bluuebunny/crossref_metadata_2025 huggingface dataset:
Tollip Orchestrates Macrophage Polarization to Alleviate Intestinal Mucosal Inflammation
Authors: Liu Xiaoming , Ren Xingxing , Zhou Lifeng , Liu Ke , Deng Liangjun , Qing Qing , Li Jin , Zhi Fachao , Li Mingsong
Published: January 2022

Background and Aims

Regulation of macrophage polarization is a promising strategy for treating inflammatory bowel disease [IBD]. Tollip is an important negative regulator of Toll-like receptor [TLR]-mediated innate immunity with downregulated expression in the colon tissues of patients with IBD. This study aimed to regulate the expression of Tollip to affect macrophage polarization.

Methods

A molecular, targeted immunotherapy method was developed by linking mannose-modified trimethyl chitosan [MTC] with Tollip-expressing plasmids via ionic cross-linking, forming MTC-Tollip nanoparticles with a targeting function. MTC-Tollip selectively targeted mouse intestinal macrophages to regulate the polarization of macrophages for mucosal repair.

Results

Orally administered MTC-Tollip significantly elevated Tollip expression in intestinal tissue. Compared with MTC-negative control [NC]-treated mice in which colitis was induced with dextran sodium sulphate [DSS], the MTC-Tollip nanoparticle-treated mice exhibited decreased body weight loss and colon shortening, lower proinflammatory cytokine expression in colon tissues, and greater mucosal barrier integrity. MTC-Tollip treatment decreased TNF-α and iNOS expression but increased CD206 and Arg-1 expression in colon tissue. Tollip overexpression in mouse peritoneal macrophages inhibited lipopolysaccharide [LPS]-induced proinflammatory cytokine production and promoted IL-4-induced M2 expression. The progression of peritoneal macrophages extracted from Tollip−/− mice confirmed the effect of Tollip on macrophage polarization. Western blots showed that Tollip overexpression attenuated the upregulation of TLR pathway-associated targets in M1 macrophages.

Conclusions

MTC nanoparticles can be ‘intelligent’ carriers in immunotherapy. The modulation of Tollip expression in macrophages may be a novel treatment approach for IBD.
Prognostic value of strain by feature-tracking cardiac magnetic resonance in arrhythmogenic right ventricular cardiomyopathy
Authors: Bourfiss M , Prakken N H J , James C A , Planken R N , Boekholdt S M , Ahmetagic D , van den Berg M P , Tichnell C , Van der Heijden J F , Loh P , Murray B , Tandri H , Kamel I , Calkins H , Asselbergs F W , Zimmerman S L , Velthuis B K , Te Riele A S J M
Published: January 2022

Aims

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by ventricular dysfunction and ventricular arrhythmias (VA). Adequate arrhythmic risk assessment is important to prevent sudden cardiac death. We aimed to study the incremental value of strain by feature-tracking cardiac magnetic resonance imaging (FT-CMR) in predicting sustained VA in ARVC patients.

Methods and results

CMR images of 132 ARVC patients (43% male, 40.6 ± 16.0 years) without prior VA were analysed for global and regional right and left ventricular (RV, LV) strain. Primary outcome was sustained VA during follow-up. We performed multivariable regression assessing strain, in combination with (i) RV ejection fraction (EF); (ii) LVEF; and (iii) the ARVC risk calculator. False discovery rate adjusted P-values were given to correct for multiple comparisons and c-statistics were calculated for each model. During 4.3 (2.0–7.9) years of follow-up, 19% of patients experienced sustained VA. Compared to patients without VA, those with VA had significantly reduced RV longitudinal (P ≤ 0.03) and LV circumferential (P ≤ 0.04) strain. In addition, patients with VA had significantly reduced biventricular EF (P ≤ 0.02). After correcting for RVEF, LVEF, and the ARVC risk calculator separately in multivariable analysis, both RV and LV strain lost their significance [hazard ratio 1.03–1.18, P > 0.05]. Likewise, while strain improved the c-statistic in combination with RVEF, LVEF, and the ARVC risk calculator separately, this did not reach statistical significance (P ≥ 0.18).

Conclusion

Both RV longitudinal and LV circumferential strain are reduced in ARVC patients with sustained VA during follow-up. However, strain does not have incremental value over RVEF, LVEF, and the ARVC VA risk calculator.
Gold-based lateral-flow strip for the detection of penconazole in watermelon and cucumber samples
Authors: Liu Yang , Xu Xinxin , Liu Liqiang , Xu Liguang , Kuang Hua , Xu Chuanlai
Published: January 2022

As a typical triazole fungicide, penconazole (PEN) is widely used in agriculture but has been proven to be toxic. In this study, we designed a new hapten to prepare a highly sensitive and specific anti-PEN monoclonal antibody (mAb) and established a gold nanoparticle-based lateral-flow immunoassay (LFIA) for the detection of PEN residues in watermelon and cucumber. The 50% inhibitory concentration (IC50) of the mAb was 0.42 ng/mL and the LFIA strip had a visual limit of detection (vLOD) of 2.5 ng/g and a cut-off value of 10 ng/g in watermelon and cucumbers. The calculated limit of detection (LOD) of the LFIA strip was 0.36 ng/g for watermelon and 0.29 ng/g for cucumber. The LFIA strip also gave a recovery rate of 92.5%–109.0% for watermelon samples and 92.5%–106.7% for cucumber samples. These results using the LFIA strip are highly consistent with those seen using liquid chromatography–tandem mass spectrometry. Thus our developed LFIA strip represents a potentially reliable tool for the rapid on-site screening for PEN in watermelons and cucumbers.
The effects of housing insecurity on children’s health: a scoping review
Authors: Bess Kiana D , Miller Alison L , Mehdipanah Roshanak
Published: January 2022

