bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid screening of high expressing Escherichia coli colonies using a novel dicistronic-autoinducible system
Authors: Shariati Fatemeh Sadat , Norouzian Dariush , Valizadeh Vahideh , Ahangari Cohan Reza , Keramati Malihe
Published: December 2021

Background

Identification of high-expressing colonies is one of the main concerns in the upstream process of recombinant protein development. The common method to screen high-producing colonies is SDS-PAGE, a laborious and time-consuming process, which is based on a random and qualitative way. The current study describes the design and development of a rapid screening system composed of a dicistronic expression system containing a reporter (enhanced green fluorescent protein, eGFP), protein model (staphylokinase, SAK), and a self-inducible system containing heat shock protein 27 (Hsp27).

Results

Dicistronic-autoinducible system expressed eGFP and SAK successfully in 5-ml and 1-L culture volumes. High expressing colonies were identified during 6 h via fluorescent signals. In addition, the biological activity of the protein model was confirmed semi-quantitatively and quantitatively through radial caseinolytic and chromogenic methods, respectively. There was a direct correlation between eGFP fluorescent intensity and SAK activity. The correlation and linearity of expression between the two genes were respectively confirmed with Pearson correlation and linear regression. Additionally, the precision, limit of detection (LOD), and limit of quantification (LOQ) were determined. The expression of eGFP and SAK was stable during four freeze–thaw cycles. In addition, the developed protocol showed that the transformants can be inoculated directly to the culture, saving time and reducing the error-prone step of colony picking.

Conclusion

The developed system is applicable for rapid screening of high-expressing colonies in most research laboratories. This system can be investigated for other recombinant proteins expressed in E. coli with a potential capability for automation and use at larger scales.
Activating transcription factor 5 (ATF5) promotes tumorigenic capability and activates the Wnt/b-catenin pathway in bladder cancer
Authors: Zhou Junhao , Tian Hu , Zhi Xi , Xiao Zhuoyu , Chen Taoyi , Yuan Haoyu , Chen Qi , Chen Mingkun , Yang Jiankun , Zhou Qizhao , Xue Kangyi , Guo Wenbin , Xia Ming , Bao Jiming , Yang Cheng , Duan Haifeng , Wang Hongyi , Huang Zhipeng , Zhu Ting , Liu Cundong
Published: December 2021

Background

In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear.

Methods

Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses.

Results

ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/β-catenin pathway.

Conclusions

This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.
Public transcriptome database-based selection and validation of reliable reference genes for breast cancer research
Authors: Song Qiang , Dou Lu , Zhang Wenjin , Peng Yang , Huang Man , Wang Mengyuan
Published: December 2021

Background

Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is the most sensitive technique for evaluating gene expression levels. Choosing appropriate reference genes (RGs) is critical for normalizing and evaluating changes in the expression of target genes. However, uniform and reliable RGs for breast cancer research have not been identified, limiting the value of target gene expression studies. Here, we aimed to identify reliable and accurate RGs for breast cancer tissues and cell lines using the RNA-seq dataset.

Methods

First, we compiled the transcriptome profiling data from the TCGA database involving 1217 samples to identify novel RGs. Next, ten genes with relatively stable expression levels were chosen as novel candidate RGs, together with six conventional RGs. To determine and validate the optimal RGs we performed qRT-PCR experiments on 87 samples from 11 types of surgically excised breast tumor specimens (n = 66) and seven breast cancer cell lines (n = 21). Five publicly available algorithms (geNorm, NormFinder, ΔCt method, BestKeeper, and ComprFinder) were used to assess the expression stability of each RG across all breast cancer tissues and cell lines.

Results

Our results show that RG combinations SF1 + TRA2B + THRAP3 and THRAP3 + RHOA + QRICH1 showed stable expression in breast cancer tissues and cell lines, respectively, and that they displayed good interchangeability. We propose that these combinations are optimal triplet RGs for breast cancer research.

Conclusions

In summary, we identified novel and reliable RG combinations for breast cancer research based on a public RNA-seq dataset. Our results lay a solid foundation for the accurate normalization of qRT-PCR results across different breast cancer tissues and cells.
A thermoreversible antibacterial zeolite-based nanoparticles loaded hydrogel promotes diabetic wound healing via detrimental factor neutralization and ROS scavenging
Authors: Qi Yao , Qian Kun , Chen Jin , E Yifeng , Shi Yijie , Li Hongdan , Zhao Liang
Published: December 2021

Background

As recovery time of diabetic wound injury is prolonged by the production of detrimental factors, including reactive oxygen species (ROS) and inflammatory cytokines, attenuating the oxidative stress and inflammatory reactions in the microenvironment of the diabetic wound site would be significant.

Experimental design

In our study, we prepared thermoreversible, antibacterial zeolite-based nanoparticles loaded hydrogel to promote diabetic wound healing via the neutralization of detrimental factors such as inflammatory cytokines and ROS.

