bluuebunny/crossref_metadata_2025 huggingface dataset:
Stem cell-derived porcine macrophages as a new platform for studying host-pathogen interactions
Authors: Meek Stephen , Watson Tom , Eory Lel , McFarlane Gus , Wynne Felicity J. , McCleary Stephen , Dunn Laura E. M. , Charlton Emily M. , Craig Chloe , Shih Barbara , Regan Tim , Taylor Ryan , Sutherland Linda , Gossner Anton , Chintoan-Uta Cosmin , Fletcher Sarah , Beard Philippa M. , Hassan Musa A. , Grey Finn , Hope Jayne C. , Stevens Mark P. , Nowak-Imialek Monika , Niemann Heiner , Ross Pablo J. , Tait-Burkard Christine , Brown Sarah M. , Lefevre Lucas , Thomson Gerard , McColl Barry W. , Lawrence Alistair B. , Archibald Alan L. , Steinbach Falko , Crooke Helen R. , Gao Xuefei , Liu Pentao , Burdon Tom
Published: January 2022

Background

Infectious diseases of farmed and wild animals pose a recurrent threat to food security and human health. The macrophage, a key component of the innate immune system, is the first line of defence against many infectious agents and plays a major role in shaping the adaptive immune response. However, this phagocyte is a target and host for many pathogens. Understanding the molecular basis of interactions between macrophages and pathogens is therefore crucial for the development of effective strategies to combat important infectious diseases.

Results

We explored how porcine pluripotent stem cells (PSCs) can provide a limitless in vitro supply of genetically and experimentally tractable macrophages. Porcine PSC-derived macrophages (PSCdMs) exhibited molecular and functional characteristics of ex vivo primary macrophages and were productively infected by pig pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV) and African swine fever virus (ASFV), two of the most economically important and devastating viruses in pig farming. Moreover, porcine PSCdMs were readily amenable to genetic modification by CRISPR/Cas9 gene editing applied either in parental stem cells or directly in the macrophages by lentiviral vector transduction.

Conclusions

We show that porcine PSCdMs exhibit key macrophage characteristics, including infection by a range of commercially relevant pig pathogens. In addition, genetic engineering of PSCs and PSCdMs affords new opportunities for functional analysis of macrophage biology in an important livestock species. PSCs and differentiated derivatives should therefore represent a useful and ethical experimental platform to investigate the genetic and molecular basis of host-pathogen interactions in pigs, and also have wider applications in livestock.
Cell-free DNA methylation markers for differential diagnosis of hepatocellular carcinoma
Authors: Luo Biyuan , Ma Fang , Liu Hao , Hu Jixiong , Rao Le , Liu Chun , Jiang Yongfang , Kuangzeng Shuyu , Lin Xuan , Wang Chenyang , Lei Yiyu , Si Zhongzhou , Chen Guangshun , Zhou Ning , Liang Chengbai , Jiang Fangqing , Liu Fenge , Dai Weidong , Liu Wei , Gao Yawen , Li Zhihong , Li Xi , Zhou Guangyu , Li Bingsi , Zhang Zhihong , Nian Weiqi , Luo Lihua , Liu Xianling
Published: January 2022

Background

Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identify a non-invasive DNA methylation-based screening approach using cell-free DNA (cfDNA) for early detection of hepatocellular carcinoma (HCC).

Methods

Differentially, DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, liver cirrhosis, and normal tissue samples with high throughput DNA bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated blocks (DMBs). This model was tested in a cohort consisting of 120 HCC, 92 liver cirrhotic, and 290 healthy plasma samples including 65 hepatitis B surface antigen-seropositive (HBsAg+) samples, independently validated in a cohort consisting of 67 HCC, 111 liver cirrhotic, and 242 healthy plasma samples including 56 HBsAg+ samples.

Results

Based on methylation profiling of tissue samples, 2321 DMBs were identified, which were subsequently used to construct a cfDNA-based HCC screening model, achieved a sensitivity of 86% and specificity of 98% in the training cohort and a sensitivity of 84% and specificity of 96% in the independent validation cohort. This model obtained a sensitivity of 76% in 37 early-stage HCC (Barcelona clinical liver cancer [BCLC] stage 0-A) patients. The screening model can effectively discriminate HCC patients from non-HCC controls, including liver cirrhotic patients, asymptomatic HBsAg+ and healthy individuals, achieving an AUC of 0.957(95% CI 0.939–0.975), whereas serum α-fetoprotein (AFP) only achieved an AUC of 0.803 (95% CI 0.758–0.847). Besides detecting patients with early-stage HCC from non-HCC controls, this model showed high capacity for distinguishing early-stage HCC from a high risk population (AUC=0.934; 95% CI 0.905–0.963), also significantly outperforming AFP. Furthermore, our model also showed superior performance in distinguishing HCC with normal AFP (< 20ng ml−1) from high risk population (AUC=0.93; 95% CI 0.892–0.969).