There is a well-established connection between housing conditions and children’s health. However, little is known on how housing insecurity indicators including, multiple moves, being behind on rent/mortgage, doubling up and crowding, affect child health. The purpose of this paper is to identify how pathways of association between housing insecurity and health may become established during childhood, using evidence from the literature. Using the Joanna Briggs Institute framework for scoping reviews, a search was conducted using key terms associated with housing insecurity and health among children. Twenty-seven articles were included in the review. Forty-six outcomes related to child health were identified throughout the articles. Physical health was the most commonly examined outcome in these articles. Multiple moves was the most common housing insecurity indicator associated with health. This review identified multiple studies showing negative associations between housing insecurity and poorer health-related indicators among children. Results from this review provide important information on the implication of certain housing insecurity indicators for children’s health. Although housing is increasingly recognized as a social determinant of health, it may be particularly important to go beyond physical housing conditions to consider and measure housing insecurity in future work, as a key social determinant shaping health in pediatric populations.
Modified implantation of a Bolton Relay branch arch device into the ascending aorta close to a mechanical aortic valve
Authors: Milnerowicz Artur , Jędrzejczak Tomasz , Rynio Paweł , Kazimierczak Arkadiusz
Published: January 2022

An aortic arch stent graft is usually contraindicated with a mechanical aortic valve. However, a modified stent graft plus the use of an externalized transapical guidewire technique allowed a safe implantation close to a mechanical aortic valve.
Deterministic and stochastic in-host tuberculosis models for bacterium-directed and host-directed therapy combination
Authors: Zhang Wenjing
Published: January 2022

Mycobacterium tuberculosis (TB) infection can involve all immune system components and can result in different disease outcomes. The antibiotic TB drugs require strict adherence to prevent both disease relapse and mutation of drug- and multidrug-resistant strains. To overcome the constraints of pathogen-directed therapy, host-directed therapy has attracted more attention in recent years as an adjunct therapy to enhance host immunity to fight against this intractable pathogen. The goal of this paper is to investigate in-host TB models to provide insights into therapy development. Focusing on therapy-targeting parameters, the parameter regions for different disease outcomes are identified from an established ODE model. Interestingly, the ODE model also demonstrates that the immune responses can both benefit and impede disease progression, depending on the number of bacteria engulfed and released by macrophages. We then develop two Itô SDE models, which consider the impact of demographic variations at the cellular level and environmental variations during therapies along with demographic variations. The SDE model with demographic variation suggests that stochastic fluctuations at the cellular level have significant influences on (1) the T-cell population in all parameter regions, (2) the bacterial population when parameters located in the region with multiple disease outcomes and (3) the uninfected macrophage population in the parameter region representing active disease. Further, considering environmental variations from therapies, the second SDE model suggests that disease progression can slow down if therapies (1) can have fast return rates and (2) can bring parameter values into the disease clearance regions.
Classification of Thompson Related Groups Arising from Jones Technology I
Authors: Brothier Arnaud
Published: January 2022

In the quest in constructing conformal field theories (CFTs), Jones has discovered a beautiful and deep connection between CFT, Richard Thompson’s groups, and knot theory. This led to a powerful functorial framework for constructing actions of particular groups arising from categories such as Thompson’s groups and braid groups. In particular, given a group and two of its endomorphisms one can construct a semidirect product where the largest Thompson’s group $V$ is acting. These semidirect products have remarkable diagrammatic descriptions that were previously used to provide new examples of groups having the Haagerup property. They naturally appear in certain field theories as being generated by local and global symmetries. Moreover, these groups occur in a construction of Tanushevski and can be realised using Brin–Zappa–Szep’s products with the technology of cloning systems of Witzel and Zaremsky. We consider in this article the class of groups obtained in that way where one of the endomorphism is trivial leaving the case of two nontrivial endomorphisms to a 2nd article. We provide an explicit description of all these groups as permutational restricted twisted wreath products where $V$ is the group acting and the twist depends on the endomorphism chosen. We classify this class of groups up to isomorphisms and provide a thin description of their automorphism group thanks to an unexpected rigidity phenomena.
Hypomethylation of thymosin β4 promoter is associated with glucocorticoid therapy in patients with acute-on-chronic hepatitis B-induced liver failure
Authors: Wang He , Qian Yu , Wang Jing-Wen , Fang Yu , Fan Yu-Chen , Liu Hui-Hui , Wang Kai
Published: January 2022

Background

We aimed to determine whether the methylation status of thymosin β4 (Tβ4) promoter reflects the severity of acute-on-chronic hepatitis B liver failure (ACHBLF) and whether glucocorticoids affect this status.

Methods

Fifty-six patients with ACHBLF, 45 with chronic hepatitis B (CHB) and 32 healthy controls (HCs), were retrospectively enrolled. Methylation-specific PCR and real-time PCR were used to detect Tβ4 methylation frequency and mRNA level. The expression of Tβ4 was measured before and after glucocorticoid treatment in patients with ACHBLF. Clinical and laboratory parameters were obtained.