Results

The cerium (Ce)-doped biotype Linde type A (LTA) zeolite nanoparticles synergistically eliminated mitochondrial ROS and neutralized free inflammatory factors, thus remodeling the anti-inflammatory microenvironment of the wound and enhancing angiogenesis. Moreover, the thermoreversible hydrogel composed of Pluronic F127 and chitosan demonstrated strong haemostatic and bactericidal behavior.

Conclusions

In conclusion, the obtained thermoreversible, antibacterial, zeolite-based nanoparticles loaded hydrogels represent a multi-targeted combination therapy for diabetic wound healing.

Graphical Abstract
A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model
Authors: Hu Yun , Paris Sébastien , Barsoumian Hampartsoum , Abana Chike O. , He Kewen , Sezen Duygu , Wasley Mark , Masrorpour Fatemeh , Chen Dawei , Yang Liangpeng , Dunn Joe D. , Gandhi Saumil , Nguyen Quynh-Nhu , Cortez Maria Angelica , Welsh James W.
Published: December 2021

Background

Combining radiotherapy with PD1 blockade has had impressive antitumor effects in preclinical models of metastatic lung cancer, although anti-PD1 resistance remains problematic. Here, we report results from a triple-combination therapy in which NBTXR3, a clinically approved nanoparticle radioenhancer, is combined with high-dose radiation (HDXRT) to a primary tumor plus low-dose radiation (LDXRT) to a secondary tumor along with checkpoint blockade in a mouse model of anti-PD1-resistant metastatic lung cancer.

Methods

Mice were inoculated with 344SQR cells in the right legs on day 0 (primary tumor) and the left legs on day 3 (secondary tumor). Immune checkpoint inhibitors (ICIs), including anti-PD1 (200 μg) and anti-CTLA4 (100 μg) were given intraperitoneally. Primary tumors were injected with NBTXR3 on day 6 and irradiated with 12-Gy (HDXRT) on days 7, 8, and 9; secondary tumors were irradiated with 1-Gy (LDXRT) on days 12 and 13. The survivor mice at day 178 were rechallenged with 344SQR cells and tumor growth monitored thereafter.

Results

NBTXR3  +  HDXRT  +  LDXRT  +  ICIs had significant antitumor effects against both primary and secondary tumors, improving the survival rate from 0 to 50%. Immune profiling of the secondary tumors revealed that NBTXR3  +  HDXRT  +  LDXRT increased CD8 T-cell infiltration and decreased the number of regulatory T (Treg) cells. Finally, none of the re-challenged mice developed tumors, and they had higher percentages of CD4 memory T cells and CD4 and CD8 T cells in both blood and spleen relative to untreated mice.

Conclusions

NBTXR3 nanoparticle in combination with radioimmunotherapy significantly improves anti-PD1 resistant lung tumor control via promoting antitumor immune response.

Graphical Abstract
Development and validation of a guideline on sexual and reproductive health services for polycystic ovary syndrome in Iran: a mixed-methods study protocol
Authors: Kalhor Mehri , Mohammadi Eesa , Shahali Shadab , Amini Leila , Moghaddam-Banaem Lida
Published: December 2021

Background

Sexual and reproductive health (SRH) is an important aspect of women's health. Polycystic ovary syndrome is a common disease among women and has long-term negative effects on women’s health. Evidence shows that polycystic ovary syndrome has different impacts on SRH needs among women. The aim of this study is to design and validate an SRH services guideline for healthcare providers in treating women with polycystic ovary syndrome.

Methods

The guideline will be developed and validated using an exploratory sequential mixed-methods approach in three phases based on the National Institute for Health and Care Excellence (NICE) model: (1) scoping phase (describing the SRH needs of women with polycystic ovary syndrome from the results of both review and qualitative studies); (2) development phase (developing a primary guideline for SRH services); (3) validation phase (validation of the guideline will be performed by a panel of experts and stakeholders using the AGREE [Appraisal of Guidelines for Research and Evaluation] tool).

Discussion

A specific and practical guideline on the SRH of Iranian women with polycystic ovary syndrome will be developed, which will be compatible with their specific needs and culture, considering the limited resources available. It will help service providers identify and address the specific needs of women with polycystic ovary syndrome.
Recommendations to improve insurance coverage for physiotherapy services in Iran: a multi criteria decision-making approach
Authors: Shahabi Saeed , Skempes Dimitrios , Behzadifar Masoud , Tabrizi Reza , Nazari Behrooz , Ghanbari Mahboubeh Khaton , Heydari Seyed Taghi , Zarei Leila , Lankarani Kamran Bagheri
Published: December 2021

Background

High toll of traffic-related injuries, climate change, natural disasters, population aging, as well as chronic diseases have all made considerable demands on receiving physiotherapy services in Iran. Nevertheless, there is an assortment of complications facing utilization of such services, particularly poor insurance coverage. Therefore, the present study investigated and identified gaps in insurance coverage in order to inform future policy reforms and the design of a more comprehensive and universal benefits package for physiotherapy services in Iran.