Conclusions

We have developed a sensitive blood-based non-invasive HCC screening model which can effectively distinguish early-stage HCC patients from high risk population and demonstrated its performance through an independent validation cohort.

Trial registration

The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). The study is registered at ClinicalTrials.gov(#NCT04383353).
Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection
Authors: Ryan Feargal J. , Hope Christopher M. , Masavuli Makutiro G. , Lynn Miriam A. , Mekonnen Zelalem A. , Yeow Arthur Eng Lip , Garcia-Valtanen Pablo , Al-Delfi Zahraa , Gummow Jason , Ferguson Catherine , O’Connor Stephanie , Reddi Benjamin A. J. , Hissaria Pravin , Shaw David , Kok-Lim Chuan , Gleadle Jonathan M. , Beard Michael R. , Barry Simon C. , Grubor-Bauk Branka , Lynn David J.
Published: January 2022

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as “long COVID”, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects.

Methods

We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and > 50% reported ongoing symptoms more than 6 months post-infection.

Results

Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not.

Conclusions

Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.
Arsenic exposure during pregnancy and postpartum maternal glucose tolerance: evidence from Bangladesh
Authors: Fleisch Abby F. , Mukherjee Sudipta Kumer , Biswas Subrata K. , Obrycki John F. , Ekramullah Sheikh Muhammad , Arman D. M. , Islam Joynul , Christiani David C. , Mazumdar Maitreyi
Published: January 2022

Background

Arsenic exposure has been associated with gestational diabetes mellitus. However, the extent to which arsenic exposure during pregnancy is associated with postpartum glucose intolerance is unknown.

Methods

We studied 323 women in Bangladesh. We assessed arsenic exposure in early pregnancy via toenail and water samples. We measured fasting glucose and insulin in serum at a mean (SD) of 4.0 (3.5) weeks post-delivery. We ran covariate-adjusted, linear regression models to examine associations of arsenic concentrations with HOMA-IR, a marker of insulin resistance, and HOMA-β, a marker of beta cell function.

Results

Median (IQR) arsenic concentration was 0.45 (0.67) μg/g in toenails and 2.0 (6.5) μg/L in drinking water. Arsenic concentrations during pregnancy were not associated with insulin resistance or beta cell function postpartum. HOMA-IR was 0.07% (− 3.13, 3.37) higher and HOMA-β was 0.96% (− 3.83, 1.99) lower per IQR increment in toenail arsenic, but effect estimates were small and confidence intervals crossed the null.

Conclusions

Although arsenic exposure during pregnancy has been consistently associated with gestational diabetes mellitus, we found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function.
EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3
Authors: Pan Ziwen , Zhao Rongrong , Li Boyan , Qi Yanhua , Qiu Wei , Guo Qindong , Zhang Shouji , Zhao Shulin , Xu Hao , Li Ming , Gao Zijie , Fan Yang , Xu Jianye , Wang Huizhi , Wang Shaobo , Qiu Jiawei , Wang Qingtong , Guo Xing , Deng Lin , Zhang Ping , Xue Hao , Li Gang
Published: January 2022

Background

Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours.

Methods

CircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted.

Results

We identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression.

Conclusions

This work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.
Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy
Authors: Légaré Cécilia , Clément Andrée-Anne , Desgagné Véronique , Thibeault Kathrine , White Frédérique , Guay Simon-Pierre , Arsenault Benoit J. , Scott Michelle S. , Jacques Pierre-Étienne , Perron Patrice , Guérin Renée , Hivert Marie-France , Bouchard Luigi
Published: January 2022

Background

During pregnancy, maternal metabolism undergoes substantial changes to support the developing fetus. Such changes are finely regulated by different mechanisms carried out by effectors such as microRNAs (miRNAs). These small non-coding RNAs regulate numerous biological functions, mostly through post-transcriptional repression of gene expression. miRNAs are also secreted in circulation by numerous organs, such as the placenta. However, the complete plasmatic microtranscriptome of pregnant women has still not been fully described, although some miRNA clusters from the chromosome 14 (C14MC) and the chromosome 19 (C19MC and miR-371-3 cluster) have been proposed as being specific to pregnancy. Our aims were thus to describe the plasma microtranscriptome during the first trimester of pregnancy, by assessing the differences with non-pregnant women, and how it varies between the 4th and the 16th week of pregnancy.

