bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of a structured practical activity to analyse student healthcare worker perceptions and compliance with prescribed infection control procedures
Authors: Pelzer Elise S. , Stewart Zachary , Peters Holly , O’Callaghan Jessica , Bryan Emily , Wager Lucas , Chiruta Juliana
Published: December 2021

Background

Non-compliance with infection control guidelines has been reported within healthcare settings. Infection control education in undergraduate healthcare education programs forms a critical component in preparing student healthcare workers for vocational roles.

Methods

Clinical sciences students (nutrition science, paramedicine, pharmacy, podiatry, optometry studying for qualifications recognised by the Australian Health Practitioner Regulation Agency) self-reported hygiene perceptions and practices and collected microbiological swabs from personal or medical equipment items before and after recommended disinfection procedures.

Results

Cultivable microorganisms were isolated from 95% of student medical equipment items. Disinfection significantly reduced microbial growth on student medical equipment items (P < 0.05).

Conclusions

Student perceptions of infection control procedures do not always correlate with infection control practice. Infection control education of undergraduate healthcare students requires ongoing assessment to ensure successful translation into clinical practice.
Effectiveness of virtual simulation and jaw model for undergraduate periodontal teaching
Authors: Zhang Jie , Xing Jiawei , Zheng Min , Sheng Jie , Zhang Kailiang , Zhang Baoping
Published: December 2021

Background

The current study explored the effect of virtual simulation and jaw model on development of preclinical periodontal skills in undergraduate students. The study also sought to explore effectiveness of VR in periodontal preclinical training and determine adequate performance mode in basic periodontal education to improve future preclinical training strategies.

Methods

Sixty volunteer sophomores and juniors from the stomatology department in Lanzhou university were enrolled to the current study. Participants were randomly assigned into four groups (each group, n = 15) including the traditional jaw model group (Group J) which was the control group, virtual reality group (Group V), virtual-jaw group (Group V-J), and jaw-virtual group (Group J-V). Participants received training on uniform basic periodontal knowledge before completing the first theoretical assessment. Participants further underwent a total 8 h of operation training and completed a second theoretical assessment. Performance of participants was evaluated using the supragingival scaling processes, and clinical operation scores were graded by a blinded professional using an established standard scoring system.

Results

The findings showed no significant difference in the first theoretical outcomes between the four groups (P > 0.05). The scores of the second theoretical assessment were significantly improved for the V-J and J-V groups (60.00 ± 4.47, 58.33 ± 4.35) compared with the scores of the first theoretical exam (49.67 ± 4.81, 48.00 ± 4.93, P < 0.05). The operation process scores of students in Group V-J and J-V (72.00 ± 5.92; 70.00 ± 3.05) were significantly higher compared with the scores in the other two groups (V: 61.67 ± 7.85; J: 60.67 ± 2.58). The scaling process performance of students in Group V-J and J-V (53.00 ± 3.05; 63.40 ± 4.39) was improved compared with that of students in the other two groups (V: 41.90 ± 5.23; J: 47.40 ± 4.31).

Conclusion

The findings show that combination of virtual reality and jaw model during periodontal preclinical training increases students’ grades and improves acquiring of professional skills. Findings from the current study indicate that the jaw model should be applied prior to virtual reality to ensure high efficacy.
Underlying factors and challenges of implementing the urban family physician program in Iran
Authors: Mehrolhassani Mohammad Hossein , Jahromi Vahid Kohpeima , Dehnavieh Reza , Iranmanesh Mahla
Published: December 2021

Background

The family physician program was launched in 2005 in rural areas of Iran and then piloted in 2012 in the cities of Fars and Mazandaran provinces due to insufficient health coverage in these cities. However, despite its pivotal role in the health system, this program has not progressed according to the policies. This study aimed to explain the underlying factors and challenges of implementing the urban family physician program in Iran.

Methods

This qualitative study was conducted on 44 policy-makers and managers at national and provincial levels selected via snowball and purposive sampling with maximum variation. The data were managed in MAXQDA 2020 and analyzed by directed content analysis. A triangulation method was adopted for this purpose.

Results

A total of 10 categories, 18 sub-categories, and 29 codes were formed. Most challenges related to underlying factors included precipitancy, economic sanctions, belief in traditional medicine, belief in the expertise of previous physicians, and global ranking of countries. For program implementation, most challenges included a diversity of insurance organizations, budget allocation, referral system, electronic file, educational system, and culture building.

Conclusions

The major challenges pertaining to underlying factors included international pressure for reforms and precipitancy in program implementation due to management changes. The challenges associated with program implementation included budget provision and interaction with insurance organizations. Therefore, to expand this program to other provinces in Iran, the identified factors should be carefully considered so that sufficient confidence and commitment can be guaranteed for all stakeholders.
Rapid screening and identification of viral pathogens in metagenomic data
Authors: Song Shiyang , Ma Liangxiao , Xu Xintian , Shi Han , Li Xuan , Liu Yuanhua , Hao Pei
Published: December 2021

Background

Virus screening and viral genome reconstruction are urgent and crucial for the rapid identification of viral pathogens, i.e., tracing the source and understanding the pathogenesis when a viral outbreak occurs. Next-generation sequencing (NGS) provides an efficient and unbiased way to identify viral pathogens in host-associated and environmental samples without prior knowledge. Despite the availability of software, data analysis still requires human operations. A mature pipeline is urgently needed when thousands of viral pathogen and viral genome reconstruction samples need to be rapidly identified.