Methods

This project was carried out in Iran, using a mix-methods (viz. qualitative-quantitative) approach. Within the first phase, a qualitative study was completed to find policy recommendations. Such recommendations were then prioritized through the Analytical Hierarchy Process (AHP), in the second phase, based on effectiveness, acceptability, cost, fairness, feasibility, and time.

Results

Within the first phase, a total number of 30 semi-structured interviews with health policy-makers, health insurers, faculty members, rehabilitation experts, and physiotherapists were completed. Several policy recommendations were also proposed by the study participants. Following the second phase, prioritized recommendations were provided to promote stewardship (e.g., informing policy-makers about physiotherapy services), collection of funds (e.g., placing value-added taxes on luxury goods and services), pooling of funds (e.g., moving allocated resources towards insurance (viz. third-party) mechanism), purchasing (e.g., using strategic purchasing), and benefit package (e.g., considering preventive interventions) as the main components of insurance coverage.

Conclusion

The study findings provided a favorable ground to improve insurance coverage for physiotherapy services in Iran. As well, decision- and policy-makers can place these recommendations on the agenda in the health sector to protect population health status, especially that of groups with disabilities.
A systematic review of artificial intelligence chatbots for promoting physical activity, healthy diet, and weight loss
Authors: Oh Yoo Jung , Zhang Jingwen , Fang Min-Lin , Fukuoka Yoshimi
Published: December 2021

Background

This systematic review aimed to evaluate AI chatbot characteristics, functions, and core conversational capacities and investigate whether AI chatbot interventions were effective in changing physical activity, healthy eating, weight management behaviors, and other related health outcomes.

Methods

In collaboration with a medical librarian, six electronic bibliographic databases (PubMed, EMBASE, ACM Digital Library, Web of Science, PsycINFO, and IEEE) were searched to identify relevant studies. Only randomized controlled trials or quasi-experimental studies were included. Studies were screened by two independent reviewers, and any discrepancy was resolved by a third reviewer. The National Institutes of Health quality assessment tools were used to assess risk of bias in individual studies. We applied the AI Chatbot Behavior Change Model to characterize components of chatbot interventions, including chatbot characteristics, persuasive and relational capacity, and evaluation of outcomes.

Results

The database search retrieved 1692 citations, and 9 studies met the inclusion criteria. Of the 9 studies, 4 were randomized controlled trials and 5 were quasi-experimental studies. Five out of the seven studies suggest chatbot interventions are promising strategies in increasing physical activity. In contrast, the number of studies focusing on changing diet and weight status was limited. Outcome assessments, however, were reported inconsistently across the studies. Eighty-nine and thirty-three percent of the studies specified a name and gender (i.e., woman) of the chatbot, respectively. Over half (56%) of the studies used a constrained chatbot (i.e., rule-based), while the remaining studies used unconstrained chatbots that resemble human-to-human communication.

Conclusion

Chatbots may improve physical activity, but we were not able to make definitive conclusions regarding the efficacy of chatbot interventions on physical activity, diet, and weight management/loss. Application of AI chatbots is an emerging field of research in lifestyle modification programs and is expected to grow exponentially. Thus, standardization of designing and reporting chatbot interventions is warranted in the near future.

Systematic review registration

International Prospective Register of Systematic Reviews (PROSPERO): CRD42020216761.
Universal coverage of the first antenatal care visit but poor continuity of care across the maternal and newborn health continuum among Nepalese women: analysis of levels and correlates
Authors: Khatri Resham B , Karkee Rajendra , Durham Jo , Assefa Yibeltal
Published: December 2021

Background

Routine maternity care visits (MCVs) such as antenatal care (ANC), institutional delivery, and postnatal care (PNC) visits are crucial to utilisation of maternal and newborn health (MNH) interventions during pregnancy-postnatal period. In Nepal, however, not all women complete these routine MCVs. Therefore, this study examined the levels and correlates of (dis)continuity of MCVs across the antenatal-postnatal period.

Methods

We conducted further analysis of the 2016 Nepal Demographic and Health Survey. A total of 1,978 women aged 15–49 years, who had live birth two years preceding the survey, were included in the analysis. The outcome variable was (dis)continuity of routine MCVs (at least four ANC visits, institutional delivery, and PNC visit) across the pathway of antennal through to postnatal period. Independent variables included several social determinants of health under structural, intermediary, and health system domains. Multinomial logistic regression was conducted to identify the correlates of routine MCVs. Relative risk ratios (RR) were reported with 95% confidence intervals at a significance level of p<0.05.