Results

Tβ4 mRNA expression of patients with ACHBLF was lower than in patients with CHB or HCs, but the methylation frequency was higher. Tβ4 promoter methylation frequency was correlated with serum total bilirubin, prothrombin activity and model for end-stage liver disease score. Moreover, Tβ4 promoter methylation frequency decreased and demethylation occurred during glucocorticoid therapy. After glucocorticoid therapy, Tβ4 mRNA expression and liver function were better in patients with low levels of methylation than in those with higher levels. After 90 d, the survival of patients with low levels of methylation was significantly higher than those with high levels.

Conclusions

Patients with ACHBLF who have low levels of Tβ4 methylation may show a more favorable response to glucocorticoid treatment.
Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)—an open-labelled pilot randomized controlled trial
Authors: Campbell A. J. , Dotel R. , Braddick M. , Britton P. N. , Eisen D. P. , Francis J. R. , Lynar S. , McMullan B. , Meagher N. , Nelson J. , O’Sullivan M. V. N. , Price D. J. , Robinson J. O. , Whelan A. , Tong S. Y. C. , Bowen A. C. , Davis J. S.
Published: January 2022

Background

Combination antibiotic therapy with an antitoxin agent, such as clindamycin, is included in some guidelines for severe, toxin-mediated Staphylococcus aureus infections. The evidence to support this practice is currently limited to in vitro, animal and observational human case-series data, with no previous randomized controlled trials (RCTs).

Objectives

This pilot RCT aimed to determine the feasibility of conducting a clinical trial to examine if adjunctive clindamycin with standard therapy has greater efficacy than standard therapy alone for S. aureus infections.

Methods

We performed an investigator-initiated, open-label, multicentre, pilot RCT (ACTRN12617001416381p) in adults and children with severe S. aureus infections, randomized to standard antibiotic therapy with or without clindamycin for 7 days.

Results

Over 28 months, across nine sites, 127 individuals were screened and 34 randomized, including 11 children (32%). The primary outcome—number of days alive and free of systemic inflammatory response syndrome ≤14 days—was similar between groups: clindamycin (3 days [IQR 1–6]) versus standard therapy (4 days [IQR 0–8]). The 90 day mortality was 0% (0/17) in the clindamycin group versus 24% (4/17) in the standard therapy group. Secondary outcomes—microbiological relapse, treatment failure or diarrhoea—were similar between groups.

Conclusions

As the first clinical trial assessing adjunctive clindamycin for S. aureus infections, this study indicates feasibility and that adults and children can be incorporated into one trial using harmonized endpoints, and there were no safety concerns. The CASSETTE trial will inform the definitive S. aureus Network Adaptive Platform (SNAP) trial, which includes an adjunctive clindamycin domain and participants with non-severe disease.
Sialyl-Tn antigen facilitates extracellular vesicle-mediated transfer of FAK and enhances motility of recipient cells
Authors: Nagao Keisuke , Maeda Kento , Hosomi Kasumi , Morioka Kaito , Inuzuka Tatsutoshi , Ohtsubo Kazuaki
Published: January 2022

Protein glycosylation plays a pivotal role in tumour development by modulating molecular interactions and cellular signals. Sialyl-Tn (sTn) antigen is a tumour-associating carbohydrate epitope whose expression correlates with metastasis and poor prognosis of various cancers; however, its pathophysiological function is poorly understood. Extracellular vesicles (EVs) derived from cancer cells act as a signal mediator amongst tumour microenvironments by transferring cargo molecules. sTn antigen has been found in the glycans of EVs, thereby the functional relevance of sTn antigen to the regulation of tumour microenvironments could be expected. In the present study, we showed that sTn antigen induced TP53 and tumour suppressor–activated pathway 6 (TSAP6) and consequently enhanced EV production. Besides, the genetic attenuation of TSAP6 resulted in the reduction of the EV production in the sTn antigen expressing cells. The enhanced EV production in the sTn antigen–expressing cells consequently augmented the delivery of EVs to recipient cells. The produced EVs selectively and abundantly encased focal adhesion kinase and transferred it to EV-recipient cells, and thus, their cellular motility was enhanced. These findings would contribute to facilitate the elucidation of the pathophysiological significance of the sTn antigen in the tumour microenvironments and tumour development.
Money, Sacrificial Work, and Poor Consumers
Authors: Varman Rohit , Sreekumar Hari , Belk Russell W
Published: January 2022

This is an ethnography among poor migrants from Kerala, India to the Middle East. This study offers insights into how the poor accumulate sacrificial money through sufferings and self-abnegation, and earmark it for consumption in Kerala. The hardships endured to earn the sacrificial money transform it into a sacred object. The phenomena of accumulation, earmarking, and meaning making of sacrificial money by the poor can be understood through the concept of sacrificial work. Sacrificial work is a spatially demarcated circuit of accumulation of money through hardships and its conflict-ridden transfer to family, community, and self for consumption. In sacrificial work, the poor erect a boundary around this money, and earmark it as caring, communal, and transformative. By delineating the various aspects of sacrificial work, this study brings to the center a behavior that has, in spite of its ubiquity, been relegated to the margins of consumer research.
Acute hepatitis A in international travellers: a GeoSentinel analysis, 2008–2020
Authors: Balogun Oluwafemi , Brown Ashley , Angelo Kristina M , Hochberg Natasha S , Barnett Elizabeth D , Nicolini Laura Ambra , Asgeirsson Hilmir , Grobusch Martin P , Leder Karin , Salvador Fernando , Chen Lin , Odolini Silvia , Díaz-Menéndez Marta , Gobbi Federico , Connor Bradley A , Libman Michael , Hamer Davidson H
Published: January 2022

Background

Non-immune international travellers are at risk of acquiring hepatitis A. Although hepatitis A vaccination is recommended for unvaccinated travellers to high or intermediate hepatitis A virus endemicity, compliance with this recommendation is not universal.