Results

In this paper, we present a rapid and accurate workflow to screen metagenomics sequencing data for viral pathogens and other compositions, as well as enable a reference-based assembler to reconstruct viral genomes. Moreover, we tested our workflow on several metagenomics datasets, including a SARS-CoV-2 patient sample with NGS data, pangolins tissues with NGS data, Middle East Respiratory Syndrome (MERS)-infected cells with NGS data, etc. Our workflow demonstrated high accuracy and efficiency when identifying target viruses from large scale NGS metagenomics data. Our workflow was flexible when working with a broad range of NGS datasets from small (kb) to large (100 Gb). This took from a few minutes to a few hours to complete each task. At the same time, our workflow automatically generates reports that incorporate visualized feedback (e.g., metagenomics data quality statistics, host and viral sequence compositions, details about each of the identified viral pathogens and their coverages, and reassembled viral pathogen sequences based on their closest references).

Conclusions

Overall, our system enabled the rapid screening and identification of viral pathogens from metagenomics data, providing an important piece to support viral pathogen research during a pandemic. The visualized report contains information from raw sequence quality to a reconstructed viral sequence, which allows non-professional people to screen their samples for viruses by themselves (Additional file 1).
Ferroptosis-related gene signature predicts the prognosis of papillary thyroid carcinoma
Authors: Shi Jinyuan , Wu Pu , Sheng Lei , Sun Wei , Zhang Hao
Published: December 2021

Background

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC), accounting for more than 80% of all cases. Ferroptosis is a novel iron-dependent and Reactive oxygen species (ROS) reliant type of cell death which is distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated that ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in PTC remains unclear. This study aims at exploring the expression of ferroptosis-related genes (FRG) and their prognostic values in PTC.

Methods

A ferroptosis-related gene signature was constructed using lasso regression analysis through the PTC datasets of the Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the bioinformatics functions of significantly different genes (SDG) of ferroptosis. Additionally, the correlations of ferroptosis and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT database. Finally, SDG were test in clinical PTC specimens and normal thyroid tissues.

Results

LASSO regression model was utilized to establish a novel FRG signature with 10 genes (ANGPTL7, CDKN2A, DPP4, DRD4, ISCU, PGD, SRXN1, TF, TFRC, TXNRD1) to predicts the prognosis of PTC, and the patients were separated into high-risk and low-risk groups by the risk score. The high-risk group had poorer survival than the low-risk group (p < 0.001). Receiver operating characteristic (ROC) curve analysis confirmed the signature's predictive capacity. Multivariate regression analysis identified the prognostic signature-based risk score was an independent prognostic indicator for PTC. The functional roles of the DEGs in the TGCA PTC cohort were explored using GO enrichment and KEGG pathway analyses. Immune related analysis demonstrated that the most types of immune cells and immunological function in the high-risk group were significant different with those in the low-risk group. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) verified the SDG have differences in expression between tumor tissue and normal thyroid tissue. In addition, cell experiments were conducted to observe the changes in cell morphology and expression of signature’s genes with the influence of ferroptosis induced by sorafenib.

Conclusions

We identified differently expressed FRG that may involve in PTC. A ferroptosis-related gene signature has significant values in predicting the patients’ prognoses and targeting ferroptosis may be an alternative for PTC’s therapy.
Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling
Authors: Zhao Yuchong , Wang Yun , Chen Wei , Bai Shuya , Peng Wang , Zheng Mengli , Yang Yilei , Cheng Bin , Luan Zhou
Published: December 2021

Background

Owing to the lack of effective treatment options, early metastasis remains the major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterized the function of eukaryotic translation initiation factors (eIFs) in epithelial-mesenchymal-transition (EMT) and metastasis in pancreatic cancer cells to investigate whether eIFs and downstream c-MYC affect EMT and metastasis by joint interference.

Methods

We used The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to analyze eIF4A1 expression in PDAC tissues and further validated the findings with a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1 and c-MYC were performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo.

Results

Elevated eIF4A1 expression was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through the c-MYC/miR-9 axis. Loss of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells, whereas upregulation of eIF4A1 attenuated the inhibition of EMT and metastasis induced by c-MYC downregulation. Treatment with the eIF4A1 inhibitor rocaglamide (RocA) or the c-MYC inhibitor Mycro3 either alone or in combination significantly decreased the expression level of EMT markers in pancreatic cancer cells in vitro. However, the efficiency and safety of RocA alone were not inferior to those of the combination treatment in vivo.