Results

Approximately 41% of women completed all routine MCVs with a high proportion of discontinuation around childbirth. Women of disadvantaged ethnicities, from low wealth status, who were illiterate had higher RR of discontinuation of MCVs (compared to completion of all MCVs). Similarly, women who speak Bhojpuri, from remote provinces (Karnali and Sudurpaschim), who had a high birth order (≥4), who were involved in the agricultural sector, and who had unwanted last birth had a higher RR of discontinuation of MCVs. Women discontinued routine MCVs if they had poor awareness of health mother-groups and perceived the problem of not having female providers.

Conclusions

Routine monitoring using composite coverage indicators is required to track the levels of (dis)continuity of routine MCVs at the maternity care continuum. Strategies such as raising awareness on the importance of maternity care, care provision from female health workers could potentially improve the completion of MCVs. In addition, policy and programmes for continuity of maternity care are needed to focus on women with socioeconomic and ethnic disadvantages and from remote provinces.
Mechanism of drug-induced liver injury and hepatoprotective effects of natural drugs
Authors: Zhou Yongfeng , Wang Junnan , Zhang Dingkun , Liu Jiaxin , Wu Qinghua , Chen Jiang , Tan Peng , Xing Boyu , Han Yanzhong , Zhang Ping , Xiao Xiaohe , Pei Jin
Published: December 2021

Drug-induced liver injury (DILI) is a common adverse drug reaction (ADR) and a serious threat to health that affects disease treatments. At present, no targeted clinical drugs are available for DILI. Traditional natural medicines have been widely used as health products. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for DILI treatment. In this review, we summarize the current knowledge, common drugs and mechanisms of DILI, as well as the clinical trials of natural drugs and their bioactive components in anticipation of the future development of potential hepatoprotective drugs.
Testing an early online intervention for the treatment of disturbed sleep during the COVID-19 pandemic in self-reported good and poor sleepers (Sleep COVID-19): study protocol for a randomised controlled trial
Authors: Sawdon Olivia L. , Elder Greg J. , Santhi Nayantara , Alfonso-Miller Pamela , Ellis Jason G.
Published: December 2021

Background

Theoretical models of insomnia suggest that stressful life events, such as the COVID-19 pandemic, can cause acute insomnia (short-term disruptions to sleep). Early interventions may prevent short-term sleep problems from progressing to insomnia disorder. Although cognitive behavioural therapy for insomnia (CBT-I) is effective in treating insomnia disorder, this can be time and resource-intensive. Further, online interventions can be used to deliver treatment to a large number of individuals. The objective of this study is to investigate if an online behavioural intervention, in the form of a leaflet, which has been successfully used alongside CBT-I for acute insomnia, can reduce symptoms of acute insomnia in poor sleepers.

Methods

A total of 124 self-reported good and poor sleepers will be enrolled in an online stratified randomised controlled trial. After baseline assessments (T1), participants will complete a 1-week pre-intervention sleep monitoring period (T2) where they will complete daily sleep-diaries. Poor sleepers (n = 62) will be randomly allocated to an invention or wait-list group, where they will receive the intervention (T3), or will do so after a 28-day delay. Good sleepers (n = 62) will be randomly assigned to an intervention or no intervention group. All participants will complete a 1-week post intervention sleep monitoring period using daily sleep diaries (T4). Participants will be followed up at 1 week (T5), 1 month (T6) and 3 months (T7) post intervention. The primary outcome measure will be insomnia severity, measured using the Insomnia Severity Index. Secondary outcome measures will include subjective mood and subjective sleep continuity, measured using sleep diaries. Data will be analysed using an intention-to-treat approach.

Discussion

It is expected that this online intervention will reduce symptoms of acute insomnia in self-reported short-term poor sleepers, and will also prevent the transition to poor sleep in good sleepers. We expect that this will demonstrate the feasibility of online interventions for the treatment and prevention of acute insomnia. Specific advantages of online approaches include the low cost, ease of administration and increased availability of treatment, relative to face-to-face therapy.

Trial registration

ISRCTN43900695 (Prospectively registered 8th of April 2020).
Critical care ultrasound training: a survey exploring the “education gap” between potential and reality in Canada
Authors: Slemko Jocelyn M. , Daniels Vijay J. , Bagshaw Sean M. , Ma Irene W. Y. , Brindley Peter G. , Buchanan Brian M.
Published: December 2021

Background

Critical care ultrasound (CCUS) is now a core competency for Canadian critical care medicine (CCM) physicians, but little is known about what education is delivered, how competence is assessed, and what challenges exist. We evaluated the Canadian CCUS education landscape and compared it against published recommendations.

Methods

A 23-item survey was developed and incorporated a literature review, national recommendations, and expert input. It was sent in the spring of 2019 to all 13 Canadian Adult CCM training programs via their respective program directors. Three months were allowed for data collection and descriptive statistics were compiled.