The main objective was to describe the demographic and travel characteristics of international travellers infected with hepatitis A during travel.

Methods

Available data on travellers with confirmed (positive molecular test) or probable (symptomatic individuals with a single positive IgM test) hepatitis A diagnosed during and after travel from January 2008 to December 2020 were obtained from the GeoSentinel Surveillance Network database. We analysed demographic and travel characteristics of infected travellers.

Results

Among 254 travellers with hepatitis A (185 confirmed and 69 probable), the median age was 28 years (interquartile range: 19–40), 150 (59%) were male, and among 54 travellers with information available, 53 (98%) were unvaccinated. The most common reasons for travel included tourism (n = 120; 47%) and visiting friends or relatives (VFR; n = 72; 28%). About two-thirds of VFR travellers with hepatitis A (n = 50; 69%) were younger than 20 years old. Hepatitis A was acquired most frequently in South-Central Asia (n = 63; 25%) and sub-Saharan Africa (n = 61; 24%), but 16 travellers (6%) acquired hepatitis A in regions with low endemicity including Western Europe (n = 7; 3%), the Caribbean (n = 6; 2%) and North America (n = 3; 1%). Median duration from illness onset to GeoSentinel site presentation was ~7 days (interquartile range : 4–14 days). Among 88 travellers with information available, 59% were hospitalized.

Conclusions

Despite availability of highly effective vaccines, travellers still acquire hepatitis A, even when traveling to low-endemicity destinations. Providing pre-departure hepatitis A vaccine to susceptible travellers is crucial to reducing travel-associated hepatitis A and should be offered to all travellers as part of the pre-travel consultation, regardless of destination.
Early Modern Economic Theology and Oikonomia in The Merchant of Venice
Authors: Kim Jaecheol
Published: January 2022

The primary purpose of this article is to survey the issue of oikonomia and risk management in Shakespeare’s The Merchant of Venice in terms of economic theology. In the theology of the Apostle Paul, ‘oikonomia’ signifies God’s miraculous dispensation to guide human souls to salvation. Nonetheless, today’s economic theologians, including Giorgio Agamben, have demonstrated that its meaning has been gradually secularised, developing into capitalist ideas semantically covering concepts such as risk calculation, shaping human conduct to market conformity, and business administration. Shakespeare’s The Merchant of Venice is an intriguing narrative, situated at the historical juncture where the idea of oikonomia was secularised by mediating Christian theology with capitalist ideologies. The paradox of this comedy, in which nobody is killed and nobody goes bankrupt, is that uncalculating and abandoned risk management becomes proper administration. It is thus not surprising to see the idea of ‘mercy’ as the theme of the play, approaching the meaning of ‘dispensation’, an English translation of ‘oikonomia’.
A deep learning framework for Square Kilometre Array Science Data Challenge 1
Authors: Yu Lei , Liu Bin , Zhu Yan , Chen Ru-Rong , Xi Hong-Wei , Jin Cheng-Jin , Peng Bo
Published: January 2022

The Square Kilometre Array (SKA), as an eminent radio telescope of the next generation, will observe a huge number of objects with complex morphologies and sizes. An efficient method for locating and classifying radio sources becomes a requirement for scientific exploration. The SKA Science Data Challenge 1 (SDC1) is focused on the source detection, characterization, and classification for the SKA mid-frequency dish array of simulated continuum data. Three frequencies are covered (560, 1400, and 9200 MHz) to three depths (8, 100, and 1000 h). In this paper, we present an efficient deep learning framework, which is an entirely parallel, Python-based method for confronting the data challenge. The method can exceptionally achieve the source finding and categorizing simultaneously for both point and extended sources. In addition, the proposed denoising model can be a good noise estimator as a plugin for other similar applications. Compared with the published best, our score has improved by at least 22 per cent and up to 125 per cent in nine images of SDC1.
Phylotranscriptomics Resolves the Phylogeny of Pooideae and Uncovers Factors for Their Adaptive Evolution
Authors: Zhang Lin , Zhu Xinxin , Zhao Yiyong , Guo Jing , Zhang Taikui , Huang Weichen , Huang Jie , Hu Yi , Huang Chien-Hsun , Ma Hong
Published: January 2022