Conclusion

Overexpression of eIF4A1 downregulated E-cadherin expression through the c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential feedback loop between eIF4A1 and c-MYC, RocA monotherapy is a promising treatment inhibiting eIF4A1-induced PDAC metastasis.
Assessment of Plasmodium falciparum anti-malarial drug resistance markers in pfcrt and pfmdr1 genes in isolates from Honduras and Nicaragua, 2018–2021
Authors: Fontecha Gustavo , Pinto Alejandra , Archaga Osman , Betancourth Sergio , Escober Lenin , Henríquez Jessica , Valdivia Hugo O. , Montoya Alberto , Mejía Rosa Elena
Published: December 2021

Background

Central America and the island of Hispaniola have set out to eliminate malaria by 2030. However, since 2014 a notable upturn in the number of cases has been reported in the Mosquitia region shared by Nicaragua and Honduras. In addition, the proportion of Plasmodium falciparum malaria cases has increased significantly relative to vivax malaria. Chloroquine continues to be the first-line drug to treat uncomplicated malaria in the region. The objective of this study was to evaluate the emergence of chloroquine resistant strains of P. falciparum using a genetic approach. Plasmodium vivax populations are not analysed in this study.

Methods

205 blood samples from patients infected with P. falciparum between 2018 and 2021 were analysed. The pfcrt gene fragment encompassing codons 72–76 was analysed. Likewise, three fragments of the pfmdr1 gene were analysed in 51 samples by nested PCR and sequencing.

Results

All samples revealed the CVMNK wild phenotype for the pfcrt gene and the N86, Y184F, S1034C, N1042D, D1246 phenotype for the pfmdr1 gene.

Conclusions

The increase in falciparum malaria cases in Nicaragua and Honduras cannot be attributed to the emergence of chloroquine-resistant mutants. Other possibilities should be investigated further. This is the first study to report the genotype of pfmdr1 for five loci of interest in Central America.
The association between acute fatty liver disease and nitric oxide during malaria in pregnancy
Authors: Niikura Mamoru , Fukutomi Toshiyuki , Mineo Shoichiro , Mitobe Jiro , Kobayashi Fumie
Published: December 2021

Background

Liver disease is a common feature of malaria in pregnancy, but its pathogenesis remains unclear.

Methods

To understand the pathogenesis of liver disease during malaria in pregnancy, comparative proteomic analysis of the liver in a mouse model of malaria in pregnancy was performed.

Results

Decreased levels of mitochondrial and peroxisomal proteins were observed in the livers of pregnant mice infected with the lethal rodent malaria parasite Plasmodium berghei strain NK65. By contrast, increased levels of perilipin-2, amyloid A-1, and interferon (IFN)-γ signalling pathway-related proteins were observed in the livers of infected pregnant mice, suggesting that IFN-γ signalling may contribute to the development of liver disease during malaria in pregnancy. IFN-γ signalling is a potential trigger of inducible nitric oxide synthase (iNOS) expression. Liver disease associated with microvesicular fatty infiltration and elevated liver enzymes in pregnant wild-type mice infected with malaria parasites was improved by iNOS deficiency.

Conclusions

In this study, a causative role of iNOS in liver disease associated with microvesicular fatty infiltration during malaria in pregnancy was demonstrated. These findings provide important insight for understanding the role of iNOS-mediated metabolic responses and the pathogenesis of high-risk liver diseases in pregnancy, such as acute fatty liver.
Temporal evolution of the resistance genotypes of Plasmodium falciparum in isolates from Equatorial Guinea during 20 years (1999 to 2019)
Authors: Berzosa Pedro , Molina de la Fuente Irene , Ta-Tang Thuy-Huong , González Vicenta , García Luz , Rodríguez-Galet Ana , Díaz-Regañón Ramón , Galán Rosario , Cerrada-Gálvez Laura , Ncogo Policarpo , Riloha Matilde , Benito Agustin
Published: December 2021

Background

Malaria is one of the deadliest diseases in the world, particularly in Africa. As such, resistance to anti-malarial drugs is one of the most important problems in terms of global malaria control. This study assesses the evolution of the different resistance markers over time and the possible influence of interventions and treatment changes that have been made in Equatorial Guinea.

Methods

A total of 1223 biological samples obtained in the period 1999 to 2019 were included in the study. Screening for mutations in the pfdhfr, pfdhps, pfmdr1, and pfcrt genes was carried out by nested PCR and restriction-fragment length polymorphisms (RFLPs), and the study of pfk13 genes was carried out by nested PCR, followed by sequencing to determine the presence of mutations.

Results

The partially and fully resistant haplotypes (pfdhfr + pfdhps) were found to increase over time. Moreover, in 2019, the fully resistant haplotype was found to be increasing, although its super-resistant counterpart remains much less prevalent. A continued decline in pfmdr1 and pfcrt gene mutations over time was also found. The number of mutations detected in pfk13 has increased since 2008, when artemisinin-based combination therapy (ACT) were first introduced, with more mutations being observed in 2019, with two synonymous and five non-synonymous mutations being detected, although these are not related to resistance to ACT. In addition, the non-synonymous A578S mutation, which is the most frequent on the African continent, was detected in 2013, although not in the following years.