Results

Eleven of 13 (85%) programs responded, of which only 7/11 (64%) followed national recommendations. Curricula differed, as did how education was delivered: 8/11 (72%) used hands-on training; 7/11 (64%) used educational rounds; 5/11 (45%) used image interpretation sessions, and 5/11 (45%) used scan-based feedback. All 11 employed academic half-days, but only 7/11 (64%) used experience gained during clinical service. Only 2/11 (18%) delivered multiday courses, and 2/11 (18%) had mandatory ultrasound rotations. Most programs had only 1 or 2 local CCUS expert-champions, and only 4/11 (36%) assessed learner competency. Common barriers included educators receiving insufficient time and/or support.

Conclusions

Our national survey is the first in Canada to explore CCUS education in critical care. It suggests that while CCUS education is rapidly developing, gaps persist. These include variation in curriculum and delivery, insufficient access to experts, and support for educators.
Accelerated nonstandard finite difference method for singularly perturbed Burger-Huxley equations
Authors: Kabeto Masho Jima , Duressa Gemechis File
Published: December 2021

Objective

The main purpose of this paper is to present an accelerated nonstandard finite difference method for solving the singularly perturbed Burger-Huxley equation in order to produce more accurate solutions.

Results

The quasilinearization technique is used to linearize the nonlinear term. A nonstandard methodology of Mickens procedure is used in the spatial direction and also within the first order temporal direction that construct the first-order finite difference approximation to solve the considered problem numerically. To accelerate the rate of convergence from first to second-order, the Richardson extrapolation technique is applied. Numerical experiments were conducted to support the theoretical results.
Interferon-γ induces interleukin-6 production by neutrophils via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway
Authors: Yoshida Shuhei , Yamada Shunya , Yokose Kohei , Matsumoto Haruki , Fujita Yuya , Asano Tomoyuki , Matsuoka Naoki , Temmoku Jumpei , Sato Shuzo , Yoshiro-Furuya Makiko , Watanabe Hiroshi , Migita Kiyoshi
Published: December 2021

Objective

Interferon-gamma (IFN-γ) is overexpressed in rheumatoid synovium and thought to be involved in the pathogenesis of rheumatoid arthritis (RA). In this study, we examined our hypothesis that IFN-γ activates innate immune cells and upregulates inflammatory cytokines. Peripheral blood neutrophils were stimulated with IFN-γ in the presence or absence of Janus kinase (JAK) inhibitors. Interleukin-6 (IL-6) mRNA and protein expression were analyzed using real-time polymerase chain reaction (PCR) method and enzyme-linked immunosorbent assay. Protein phosphorylation of JAKs or STAT1 was assessed by Western blot using phospho-specific antibodies.

Results

IFN-γ stimulation induces IL-6 expression in protein and mRNA levels in human neutrophils. Furthermore, IFN-γ stimulation induces JAK1/JAK2 phosphorylation and downstream signal transducer and activator of transcription (STAT) 1 phosphorylation in human neutrophils. Although all JAKi, blocked IFN-γ-induced JAK1.2/STAT1 phosphorylation at higher concentrations (100 nM), baricitinib most efficiently inhibited IFN-γ-induced JAK1.2/STAT1 phosphorylation at lower concentrations (≤ 25 nM). Among these JAKi, baricitinib was the most potent regulator for IFN-γ-induced IL-6 production in human neutrophils. Our data indicate that IFN-γ upregulates IL-6 production via the JAK1/2-STAT1 pathway in human innate immune cells. Furthermore, this IFN-γ-mediated IL-6 induction via JAK/STAT was downregulated by JAKi.
Genome-wide methylation patterns in Marfan syndrome
Authors: van Andel Mitzi M. , Groenink Maarten , van den Berg Maarten P. , Timmermans Janneke , Scholte Arthur J. H. A. , Mulder Barbara J. M. , Zwinderman Aeilko H. , de Waard Vivian
Published: December 2021

Background

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process.

Methods

The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed.

Results

We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP’s that associated with clinical events. No significant associations at p < 10–8 or p < 10–6 were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18–22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before.

Conclusion

This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.
Infiltrative pattern of metastatic invasive lobular breast carcinoma in the abdomen: a pictorial review
Authors: Wong Ying Mei , Jagmohan Pooja , Goh Yong Geng , Putti Thomas Choudary , Ow Samuel Guan Wei , Thian Yee Liang , Pillay Premilla
Published: December 2021