Adaptation to cool climates has occurred several times in different angiosperm groups. Among them, Pooideae, the largest grass subfamily with ∼3,900 species including wheat and barley, have successfully occupied many temperate regions and play a prominent role in temperate ecosystems. To investigate possible factors contributing to Pooideae adaptive evolution to cooling climates, we performed phylogenetic reconstruction using five gene sets (with 1,234 nuclear genes and their subsets) from 157 transcriptomes/genomes representing all 15 tribes and 24 of 26 subtribes. Our phylogeny supports the monophyly of all tribes (except Diarrheneae) and all subtribes with at least two species, with strongly supported resolution of their relationships. Molecular dating suggests that Pooideae originated in the late Cretaceous, with subsequent divergences under cooling conditions first among many tribes from the early middle to late Eocene and again among genera in the middle Miocene and later periods. We identified a cluster of gene duplications (CGD5) shared by the core Pooideae (with 80% Pooideae species) near the Eocene–Oligocene transition, coinciding with the transition from closed to open habitat and an upshift of diversification rate. Molecular evolutionary analyses homologs of CBF for cold resistance uncovered tandem duplications during the core Pooideae history, dramatically increasing their copy number and possibly promoting adaptation to cold habitats. Moreover, duplication of AP1/FUL-like genes before the Pooideae origin might have facilitated the regulation of the vernalization pathway under cold environments. These and other results provide new insights into factors that likely have contributed to the successful adaptation of Pooideae members to temperate regions.
Structural characterization of a new subclass of panicum mosaic virus-like 3′ cap-independent translation enhancer
Authors: Johnson Philip Z , Kasprzak Wojciech K , Shapiro Bruce A , Simon Anne E
Published: January 2022

Canonical eukaryotic mRNA translation requires 5′cap recognition by initiation factor 4E (eIF4E). In contrast, many positive-strand RNA virus genomes lack a 5′cap and promote translation by non-canonical mechanisms. Among plant viruses, PTEs are a major class of cap-independent translation enhancers located in/near the 3′UTR that recruit eIF4E to greatly enhance viral translation. Previous work proposed a single form of PTE characterized by a Y-shaped secondary structure with two terminal stem-loops (SL1 and SL2) atop a supporting stem containing a large, G-rich asymmetric loop that forms an essential pseudoknot (PK) involving C/U residues located between SL1 and SL2. We found that PTEs with less than three consecutive cytidylates available for PK formation have an upstream stem-loop that forms a kissing loop interaction with the apical loop of SL2, important for formation/stabilization of PK. PKs found in both subclasses of PTE assume a specific conformation with a hyperreactive guanylate (G*) in SHAPE structure probing, previously found critical for binding eIF4E. While PTE PKs were proposed to be formed by Watson–Crick base-pairing, alternative chemical probing and 3D modeling indicate that the Watson–Crick faces of G* and an adjacent guanylate have high solvent accessibilities. Thus, PTE PKs are likely composed primarily of non-canonical interactions.
Multiple in vivo roles for the C-terminal domain of the RNA chaperone Hfq
Authors: Kavita Kumari , Zhang Aixia , Tai Chin-Hsien , Majdalani Nadim , Storz Gisela , Gottesman Susan
Published: January 2022

Hfq, a bacterial RNA chaperone, stabilizes small regulatory RNAs (sRNAs) and facilitates sRNA base-pairing with target mRNAs. Hfq has a conserved N-terminal domain and a poorly conserved disordered C-terminal domain (CTD). In a transcriptome-wide examination of the effects of a chromosomal CTD deletion (Hfq1-65), the Escherichia coli mutant was most defective for the accumulation of sRNAs that bind the proximal and distal faces of Hfq (Class II sRNAs), but other sRNAs also were affected. There were only modest effects on the levels of mRNAs, suggesting little disruption of sRNA-dependent regulation. However, cells expressing Hfq lacking the CTD in combination with a weak distal face mutation were defective for the function of the Class II sRNA ChiX and repression of mutS, both dependent upon distal face RNA binding. Loss of the region between amino acids 66–72 was critical for this defect. The CTD region beyond amino acid 72 was not necessary for distal face-dependent regulation, but was needed for functions associated with the Hfq rim, seen most clearly in combination with a rim mutant. Our results suggest that the C-terminus collaborates in various ways with different binding faces of Hfq, leading to distinct outcomes for individual sRNAs.
The level of urinary C4d is associated with disease progression in IgA nephropathy with glomerular crescentic lesions: a cohort study
Authors: Wang Zi , Jiang Yuanyuan , Chen Pei , Wang Jinwei , Zhang Xue , Huang Bo , Zhou Xujie , Shi Sufang , Liu Lijun , Lv Jicheng , Zhang Hong
Published: January 2022

Background

Positive glomerular C4d staining, representative of lectin pathway activation, has been proven to be associated with unfavorable outcomes in immunoglobulin A nephropathy (IgAN). Our previous study suggested that urinary C4d correlated positively with an increase in crescents while the relationship between urinary C4d and disease severity and progression remains unelucidated.

Methods

In this study we enrolled 168 patients diagnosed with IgAN with varying proportions of crescent formation at the time of biopsy. An independent cohort of 107 IgAN patients was enrolled for validation. Kidney biopsy specimens were stained using immunohistochemistry. Urinary C4d levels at renal biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was end-stage kidney disease (ESKD).

Results

Higher urinary C4d/creatinine levels were associated with a lower estimated glomerular filtration rate (eGFR); massive proteinuria; hypertension and severe Oxford M, E, T and C scores. After a median follow-up of 19 months (interquartile range 9–27), 53 (31.5%) participants reached ESKD. High urinary C4d/creatinine levels were independently and significantly associated with a risk of developing ESKD [hazard ratio per standard deviation increment of log-transformed C4d/creatinine 7.623 (95% confidence interval 4.117–14.113)].