Conclusions

Withdrawal of the use of chloroquine (CQ) as a treatment in Equatorial Guinea has been shown to be effective over time, as wild-type parasite populations outnumber mutant populations. The upward trend observed in sulfadoxine-pyrimethamine (SP) resistance markers suggest its misuse, either alone or in combination with artesunate (AS) or amodiaquine (AQ), in some areas of the country, as was found in a previous study conducted by this group, which allows selective pressure from SP to continue. Single nucleotide polymorphisms (SNPs) 540E and 581G do not exceed the limit of 50 and 10%, respectively, thus meaning that SP is still effective as an intermittent preventive treatment (IPT) in this country. As for the pfk13 gene, no mutations have been detected in relation to resistance to ACT. However, in 2019 there is a greater accumulation of non-synonymous mutations compared to years prior to 2008.

Graphical Abstract
Insecticidal effect of ethnobotanical plant extracts against Anopheles arabiensis under laboratory conditions
Authors: Ejeta Desta , Asme Ansha , Asefa Animut
Published: December 2021

Background

The emergence and spread of resistant strains of malaria vectors to chemical insecticides are becoming major problems for malaria vector management. Natural plant products have a vital role to play in the current challenge of malaria control. The current study was conducted to evaluate insecticidal effect of ethnobotanical plant extracts against the primary malaria vector, Anopheles arabiensis in northwestern Ethiopia.

Methods

Primarily, ethnobotanical plants used for Anopheles mosquito control were surveyed in Dangur district, northwestern Ethiopia. Insecticide-susceptible strains of Anopheles arabiensis mosquito were reared in the insectary of the Tropical and Infectious Diseases Research Centre, Assosa University. After surveying plants used for mosquito control in local people, four frequently used plants were identified for extraction. The larvicidal and adulticidal potential of frequently used plant extracts against susceptible strains of the laboratory colony were evaluated.

Results

A total of 15 plants were identified as ethnobotanical plants that help local people with mosquito control. Azadirachta indica, Ocimum lamiifolium, Ocimum americanum, Moringa olifeira leaf, and Moringa olifeira seed species of local plants were found to be frequently used to kill and/or repel mosquitoes in the study district. All the plant extracts were found to have potential larvicidal activity against fourth instar larvae of An. arabiensis and only ethanol and methanol extract of Azadirachta indica and Ocimum lamiifolium were found to have potential adulticidal effect against adult of An. arabiensis. The highest larvicidal activity was observed in ethanol extract of Azadirachta indica with 95% larval mortality and lowest Lethal Concentration 50 (LC 50) of 40.73parts per million (ppm) and LC90 of 186.66 ppm. The highest adulticidal activity was observed in methanol extract of Azadirachta indica with 75% adult mortality at 300 ppm and lowest LC50 of 106.65 ppm and LC90 of 1,293 ppm. The lowest larvicidal and adulticidal activity was observed in methanol extracts of Ocimum lamiifolium with 63.35% larval mortality and leaf extract of Moringa olifeira with 50% adult mortality at 300 ppm, respectively.

Conclusion

Ethanol extract of Azadirachta indica exerted a remarkable larvicidal effect against An. arabiensis and thus it can be used for botanical mosquito insecticide development. Since the current finding is based on susceptible strain of An. arabiensis, further work on wild mosquitoes is recommended.
Spatiotemporal regulation of angiogenesis/osteogenesis emulating natural bone healing cascade for vascularized bone formation
Authors: Zhou Xingzhi , Chen Jiayu , Sun Hangxiang , Wang Fangqian , Wang Yikai , Zhang Zengjie , Teng Wangsiyuan , Ye Yuxiao , Huang Donghua , Zhang Wei , Mo Xianan , Liu An , Lin Peng , Wu Yan , Tao Huimin , Yu Xiaohua , Ye Zhaoming
Published: December 2021

Engineering approaches for growth factor delivery have been considerably advanced for tissue regeneration, yet most of them fail to provide a complex combination of signals emulating a natural healing cascade, which substantially limits their clinical successes. Herein, we aimed to emulate the natural bone healing cascades by coupling the processes of angiogenesis and osteogenesis with a hybrid dual growth factor delivery system to achieve vascularized bone formation. Basic fibroblast growth factor (bFGF) was loaded into methacrylate gelatin (GelMA) to mimic angiogenic signalling during the inflammation and soft callus phases of the bone healing process, while bone morphogenetic protein-2 (BMP-2) was bound onto mineral coated microparticles (MCM) to mimics osteogenic signalling in the hard callus and bone remodelling phases. An Initial high concentration of bFGF accompanied by a sustainable release of BMP-2 and inorganic ions was realized to orchestrate well-coupled osteogenic and angiogenic effects for bone regeneration. In vitro experiments indicated that the hybrid hydrogel markedly enhanced the formation of vasculature in human umbilical vein endothelial cells (HUVECs), as well as the osteogenic differentiation of mesenchymal stem cells (BMSCs). In vivo results confirmed the optimal osteogenic performance of our F/G-B/M hydrogel, which was primarily attributed to the FGF-induced vascularization. This research presents a facile and potent alternative for treating bone defects by emulating natural cascades of bone healing.