Invasive lobular carcinoma (ILC) has a greater tendency to metastasize to the peritoneum, retroperitoneum, and gastrointestinal (GI) tract as compared to invasive carcinoma of no special type (NST). Like primary ILC in the breast, ILC metastases are frequently infiltrative and hypometabolic, rather than mass forming and hypermetabolic in nature. This renders them difficult to detect on conventional and metabolic imaging studies. As a result, intra-abdominal ILC metastases are often detected late,
with patients presenting with clinical complications such as liver failure, hydronephrosis, or bowel obstruction. In patients with known history of ILC, certain imaging features are very suggestive of infiltrative metastatic ILC. These include retroperitoneal or peritoneal nodularity and linitis plastica appearance of the bowel. Recognition of linitis plastica on imaging should prompt deep or repeat biopsies. In this pictorial review, the authors aim to familiarize readers with imaging features and pitfalls for evaluation of intra-abdominal metastatic ILC. Awareness of these will allow the radiologist to assess these patients with a high index of suspicion and aid detection of metastatic disease. Also, this can direct histopathology and immunohistochemical staining to obtain the correct diagnosis in suspected metastatic disease.
Using amide proton transfer-weighted MRI to non-invasively differentiate mismatch repair deficient and proficient tumors in endometrioid endometrial adenocarcinoma
Authors: Li Yuan , Liu Xinyu , Wang Xiaoqi , Lin Chengyu , Qi Yafei , Chen Bo , Zhou Hailong , Wu Qiaoling , Ren Jing , Zhao Jia , Yang Junjun , Xiang Yang , He Yonglan , Jin Zhengyu , Xue Huadan
Published: December 2021

Objectives

To investigate the utility of three-dimensional (3D) amide proton transfer-weighted (APTw) imaging to differentiate mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) tumors in endometrioid endometrial adenocarcinoma (EEA).

Methods

Forty-nine patients with EEA underwent T1-weighted imaging, T2-weighted imaging, 3D APTw imaging, and diffusion-weighted imaging at 3 T MRI. Image quality and measurement confidence of APTw images were evaluated on a 5-point Likert scale. APTw and apparent diffusion coefficient (ADC) values were calculated and compared between the dMMR and pMMR groups and among the three EEA histologic grades based on the Federation of Gynecology and Obstetrics (FIGO) grading system criteria. Student’s t-test, analysis of variance with Scheffe post hoc test, and receiver operating characteristic analysis were performed. Statistical significance was set atp < 0.05.

Results

Thirty-five EEA patients (9 with dMMR tumors and 26 with pMMR tumors) with good image quality were enrolled in quantitative analysis. APTw values were significantly higher in the dMMR group than in the pMMR group (3.2 ± 0.3% and 2.8 ± 0.5%, respectively;p = 0.019). ADC values of the dMMR and pMMR groups were 0.874 ± 0.104 × 10−3mm2/s and 0.903 ± 0.100 × 10−3mm2/s, respectively. No significant between-group difference was noted (p = 0.476). No statistically significant differences were observed in APTw values or ADC values among the three histologic grades (p = 0.766 andp = 0.295, respectively).

Conclusions

APTw values may be used as potential imaging markers to differentiate dMMR from pMMR tumors in EEA.
Prediction of small-molecule compound solubility in organic solvents by machine learning algorithms
Authors: Ye Zhuyifan , Ouyang Defang
Published: December 2021

Rapid solvent selection is of great significance in chemistry. However, solubility prediction remains a crucial challenge. This study aimed to develop machine learning models that can accurately predict compound solubility in organic solvents. A dataset containing 5081 experimental temperature and solubility data of compounds in organic solvents was extracted and standardized. Molecular fingerprints were selected to characterize structural features. lightGBM was compared with deep learning and traditional machine learning (PLS, Ridge regression, kNN, DT, ET, RF, SVM) to develop models for predicting solubility in organic solvents at different temperatures. Compared to other models, lightGBM exhibited significantly better overall generalization (logS  ± 0.20). For unseen solutes, our model gave a prediction accuracy (logS  ± 0.59) close to the expected noise level of experimental solubility data. lightGBM revealed the physicochemical relationship between solubility and structural features. Our method enables rapid solvent screening in chemistry and may be applied to solubility prediction in other solvents.
Evaluation of the mechanisms of sarcopenia in chronic inflammatory disease: protocol for a prospective cohort study
Authors: Dhaliwal Amritpal , Williams Felicity R. , Quinlan Jonathan I. , Allen Sophie L. , Greig Carolyn , Filer Andrew , Raza Karim , Ghosh Subrata , Lavery Gareth G. , Newsome Philip N. , Choudhary Surabhi , Breen Leigh , Armstrong Matthew J. , Elsharkawy Ahmed M. , Lord Janet M.
Published: December 2021

Background

Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use.

Methods

This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis.

Discussion

This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups.

Ethics and dissemination

The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server.