Conclusions

The urinary C4d/creatinine level is a potential useful biomarker that was associated with disease severity and progression in patients with IgAN and crescents.
Hospital clinicians’ psychosocial well-being during the COVID-19 pandemic: longitudinal study
Authors: Wynter Karen , Holton Sara , Trueman Melody , Bruce Suellen , Sweeney Sue , Crowe Shane , Dabscheck Adrian , Eleftheriou Paul , Booth Sarah , Hitch Danielle , Said Catherine M , Haines Kimberley J , Rasmussen Bodil
Published: January 2022

Background

Hospital clinicians report poor psychosocial well-being during the COVID-19 pandemic. Few studies have reported data at more than one time point.

Aims

To compare psychosocial well-being among hospital clinicians at two different time points during the COVID-19 pandemic in 2020.

Methods

Participants included doctors, nurses, midwives and allied health clinicians at a multi-site, public health service in Melbourne, Australia. Data were collected via two cross-sectional, online surveys: May to June (wave 1; n = 638) and October to December 2020 (wave 2; n = 358). The Depression, Anxiety and Stress Scale (DASS-21) assessed psychological well-being in the past week. Investigator-devised questions assessed COVID-19 concerns and perceived work impacts. General linear models were used to assess impact of wave on psychological distress.

Results

There were no significant demographic differences between the two groups. Both positive (e.g. learning experience) and negative (e.g. risk of getting COVID-19) impacts were reported. In both waves, staff were most concerned about health risks to family members. Wave 2 respondents were significantly more likely than wave 1 respondents to indicate concerns about colleagues having COVID-19, increased workloads, leave cancellation and increased conflict at work (all P < 0.001). Adjusting for sex, age, self-rated health and discipline group, depression, anxiety and stress scores were significantly higher for respondents in the second than the first wave (all P < 0.001).

Conclusions

Psychological well-being of hospital clinicians was significantly worse during the second wave of the COVID-19 pandemic than the first. Sustained occupational and psychosocial support is recommended even when immediate COVID-19 concerns and impacts resolve.
Transforming project delivery: integrated project delivery
Authors: Ashcraft Howard
Published: January 2022

The design and construction industry has long suffered low productivity and poor project outcomes. Collaborative approaches to project delivery offer an opportunity to transform outcomes by creating incentives in an environment that incentivizes high performance. This paper examines integrated project delivery (IPD), a collaborative contractual approach that alters a project’s fundamental commercial, organizational, and legal structures to minimize dysfunction and stimulate performance. IPD’s basic structures are introduced, followed by a critical examination of current and new research on IPD augmented by the author’s insights from structuring over 150 IPD projects. An online appendix provides additional information regarding the reasoning behind the IPD structures.
Lymphocyte subset abnormalities in early severe scleroderma favor a Th2 phenotype and are not altered by prior immunosuppressive therapy
Authors: Shah Ankoor , Storek Jan , Woolson Rob , Pinckney Ashley , Keyes-Elstein Lynnette , Wallace Paul K , Sempowski Gregory D , McSweeney Peter , Mayes Maureen D , Crofford Leslie , Csuka M E , Phillips Kristine , Khanna Dinesh , Simms Robert , Ballen Karen , LeClercq Sharon , Clair William St , Nixon Andrew B , Nash Richard , Wener Mark , Brasington Richard , Silver Richard , Griffith Linda M , Furst Daniel E , Goldmuntz Ellen , Sullivan Keith M
Published: January 2022

Objectives

The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy.

Methods

Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization.

Results

Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs.

Conclusions

In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself.

Trial registration

ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530.
Implementation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System in a randomized phase IIb study of abatacept in psoriatic arthritis
Authors: Østergaard Mikkel , Bird Paul , Pachai Chahin , Du Shuyan , Wu Chun , Landis Jessica , Fuerst Thomas , Ahmad Harris A , Connolly Sean E , Conaghan Philip G
Published: January 2022

Objectives

To investigate if the OMERACT PsA MRI Scoring System (PsAMRIS), including a novel total inflammation score, shows sensitivity to change with an agent (abatacept) known to impact clinical outcomes in PsA.

Methods

We performed a post hoc analysis of a randomized phase IIb study of abatacept in patients with PsA and inadequate DMARD response. Participants received one of three abatacept dosing regimens [ABA3, ABA10 or ABA30/10 mg/kg (30 mg/kg switched to 10 mg/kg after two doses)] or placebo until day 169, then ABA10 through day 365. MRIs at baseline and days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, osteitis, tenosynovitis, periarticular inflammation, bone erosions, joint space narrowing and bone proliferation were assessed using the PsAMRIS. A novel total inflammation score was tested.

Results

MRIs for 123 patients were included. On day 169, ABA10 and ABA30/10 significantly reduced MRI synovitis and tenosynovitis, respectively, vs placebo [differences −0.966 (P = 0.039) and −1.652 (P = 0.014), respectively]. Synovitis in the placebo group increased non-significantly from baseline to day 169, total inflammation and tenosynovitis decreased non-significantly and all measures improved significantly after a switch to ABA10 [−1.019, −0.940, −2.275 (P < 0.05), respectively, day 365 vs day 169]. Structural outcomes changed minimally across groups.

Conclusion

Adults with PsA receiving ABA10 and ABA30/10 demonstrated significant resolution of inflammatory components of disease, confirmed by MRI, with synovitis and tenosynovitis improvements consistent with previously reported clinical responses for these doses. Results indicate that a reduction in OMERACT PsAMRIS inflammation scores may provide proof of tissue-level efficacy in PsA clinical trials.