Graphical Abstract
Assessing the relative importance of key quality of life dimensions for people with and without a disability: an empirical ranking comparison study
Authors: Crocker Matthew , Hutchinson Claire , Mpundu-Kaambwa Christine , Walker Ruth , Chen Gang , Ratcliffe Julie
Published: December 2021

Background

In economic evaluation, the quality of life of people with a disability has traditionally been assessed using preference-based instruments designed to measure and value quality of life. To provide robust measurement of the effectiveness of programs designed to improve the quality of life of people living with a disability, preference-based measures need to be sufficiently sensitive to detect incremental changes in the quality of life dimensions that are most important to people who have a disability. This study sought to explore whether there was a difference in the ranked order of importance of quality of life dimensions between people with a disability and people without a disability.

Methods

An online survey was developed and administered Australia wide. The first sample (n = 410) comprised adults (aged ≥ 18 years) with a disability (n = 208) and family carers of person/s with a disability who were asked to respond on behalf of the person with a disability (n = 202). The second sample included adults without disability (n = 443). Respondents were asked to rank the importance of 12 quality of life dimensions extracted from the content of established preference-based quality of life measures (EQ-5D, AQoL and ASCOT).

Results

People with a disability placed relatively higher importance on broader quality of life dimensions (e.g. Control, Independence, Self-care) relative to health status focused dimensions (e.g. Vision, Hearing, Physical mobility). This distinction was less differentiable for those ‘without a disability’. The biggest differences in ranked importance of dimensions were in: Vision (‘with disability’ = 10th, ‘without disability’ = 4th), Self-care (‘with disability’ = 3rd, ‘without disability’ = 7th) and Mental well-being (‘with disability’ = 6th, ‘without disability’ = 2nd).

Conclusions

The relative importance of quality of life dimensions for people with a disability differs to people without a disability. Quality of life is a key outcome for economic evaluation and for assessing the impact of disability care policy and practice in Australia and internationally. It is important that the effectiveness of interventions is measured and valued in ways which are fully reflective of the quality of life preferences of people with a disability.
Changes of antithrombotic prescription in atrial fibrillation patients with acute coronary syndrome or percutaneous coronary intervention and the subsequent impact on long-term outcomes: a longitudinal cohort study
Authors: Lee Chiao-Chin , Chang Chiao-Hsiang , Hung Yuan , Lin Chin-Sheng , Yang Shih-Ping , Cheng Shu-Meng , Yu Fan-Han , Lin Wei-Shiang , Lin Wen-Yu
Published: December 2021

Objectives

The choice of optimal antithrombotic therapy in atrial fibrillation (AF) patients with acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) remains controversial. The aim of this longitudinal cohort study is to investigate the prescribing pattern of antithrombotic regimen in different cohorts and its subsequent impact.

Setting and design

Longitudinal data from the Tri-Service General Hospital-Coronary Heart Disease (TSGH-CHD) registry, between January 2016 and August 2018 was screened.

Participants and method

Patients with prior history of nonvalvular AF, who had ACS presentation or underwent PCI were selected, and these patients were divided into cohort 1 and cohort 2, according to the index date of antithrombotic prescription before and after the PIONEER AF-PCI study.

Primary and secondary outcomes

The primary safety endpoints were composites of major bleeding and/or clinically relevant non-major bleeding. The secondary efficacy endpoints included the occurrence of all-cause mortality, stroke/systemic embolization, nonfatal myocardial infarction (MI), and >30-days coronary revascularization.

Results

A total of 121 patients were included into analysis (cohort 1=35; cohort 2=86). Comparing with cohort 1, the prescription rate of triple antithrombotic therapy (TAT) increased from 17.1 to 38.4%, especially the regimen with dual antiplatelet therapy (DAPT) plus low-dose non-vitamin-K dependent oral anticoagulation (NOAC). However, the prescription rate of dual antithrombotic therapy (DAT) decreased (14.3–10.5%), as well as the prescription rate of DAPT (68.6–51.2%). These changes of antithrombotic prescription across different cohorts were not associated with risk of adverse safety (HR= 0.87; 95% CI, 0.42-1.80, p=0.710) and efficacy outcomes (HR=0.96; 95% CI, 0.40-2.32, p=0.930).

Conclusions

Entering the NOAC era, the prescription of TAT increased alongside the decrease in DAT. As the prescription rate of DAPT without anticoagulation remained high, future efforts are mandatory to improve the implementation of guidelines and clinical practice.
Flavivirus replication kinetics in early-term placental cell lines with different differentiation pathways
Authors: Carrera Julio , Trenerry Alice M. , Simmons Cameron P. , Mackenzie Jason M.
Published: December 2021

Background

The uncontrollable spread of Zika virus (ZIKV) in the Americas during 2015–2017, and its causal link to microcephaly in newborns and Guillain-Barré syndrome in adults, led the World Health Organisation to declare it a global public health emergency. One of the most notable features of ZIKV pathogenesis was the ability of the virus to pass the placental barrier to infect the growing foetus. This pathogenic trait had not been observed previously for medically important flaviviruses, including dengue and yellow fever viruses.

Methods

In this study we evaluated the replication kinetics of ZIKV and the related encephalitic flavivirus West Nile strain Kunjin virus (WNVKUN) in early-term placental cell lines.

Results

We have observed that WNVKUNin fact replicates with a greater rate and to higher titres that ZIKV in these cell lines.