Trial registration

ClinicalTrials.gov Identifier:
NCT04734496
Association between mortality and age among mechanically ventilated COVID-19 patients: a Japanese nationwide COVID-19 database study
Authors: Tanaka Chie , Tagami Takashi , Nakayama Fumihiko , Kudo Saori , Takehara Akiko , Fukuda Reo , Kaneko Junya , Ishiki Yoshito , Sato Shin , Shibata Ami , Kuno Masamune , Unemoto Kyoko , Hojo Masayuki , Mizoue Tetsuya , Asai Yusuke , Suzuki Setsuko , Ohmagari Norio
Published: December 2021

Background

Only a few studies have reported the association between age and mortality in COVID-19 patients who require invasive mechanical ventilation (IMV). We aimed to evaluate the effect of age on COVID-19-related mortality among patients undergoing IMV therapy.

Methods

This cohort study was conducted using the COVID-19 Registry Japan database, a nationwide multi-centre study of hospitalized patients with laboratory-confirmed COVID-19. Of all 33,808 cases registered between 1 January 2020 to 28 February 2021, we analysed 1555 patients who had undergone IMV. We evaluated mortality rates between age groups using multivariable regression analysis after adjusting for known potential components, such as within-hospital clustering, comorbidities, steroid use, medication for COVID-19, and vital signs on admission, using generalized estimation equation.

Results

By age group, the mortality rates in the IMV group were 8.6%, 20.7%, 34.9%, 49.7% and 83.3% for patients in their 50s, 60s, 70s, 80s, and 90s, respectively. Multivariable analysis showed that compared with those for patients aged < 60 years, the odds ratios (95% confidence interval) of death were 2.6 (1.6–4.1), 6.9 (4.2–11.3), 13.2 (7.2–24.1), 92.6 (16.7–515.0) for patients in their 60s, 70s, 80s, and 90s, respectively.

Conclusions

In this cohort study, age had a great effect on mortality in COVID-19 patients undergoing IMV, after adjusting for variables independently associated with mortality. This study suggested that age was associated with higher mortality and that preventing progression to severe COVID-19 in elderly patients may be a great public health issue.
Rural opioid treatment program patient perspectives on take-home methadone policy changes during COVID-19: a qualitative thematic analysis
Authors: Levander Ximena A. , Hoffman Kim A. , McIlveen John W. , McCarty Dennis , Terashima Javier Ponce , Korthuis P. Todd
Published: December 2021

Background

In the United States, methadone for opioid use disorder (OUD) is highly regulated. Federal agencies announced guidelines in March 2020 allowing for relaxation of take-home methadone dispensing at opioid treatment programs (OTPs) to improve treatment access and reduce COVID-19 transmission risk during the public health emergency. We explored patient perspectives at three OTPs serving rural communities on how take-home policy changes were received and implemented and how these changes impacted their addiction treatment and recovery.

Methods

We completed semi-structured individual qualitative interviews in 2 phases: (1) August–October 2020 and (2) November 2020–January 2021 (total n = 46), anticipating possible policy changes as the pandemic progressed. We interviewed patients with OUD enrolled at 3 rural OTPs in Oregon. Participants received varying take-home methadone allowances following the COVID-19-related policy changes. All interviews were conducted via phone, audio-recorded, and transcribed. We conducted a thematic analysis, iteratively coding transcripts, and deductively and inductively generating codes.

Results

The 46 participants included 50% women and 89% had Medicaid insurance. Three main themes emerged in the analysis, with no differences between study phases: (1) Adapting to changing OTP policies throughout the pandemic; (2) Recognizing the benefits, and occasional struggles, with increased take-home methadone dosing; and (3) Continuing policies and procedures post-pandemic. Participants described fears and anxieties around ongoing methadone access and safety concerns prior to OTP policy changes, but quickly adapted as protocols soon seemed “natural.” The majority of participants acknowledged significant benefits to increased take-homes independent of reducing COVID-19 infection risk including feeling “more like a normal person,” improved recovery support, reduced time traveling, and having more time with family and for work. Looking to a post-pandemic future, participants thought some COVID-19-related safety protocols should continue that would reduce risk of other infections, make OTP settings less stressful, and result in more individualized care.

Conclusions

As the pandemic progressed, study participants adapted to rapidly changing OTP policies. Participants noted many unanticipated benefits to increased take-home methadone and other COVID-19 protocols including strengthened self-efficacy and recovery and reduced interpersonal conflict, with limited evidence of diversion. Patient perspectives should inform future policies to better address the ongoing overdose epidemic.
Crisis hazard assessment for snow-related lahars from an unforeseen new vent eruption: the 2018 eruption of Kusatsu-Shirane volcano, Japan
Authors: Kataoka Kyoko S. , Tsunematsu Kae , Matsumoto Takane , Urabe Atsushi , Kawashima Katsuhisa
Published: December 2021

