne , de Mello Maeve Britto , Fairley Christopher K. , Ong Jason J.
Published: February 2022

Background

There is a significant global burden of herpes simplex virus (HSV) related genital ulcer disease yet little is known about its impact on quality of life. This systematic review aimed to identify studies that quantitatively evaluated the effect of genital herpes on various aspects of health-related quality of life.

Methods

Six databases were searched (MEDLINE, EMBASE, NHS Economic Evaluation Database, Health Technology Assessment, Database of Abstracts of Reviews of Effects, Web of Science Core Collection) for primary quality of life and economic evaluations of genital herpes from January 1, 2000 to January 7, 2021. Qualitative studies or those without primary data were excluded. Two authors independently extracted data from the publications. The study’s registration number with PROSPERO was CRD42021239410.

Findings

We identified 26 relevant publications: 19 presented primary quality of life data, and seven were economic evaluations. The primary studies presented a range of condition-specific tools for describing the quality of life in individuals with genital herpes, but only one study used a direct valuation that could be used to generate utility weights. All economic evaluations of HSV infection were from high-income country settings. Most (6 of 7) focused on neonatal HSV infection with utilities adopted from studies prior to 2000.

Interpretation

The extant literature on genital herpes-related quality of life is limited and requires updating. We recommend future studies be conducted in geographic- and population- diverse settings, and use preference-based condition-specific or generic-instruments to better inform economic modelling.
Health-related quality of life in outpatients with substance use disorder: evolution over time and associated factors
Authors: Simirea Melexima , Baumann Cédric , Bisch Michael , Rousseau Hélène , Di Patrizio Paolo , Viennet Sarah , Bourion-Bédès Stéphanie
Published: February 2022

Background

Health-related quality of life (HRQoL) is an important element of patient care and clinical research. The aim of this study was to describe HRQoL changes and identify associated factors during a 6-month follow-up of outpatients starting care for alcohol or opioid dependence.

Methods

HRQoL was measured at baseline and 3 and 6 months later using the SF-12. Data on the patients’ sociodemographics, clinical characteristics and levels of anxiety and depression were collected using the Hospital Anxiety and Depression Scale (HADS). Repeated-measures analyses were performed to assess factors associated with global HRQoL differences and the evolution of HRQoL indicated by both physical and mental scores (PCS and MCS, respectively).

Results

The mean PCS and MCS scores were initially low at 45.4 (SD = 8.6) and 36.0 (SD = 10.9), respectively. The improvement in HRQoL was rapid in the first 3-month period and then slowed and remained stable over the subsequent 3-month period. Being employed (p = 0.012), having no comorbidities (p = 0.014) and having no depression (p = 0.004) were associated with significant differences in the average PCS scores at the 3 time points. Patients who had lower overall HRQoL MCS scores on average were those for whom a medication was initiated (p = 0.009), as was the case for patients with anxiety (p < 0.001) and depression (p < 0.001). Patients with depression at baseline were also those for whom a significantly greater increase in MCS score during the 6 months of follow-up was observed.

Conclusion

Our findings highlight the importance of screening early psychological distress and considering other factors associated with HRQoL changes in outpatients after the first 3-month period of treatment for substance use disorder.
Physiological assessment of orthostatic intolerance in chronic fatigue syndrome
Authors: Natelson Benjamin H. , Lin Jin-Mann S. , Blate Michelle , Khan Sarah , Chen Yang , Unger Elizabeth R.
Published: February 2022

Background

Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia.

Objective

Evaluate the physiologic response of patients with ME/CFS to a standardized OC.

Design

Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2.

Patients

63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29).

Measures

Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension.

Results

The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia.

Conclusions

The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography.
Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients
Authors: Eaton-Fitch Natalie , Du Preez Stanley , Cabanas Hélène , Muraki Katsuhiko , Staines Donald , Marshall-Gradisnik Sonya
Published: February 2022

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca2+) influx. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients. It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients.

Methods

Live cell immunofluorescent imaging was used to measure TRPM3-dependent Ca2+influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca2+influx was determined.

Results

The amplitude (p < 0.0001) and half-time of Ca2+response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca2+influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca2+influx was significantly increased in ME/CFS patients (p < 0.0001).

Conclusion

TRPM3-dependent Ca2+influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.