Conclusions

These results would indicate the potential for all flaviviruses to replicate in placental tissue but it is the ability to cross the placenta itself that is the restrictive factor in the clinical progression and presentation of congenital Zika syndrome.
Exposure to combustion derived particulate matter exacerbates influenza infection in neonatal mice by inhibiting IL22 production
Authors: Kumar Avinash , Patel Vivek S. , Harding Jeffrey N. , You Dahui , Cormier Stephania A.
Published: December 2021

Background

Particulate matter (PM) containing environmentally persistent free radicals (EPFRs) are formed during various combustion processes, including the thermal remediation of hazardous wastes. Exposure to PM adversely affects respiratory health in infants and is associated with increased morbidity and mortality due to acute lower respiratory tract infections. We previously reported that early-life exposure to PM damages the lung epithelium and suppresses immune responses to influenza virus (Flu) infection, thereby enhancing Flu severity. Interleukin 22 (IL22) is important in resolving lung injury following Flu infection. In the current study, we determined the effects of PM exposure on pulmonary IL22 responses using our neonatal mouse model of Flu infection.

Results

Exposure to PM resulted in an immediate (0.5–1-day post-exposure; dpe) increase in IL22 expression in the lungs of C57BL/6 neonatal mice; however, this IL22 expression was not maintained and failed to increase with either continued exposure to PM or subsequent Flu infection of PM-exposed mice. This contrasts with increased IL22 expression in age-matched mice exposed to vehicle and Flu infected. Activation of the aryl hydrocarbon receptor (AhR), which mediates the induction and release of IL22 from immune cells, was also transiently increased with PM exposure. The microbiome plays a major role in maintaining epithelial integrity and immune responses by producing various metabolites that act as ligands for AhR. Exposure to PM induced lung microbiota dysbiosis and altered the levels of indole, a microbial metabolite. Treatment with recombinant IL22 or indole-3-carboxaldehyde (I3A) prevented PM associated lung injury. In addition, I3A treatment also protected against increased mortality in Flu-infected mice exposed to PMs.

Conclusions

Together, these data suggest that exposure to PMs results in failure to sustain IL22 levels and an inability to induce IL22 upon Flu infection. Insufficient levels of IL22 may be responsible for aberrant epithelial repair and immune responses, leading to increased Flu severity in areas of high PM.
Clinical application of anterior ring internal fixator system combined with sacroiliac screw fixation in Tile C pelvic fracture treatment
Authors: Liu Lin , Fan Shicai , Zeng Donggui , Chen Yuhui , Song Hui , Zeng Letian , Jin Dadi
Published: December 2021

Background

How to perform minimally invasive surgery for Tile C pelvic fracture is a major problem in clinical practice. We performed minimally invasive surgery for Tile C pelvic fracture using anterior ring internal fixator systems combined with sacroiliac screw fixation.

Objective

To investigate the advantages and efficacy of anterior ring internal fixator systems combined with sacroiliac screw fixation in the treatment of Tile C pelvic fracture.

Methods

From May 2017 to May 2020, 27 patients with Tile C pelvic fracture who underwent anterior ring internal fixator system combined with sacroiliac screw fixation (group A) and 21 patients with Tile C pelvic fracture who underwent plate-screw system combined with sacroiliac screw fixation (group B) were retrospectively analyzed.

Results

All 48 patients were followed up for more than 12 months, all fractures healed within 3–6 months. The operative time, intraoperative bleeding volume, blood transfusion volume, incision length, hospital stay, complication rate and Majeed score were 63.5 ± 10.7 min, 48.3 ± 27.9 ml, 0 ml, 4.5 ± 0.8 cm, 10.2 ± 2.7 d, 3.7% and 89.7 ± 4.6 points, respectively, in group A and 114.8 ± 19.1 min, 375 ± 315.8 ml, 266.7 ± 326.6 ml, 9.2 ± 3.9 cm, 20.9 ± 5.7 d, 23.8% and 88.7 ± 4.9 points, respectively, in group B. Combined excellent and good rates of the Matta evaluation and Majeed score were 100% in both groups. There were no significant differences in the Matta evaluation or Majeed score between the two groups (both P > 0.05), whereas the operative time, intraoperative bleeding volume, blood transfusion volume, incision length and hospital stay were significantly less in group A (all P < 0.05).

Conclusion

An anterior ring internal fixator system combined with sacroiliac screw fixation can effectively treat Tile C pelvic fracture, and has advantages, including minimal invasiveness, simple operation, short operative time, safe and reliable features, fewer complications, short hospital stay and a good curative effect.
Flavonoids kaempferol and quercetin are nuclear receptor 4A1 (NR4A1, Nur77) ligands and inhibit rhabdomyosarcoma cell and tumor growth
Authors: Shrestha Rupesh , Mohankumar Kumaravel , Martin Greg , Hailemariam Amanuel , Lee Syng-ook , Jin Un-ho , Burghardt Robert , Safe Stephen
Published: December 2021

Background

Flavonoids exhibit both chemopreventive and chemotherapeutic activity for multiple tumor types, however, their mechanisms of action are not well defined. Based on some of their functional and gene modifying activities as anticancer agents, we hypothesized that kaempferol and quercetin were nuclear receptor 4A1 (NR4A1, Nur77) ligands and confirmed that both compounds directly bound NR4A1 with KD values of 3.1 and 0.93 μM, respectively.