Two-thirds of the 111 active volcanoes in Japan are covered with snow for several months during winter and demonstrate high hazard and risk potentials associated with snow-related lahars during and after eruptions. On 23 January 2018, a sudden phreatic eruption occurred at the ski field on Kusatsu-Shirane (Mt. Motoshirane) volcano, Japan. This new vent eruption from the snow-clad pyroclastic cone required forecasting of future snow-related lahars and crisis hazards zonation of downslope areas including Kusatsu town, a popular tourist site for skiing and hot springs. In order to achieve a prompt hazard assessment for snow-related lahars, a multidisciplinary approach was carried out involving characterization of proximal tephra deposits, snow surveys, and numerical lahar flow simulations using the Titan2D model. To determine the input parameters for the flow model, the consideration of snow water equivalent (SWE) immediately after the eruption (on 29 January) and in the post-eruptive period (on 12 March), was significant. In the case of Kusatsu-Shirane volcano during the winter of 2018, linear relationships between altitude and SWE, obtained at different elevations, were used to estimate the snow volume around the new vents. Several scenarios incorporating snow and snowmelt (water), with or without the occurrence of a new eruption, were simulated for the prediction of future lahars. Three lahar scenarios were simulated, including A) rain-on-snow triggered, B) ice/snow slurry, and C) full snowmelt triggered by a new eruption, and indicated the flow paths (inundation areas) and travel distances. These were useful for lahar hazard zonation and identification of potential high-risk areas. Since the input parameters required for the Titan2D flow model can be relatively easily determined, the model was suitable for the 2018 eruption at Motoshirane where historical and geological lahar records are not available for calibration. The procedure used in the study will enable rapid lahar prediction and hazard zonation at snow-clad volcanoes. Further consideration for simulating a cohesive-type flow, which was predicted by the primary deposits containing large amounts of clay minerals and could not be expressed in the Titan2D flow model, is necessary.
The numerical simulation of the generation of lower-band VLF chorus using a quasi-broadband Vlasov Hybrid Simulation code
Authors: Nunn David
Published: December 2021

In this paper, we perform the numerical modelling of lower-band VLF chorus in the earth’s magnetosphere. Assuming parallel propagation the 1d3v code has one spatial dimension z along the ambient magnetic field, which has a parabolic z dependence about the equator. The method used is Vlasov Hybrid Simulation (VHS) also known in the literature as the method of Kinetic Phase Point Trajectories (Nunn in Computer Physics Comms 60:1–25, 1990, J Computational Phys 108(1):180–196, 1993; Kazeminezhad et al. in Phys Rev E67:026704, 2003). The method is straightforward and easy to program, and robust against distribution function filamentation. Importantly, VHS does not invoke unphysical smoothing of the distribution function. Previous versions of the VLF/VHS code had a narrow bandwidth ~ 100 Hz, which enabled simulation of a wide variety of discrete triggered emissions. The present quasi-broadband VHS code has a bandwidth of ~ 3000 Hz, which is far more realistic for the simulation of chorus in its entirety. Further, the quasi-broadband code does not require artificial saturation, and does not need to employ matched filtering to accommodate large spatial frequency gradients. The aim of this paper which has been achieved is to produce VLF chorus Vlasov simulations employing a systematic variety of triggering input signals, namely key down, single pulse, PLHR, and broadband hiss.

Graphical Abstract
The personalized Berger method is usable to solve the problem of tibial rotation
Authors: András Gömöri , Németh Gábor , Oláh Csaba Zsolt , Lénárt Gábor , Drén Zsanett , Papp Miklós
Published: December 2021

Purpose

The revision of any total knee replacement is carried out in a significant number of cases, due to the excessive internal rotation of the tibial component. The goal was to develop a personalized method, using only the geometric parameters of the tibia, without the femoral guidelines, to calculate the postoperative rotational position of tibial component malrotation within a tolerable error threshold in every case.

Methods

Preoperative CT scans of eighty-five osteoarthritic knees were examined by three independent medical doctors twice over 7 weeks.

The geometric centre of the tibia was produced by the ellipse annotation drawn 8 mm below the tibial plateau, the sagittal and frontal axes of the ellipse were transposed to the slice of the tibial tuberosity. With the usage of several guide lines, a right triangle was drawn within which the personalized Berger angle was calculated.

Results

A very good intra-observer (0.89-0.925) and inter-observer (0.874) intra-class correlation coefficient (ICC) was achieved. Even if the average of the personalized Berger values were similar to the original 18° (18.32° in our case), only 70.6% of the patients are between the clinically tolerable thresholds (12.2° and 23.8°).

Conclusion

The method, measured on the preoperative CT scans, is capable of calculating the required correction during the planning of revision arthroplasties which are necessary due to the tibial component malrotation. The personalized Berger angle isn’t altered during arthroplasty, this way it determines which one of the anterior reference points of the tibia (medial 1/3 or the tip of the tibial tuberosity, medial border or 1/6 or 1/3 or the centre of the patellar tendon) can be used during the positioning of the tibial component.

Level of evidence

Level II, Diagnostic Study (Methodological Study).