Registration

ClinicalTrials.gov (https://clinicaltrials.gov), NCT00534313.
Gastroparesis in systemic sclerosis: a detailed analysis using whole-gut scintigraphy
Authors: Adler Brittany , Hummers Laura K , Pasricha P Jay , McMahan Zsuzsanna H
Published: January 2022

Objectives

Gastroparesis is a common complication of SSc. We sought to determine the degree of overlap between gastroparesis and dysmotility in other areas of the gut, correlate our findings with gastrointestinal (GI) symptoms, and examine associations between gastroparesis and SSc features.

Methods

Whole-gut scintigraphy was performed on SSc patients who were enrolled in the Johns Hopkins Scleroderma Cohort, for whom detailed longitudinal clinical and serologic data are collected. A subset of patients completed the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA GIT 2.0) to quantify their GI symptoms. We examined associations between the presence and severity of gastroparesis, GI symptoms, and SSc clinical features.

Results

Ninety-seven SSc patients with and without GI symptoms underwent whole-gut scintigraphy and completed the gastric emptying study. Of the 97, 34 (35%) met criteria for gastroparesis. Of the measures assessed, delayed liquid emptying captured more patients with delayed gastric transit than delayed solid emptying (74% vs 55%), and percentage liquid emptying correlated best with GIT Reflux (ρ = −0.33, P = 0.01) and Distension (ρ = −0.30, P = 0.03) scores. Of 33 patients with gastroparesis, 30 (91%) had abnormal transit in other areas of the GI tract. Higher anti-centromere protein B (CENP-B) titres correlated with slower gastric emptying (ρ = −0.26, P = 0.03), but no specific clinical features of SSc were associated with gastroparesis.

Conclusions

Gastric emptying of liquids when given alongside solids may be more sensitive and provide a more clinically relevant measure of gastroparesis in SSc than solid gastric emptying or liquid gastric emptying alone. SSc patients with gastroparesis frequently have dysmotility in other areas of the GI tract, underscoring the need for whole-gut scintigraphy to evaluate the entire gut.
LINC00173 Interacts With DNMT1 to Regulate LINC00173 Expression via Promoter Methylation in Hydroquinone-Induced Malignantly Transformed TK6 Cells and Benzene-Exposed Workers
Authors: Zhang Haiqiao , Pan Zhijie , Ling Xiaoxuan , Tan Qiang , Yuan Qian , Qin Jiheng , Zhong Bohuan , Li Huifang , Chen Jialong , Zhang He , Chen Xiaowen , Shi Zhizhen , Liu Linhua
Published: January 2022

Long-term exposure to benzene or its metabolite, hydroquinone (HQ), can causally contribute to acute myeloid leukemia. Long-noncoding RNAs are essential epigenetic regulators with critical roles in tumor initiation and malignant progression; however, the mechanism by which aberrantly expressed LINC00173 (long intergenic nonprotein coding RNA 173) regulates the pathogenesis of acute myeloid leukemia is not fully understood. Here, we found that the expression of LINC00173 decreased while the expression of DNA methyltransferase 1 (DNMT1) increased, and the methylation of LINC00173 promoter was negatively correlated with LINC00173 expression in GEPIA, CCLE databases, benzene-exposed workers, B-cell non-Hodgkin’s lymphoma, K562, U937, or HQ-induced malignantly transformed TK6 (HQ-MT cells). Furthermore, in 5-aza-2’-deoxycytidine (DNA methyltransferase inhibitor) or trichostatin A (histone deacetylation inhibitor)-treated HQ-MT cells, the expression of LINC00173 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT1 knockout by CRISPR/Cas9 restored the expression of LINC00173 and inhibited the DNA methylation of its promoter as well as enrichment of DNMT1 to promoter. Overexpression of LINC00173 inhibited the expression of DNMT1, cell proliferation, tumor growth, enhanced chemosensitivity to cisplatin, and apoptosis in HQ-MT cells. LINC00173 interacts with DNMT1 to regulate the methylation of LINC00173 promoter. Overall, this study provides evidence that interaction between DNMT1 and LINC00173 regulates the expression of LINC00173 by regulating its promoter methylation level, thus regulating the function of HQ-MT cells in vitro and in vivo, providing a new therapeutic target for benzene-induced tumor.
Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons
Authors: You Dahea , Cohen Jennifer D , Pustovalova Olga , Lewis Lauren , Shen Lei
Published: January 2022