Methods

The activities of kaempferol and quercetin were determined in direct binding to NR4A1 protein and in NR4A1-dependent transactivation assays in Rh30 and Rh41 rhabdomyosarcoma (RMS) cells. Flavonoid-dependent effects as inhibitors of cell growth, survival and invasion were determined in XTT and Boyden chamber assays respectively and changes in protein levels were determined by western blots. Tumor growth inhibition studies were carried out in athymic nude mice bearing Rh30 cells as xenografts.

Results

Kaempferol and quercetin bind NR4A1 protein and inhibit NR4A1-dependent transactivation in RMS cells. NR4A1 also regulates RMS cell growth, survival, mTOR signaling and invasion. The pro-oncogenic PAX3-FOXO1 and G9a genes are also regulated by NR4A1 and, these pathways and genes are all inhibited by kaempferol and quercetin. Moreover, at a dose of 50 mg/kg/d kaempferol and quercetin inhibited tumor growth in an athymic nude mouse xenograft model bearing Rh30 cells.

Conclusion

These results demonstrate the clinical potential for repurposing kaempferol and quercetin for clinical applications as precision medicine for treating RMS patients that express NR4A1 in order to increase the efficacy and decrease dosages of currently used cytotoxic drugs.
A guide to enteral nutrition in intensive care units: 10 expert tips for the daily practice
Authors: Preiser Jean-Charles , Arabi Yaseen M. , Berger Mette M. , Casaer Michael , McClave Stephen , Montejo-González Juan C. , Peake Sandra , Reintam Blaser Annika , Van den Berghe Greet , van Zanten Arthur , Wernerman Jan , Wischmeyer Paul
Published: December 2021

The preferential use of the oral/enteral route in critically ill patients over gut rest is uniformly recommended and applied. This article provides practical guidance on enteral nutrition in compliance with recent American and European guidelines. Low-dose enteral nutrition can be safely started within 48 h after admission, even during treatment with small or moderate doses of vasopressor agents. A percutaneous access should be used when enteral nutrition is anticipated for ≥ 4 weeks. Energy delivery should not be calculated to match energy expenditure before day 4–7, and the use of energy-dense formulas can be restricted to cases of inability to tolerate full-volume isocaloric enteral nutrition or to patients who require fluid restriction. Low-dose protein (max 0.8 g/kg/day) can be provided during the early phase of critical illness, while a protein target of > 1.2 g/kg/day could be considered during the rehabilitation phase. The occurrence of refeeding syndrome should be assessed by daily measurement of plasma phosphate, and a phosphate drop of 30% should be managed by reduction of enteral feeding rate and high-dose thiamine. Vomiting and increased gastric residual volume may indicate gastric intolerance, while sudden abdominal pain, distension, gastrointestinal paralysis, or rising abdominal pressure may indicate lower gastrointestinal intolerance.
Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry
Authors: Gampenrieder Simon Peter , Rinnerthaler Gabriel , Tinchon Christoph , Petzer Andreas , Balic Marija , Heibl Sonja , Schmitt Clemens , Zabernigg August Felix , Egle Daniel , Sandholzer Margit , Singer Christian Fridolin , Roitner Florian , Hager Christopher , Andel Johannes , Hubalek Michael , Knauer Michael , Greil Richard
Published: December 2021

Background

About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody–drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC).

Patients and methods

The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included.

Results

As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74–1.05;P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68–1.25;P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients.

Conclusion

Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.
Quantitative assessment of the immune microenvironment in African American Triple Negative Breast Cancer: a case–control study
Authors: Yaghoobi Vesal , Moutafi Myrto , Aung Thazin Nwe , Pelekanou Vasiliki , Yaghoubi Sanam , Blenman Kim , Ibrahim Eiman , Vathiotis Ioannis A. , Shafi Saba , Sharma Anup , O’Meara Tess , Fernandez Aileen I. , Pusztai Lajos , Rimm David L.
Published: December 2021

Purpose

Triple negative breast cancer (TNBC) is more common in African American (AA) than Non-AA (NAA) population. We hypothesize that tumor microenvironment (TME) contributes to this disparity. Here, we use multiplex quantitative immunofluorescence to characterize the expression of immunologic biomarkers in the TME in both populations.

Patients and methods

TNBC tumor resection specimen tissues from a 100-patient case: control cohort including 49 AA and 51 NAA were collected. TME markers including CD45, CD14, CD68, CD206, CD4, CD8, CD20, CD3, Ki67, GzB, Thy1, FAP, aSMA, CD34, Col4, VWF and PD-L1 we quantitatively assessed in every field of view. Mean expression levels were compared between cases and controls.

Results

Although no significant differences were detected in individual lymphoid and myeloid markers, we found that infiltration with CD45+ immune cells (p = 0.0102) was higher in TNBC in AA population. AA TNBC tumors also had significantly higher level of lymphocytic infiltration defined as CD45+ CD14− cells (p = 0.0081). CD3+ T-cells in AA tumors expressed significantly higher levels of Ki67 (0.0066) compared to NAAs, indicating that a higher percentage of AA tumors contained activated T-cells. All other biomarkers showed no significant differences between the AA and NAA group.

Conclusions

While the TME in TNBC is rich in immune cells in both racial groups, there is a numerical increase in lymphoid infiltration in AA compared to NAA TNBC. Significantly, higher activated T cells seen in AA patients raises the possibility that there may be a subset of AA patients with improved response to immunotherapy.
Benchmarking UMI-based single-cell RNA-seq preprocessing workflows
Authors: You Yue , Tian Luyi , Su Shian , Dong Xueyi , Jabbari Jafar S. , Hickey Peter F. , Ritchie Matthew E.
Published: December 2021

Background

Single-cell RNA-sequencing (scRNA-seq) technologies and associated analysis methods have rapidly developed in recent years. This includes preprocessing methods, which assign sequencing reads to genes to create count matrices for downstream analysis. While several packaged preprocessing workflows have been developed to provide users with convenient tools for handling this process, how they compare to one another and how they influence downstream analysis have not been well studied.

Results

Here, we systematically benchmark the performance of 10 end-to-end preprocessing workflows (Cell Ranger, Optimus, salmon alevin, alevin-fry, kallisto bustools, dropSeqPipe, scPipe, zUMIs, celseq2, and scruff) using datasets yielding different biological complexity levels generated by CEL-Seq2 and 10x Chromium platforms. We compare these workflows in terms of their quantification properties directly and their impact on normalization and clustering by evaluating the performance of different method combinations. While the scRNA-seq preprocessing workflows compared vary in their detection and quantification of genes across datasets, after downstream analysis with performant normalization and clustering methods, almost all combinations produce clustering results that agree well with the known cell type labels that provided the ground truth in our analysis.

Conclusions

In summary, the choice of preprocessing method was found to be less important than other steps in the scRNA-seq analysis process. Our study comprehensively compares common scRNA-seq preprocessing workflows and summarizes their characteristics to guide workflow users.
Flimma: a federated and privacy-aware tool for differential gene expression analysis
Authors: Zolotareva Olga , Nasirigerdeh Reza , Matschinske Julian , Torkzadehmahani Reihaneh , Bakhtiari Mohammad , Frisch Tobias , Späth Julian , Blumenthal David B. , Abbasinejad Amir , Tieri Paolo , Kaissis Georgios , Rückert Daniel , Wenke Nina K. , List Markus , Baumbach Jan
Published: December 2021

Aggregating transcriptomics data across hospitals can increase sensitivity and robustness of differential expression analyses, yielding deeper clinical insights. As data exchange is often restricted by privacy legislation, meta-analyses are frequently employed to pool local results. However, the accuracy might drop if class labels are inhomogeneously distributed among cohorts. Flimma (https://exbio.wzw.tum.de/flimma/) addresses this issue by implementing the state-of-the-art workflow limma voom in a federated manner, i.e., patient data never leaves its source site. Flimma results are identical to those generated by limma voom on aggregated datasets even in imbalanced scenarios where meta-analysis approaches fail.
Pharmacist-guided pre-emptive pharmacogenetic testing in antidepressant therapy (PrePGx): study protocol for an open-label, randomized controlled trial
Authors: Stäuble Céline K. , Lampert Markus L. , Allemann Samuel , Hatzinger Martin , Hersberger Kurt E. , Meyer zu Schwabedissen Henriette E. , Imboden Christian , Mikoteit Thorsten
Published: December 2021

Background

It is known that only 50% of patients diagnosed with major depressive disorders (MDD) respond to the first-line antidepressant treatment. Accordingly, there is a need to improve response rates to reduce healthcare costs and patient suffering. One approach to increase rates of treatment response might be the integration of pharmacogenetic (PGx) testing to stratify antidepressant drug selection. The goal of PGx assessments is to identify patients who have an increased risk to experience adverse drug reactions or non-response to specific drugs. Especially for antidepressants, there is compiling evidence on PGx influencing drug exposure as well as response.

Methods

This study is an open-label, randomized controlled trial conducted in two study centers in Switzerland: (1) the Psychiatric Clinic of Solothurn and (2) the Private Clinic Wyss in Münchenbuchsee. Adult inpatients diagnosed with a unipolar moderate or severe depressive episode are recruited at clinic admission and are included in the study. If the adjustment to a new antidepressant pharmacotherapy is necessary, the participants are randomized to either Arm A (intervention group) or Arm B (control group). If no new antidepressant pharmacotherapy is introduced the participants will be followed up in an observational arm. The intervention is the service of pharmacist-guided pre-emptive PGx testing to support clinical decision making on antidepressant selection and dosing. As a comparison, in the control group, the antidepressant pharmacotherapy is selected by the treating physician according to current treatment guidelines (standard of care) without the knowledge of PGx test results and support of clinical pharmacists. The primary outcome of this study compares the response rates under antidepressant treatment after 4 weeks between intervention and control arm.

Discussion

The findings from this clinical trial are expected to have a direct impact on inter-professional collaborations for the handling and use of PGx data in psychiatric practice.

Trial registration

ClinicalTrials.govNCT04507555. Registered on August 11, 2020. Swiss National Clinical Trials PortalSNCTP000004015. Registered August 18, 2020.