Elucidation of predictive fluidic biochemical markers to detect and monitor chemical-induced neurodegeneration has been a major challenge due to a lack of understanding of molecular mechanisms driving altered neuronal morphology and function, as well as poor sensitivity in methods to quantify low-level biomarkers in bodily fluids. Here, we evaluated 5 neurotoxicants (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, doxorubicin, paclitaxel, and rotenone) in human-induced pluripotent stem cell-derived neurons to profile secreted microRNAs (miRNAs) at early and late stages of decline in neuronal cell morphology and viability. Based on evaluation of these morphological (neurite outgrowth parameters) and viability (adenosine triphosphate) changes, 2 concentrations of each chemical were selected for analysis in a human 754 miRNA panel: a low concentration with no/minimal effect on cell viability but a significant decrease in neurite outgrowth, and a high concentration with a significant decrease in both endpoints. A total of 39 miRNAs demonstrated significant changes (fold-change ≥ 1.5 or ≤ 0.67, p value < .01) with at least 1 exposure. Further analyses of targets modulated by these miRNAs revealed 38 key messenger RNA targets with roles in neurological dysfunctions, and identified transforming growth factor-beta (TGF-β) signaling as a commonly enriched pathway. Of the 39 miRNAs, 5 miRNAs, 3 downregulated (miR-20a, miR-30b, and miR-30d) and 3 upregulated (miR-1243 and miR-1305), correlated well with morphological changes induced by multiple neurotoxicants and were notable based on their relationship to various neurodegenerative conditions and/or key pathways, such as TGF-β signaling. These datasets reveal miRNA candidates that warrant further evaluation as potential safety biomarkers of chemical-induced neurodegeneration.
Comparison of Effects of Propofol and Sevoflurane on the Cerebral Vasculature Assessed by Digital Subtraction Angiographic Parameters in Patients Treated for Ruptured Cerebral Aneurysm: A Preliminary Study
Authors: Joys Steve , Panda Nidhi B. , Ahuja Chirag K. , Luthra Ankur , Tripathi Manjul , Mahajan Shalvi , Kaloria Narender , Jain Chirag , Singh Nidhi , Regmi Sabina , Jangra Kiran , Chauhan Rajeev , Soni Shiv L. , Bhagat Hemant
Published: January 2022

Background:

Studies have evaluated the effects of volatile and intravenous anesthetic agents on the cerebral vasculature with inconsistent results. We used digital subtraction angiography to compare the effects of propofol and sevoflurane on the luminal diameter of cerebral vessels and on cerebral transit time in patients with aneurysmal subarachnoid hemorrhage (aSAH).

Methods:

This prospective preliminary study included adult patients with good-grade aSAH scheduled for endovascular coil embolization; patients were randomized to receive propofol or sevoflurane anesthesia during endovascular coiling. The primary outcome was the luminal diameter of 7 cerebral vessel segments measured on the diseased and nondiseased sides of the brain at 3 time points: awake, postinduction of anesthesia, and postcoiling. Cerebral transit time was also measured as a surrogate for cerebral blood flow.

Results:

Eighteen patients were included in the analysis (9 per group). Baseline and intraoperative parameters were similar between the groups. Propofol increased the diameter of 1 vessel segment at postinduction and postcoiling on the diseased side and in 1 segment at postcoiling on the nondiseased side of the brain (P<0.05). Sevoflurane increased vessel diameter in 3 segments at postinduction and in 2 segments at postcoiling on the diseased side, and in 4 segments at postcoiling on the nondiseased side (P<0.05). Cerebral transit time did not change compared with baseline awake state in either group and was not different between the groups.

Conclusions:

Sevoflurane has cerebral vasodilating properties compared with propofol in patients with good-grade aSAH. However, sevoflurane affects cerebral transit time comparably to propofol.
Irreversible Electroporation Ablation for Atrial Fibrillation: Status and Challenges
Authors: Xie Fei , Chen Yonggang , Chen Xinhua , Zhao Zhihong
Published: January 2022

Pulsed electric field (PEF) is a novel energy source by which high-voltage electric pulses are used to create irreversible electroporation. PEF is non-thermal and highly tissue-dependent in which specific targeting of the atrial myocardium is achieved and sparing of adjacent tissues is feasible, theoretically increasing the safety of the procedure, which could potentially break the trade-off between effective lesions and collateral damage and substantially improve risk-benefit ratios in atrial fibrillation (AF) ablation. Although recently published trials have shown a clear effect of AF ablation, large-scale clinical trials are lacking. Current clinical evidence has demonstrated significant efficacy in achieving durable pulmonary vein isolation without ablation-related adverse events. However, their putative benefits regarding efficacy, efficiency, and safety remain to be proven in randomized controlled trials.
With Fearful Eyes: Exploring Relatives' Experiences With Out-of-Hospital Cardiac Arrest
Authors: Larsen Malene Kaas , Mikkelsen Randi , Budin Susanne Holst , Lamberg Dorte Nees , Thrysoe Lars , Borregaard Britt
Published: January 2022

Background

Out-of-hospital cardiac arrest (OHCA) imposes significant consequences for a family, but little is known about relatives' experiences.

Objective

Our aim was to explore relatives' experiences with the OHCA and the following months after.

Method

A qualitative approach using phenomenological-hermeneutic methodology was applied. Data consisted of semistructured interviews with 12 relatives of OHCA survivors. We analyzed data based on Paul Ricoeur's theory of interpretation.

Results

Relatives experienced OHCA as an abrupt and stressful event filled with imposing concerns for the cardiac arrest survivor. Relatives were fellow sufferers confronted with the possibility of bereavement, watching from the sideline with fearful eyes. After the OHCA, relatives experienced a troubled time with anxiety and edginess, monitoring the survivor for signs of a new cardiac arrest and trying to adapt to a new normality. Relatives' previous identities and positions within their families were disrupted.

Conclusion

Relatives were challenged with the OHCA and the trajectory after it, experiencing a high level of distress and anxiety. Relatives took on an immense responsibility, always watching the survivor for potential symptoms of a new cardiac arrest. The cardiac arrest and the survivor's possible cognitive impairments gave rise to assuming a new authority as a relative. We advocate for a new family approach to relatives, acknowledging relatives' stress and central role in supporting cardiac arrest survivors.