Methods

Plasmatic miRNAs from 436 pregnant (gestational week 4 to 16) and 15 non-pregnant women were quantified using Illumina HiSeq next-generation sequencing platform. Differentially abundant miRNAs were identified using DESeq2 package (FDR q-value ≤ 0.05) and their targeted biological pathways were assessed with DIANA-miRpath.

Results

A total of 2101 miRNAs were detected, of which 191 were differentially abundant (fold change < 0.05 or > 2, FDR q-value ≤ 0.05) between pregnant and non-pregnant women. Of these, 100 miRNAs were less and 91 miRNAs were more abundant in pregnant women. Additionally, the abundance of 57 miRNAs varied according to gestational age at first trimester, of which 47 were positively and 10 were negatively associated with advancing gestational age. miRNAs from the C19MC were positively associated with both pregnancy and gestational age variation during the first trimester. Biological pathway analysis revealed that these 191 (pregnancy-specific) and 57 (gestational age markers) miRNAs targeted genes involved in fatty acid metabolism, ECM-receptor interaction and TGF-beta signaling pathways.

Conclusion

We have identified circulating miRNAs specific to pregnancy and/or that varied with gestational age in first trimester. These miRNAs target biological pathways involved in lipid metabolism as well as placenta and embryo development, suggesting a contribution to the maternal metabolic adaptation to pregnancy and fetal growth.
Outcomes of patients with HIV and COVID-19 co-infection: a systematic review and meta-analysis
Authors: Danwang Celestin , Noubiap Jean Jacques , Robert Annie , Yombi Jean Cyr
Published: January 2022

Background

Data on the association of human immunodeficiency virus (HIV) infection with adverse outcomes in patients with COVID-19 are conflicting. This systematic review and meta-analysis aimed to summarize the available information on the risk of hospitalization, severe disease, and death attributable to HIV in patients with COVID-19.

Methods

PubMed, EMBASE, Web of Science, and SCOPUS were searched through October 25, 2021, to identify relevant studies, without language restriction. A random-effects model was used to pool estimates.

Results

We included 44 studies reporting information from 38,971,065 patients with COVID-19. The pooled prevalence of HIV among COVID-19 patients was 26.9 ‰ (95% CI 22.7–31.3) and was significantly higher in studies conducted in Africa compared to those conducted elsewhere (118.5‰ [95% CI 84.8–156.9, 11 studies] vs 10.9‰ [95% CI 8.8–13.2, 27 studies]). In pooled analyses of unadjusted odds ratio, HIV-positive individuals were more likely to be admitted to hospital (OR: 1.49; 95% CI 1.01–2.21, 6 studies) compared to HIV-negative individuals. In the adjusted (for age and sex) analyses, HIV was associated with an increased risk of death (hazard ratio: 1.76, 95% CI 1.31–2.35, 2 studies). However, HIV was not associated with the severity of the disease (OR: 1.28; 95% CI 0.77–2.13, 13 studies), or death (OR: 0.81; 95% CI 0.47; 1.41, 23 studies) in patients with COVID-19 in the meta-analysis of unadjusted odds ratio.

Conclusion

Our findings suggest that patients with HIV have an increased risk of hospital admission for COVID-19. HIV seems to be independently associated with increased risk of mortality in COVID-19 patient in adjusted analysis. However, this evidence was derived from only two studies.
Repeatability of endocrine traits and dominance rank in female guinea pigs
Authors: Rystrom Taylor L. , Prawitt Romy C. , Richter S. Helene , Sachser Norbert , Kaiser Sylvia
Published: January 2022

Background

Glucocorticoids (e.g. cortisol) are associated with variation in social behavior, and previous studies have linked baseline as well as challenge-induced glucocorticoid concentrations to dominance status. It is known that cortisol response to an acute challenge is repeatable and correlates to social behavior in males of many mammal species. However, it is unclear whether these patterns are also consistent for females. The aim of this study was to investigate whether baseline and response cortisol concentrations are repeatable in female guinea pigs (Cavia apereaf.porcellus) and whether dominance rank is stable and correlated to baseline cortisol concentration and/or cortisol responsiveness.

Results

Our results show that cortisol responsiveness (after 1 h: R = 0.635, 95% CI = 0.229, 0.927; after 2 h: R = 0.764, 95% CI = 0.433, 0.951) and dominance rank (R = 0.709, 95% CI = 0.316, 0.935) of females were significantly repeatable after six weeks but not correlated. Baseline cortisol was not repeatable (R = 0, 95% CI = 0, 0.690) and also did not correlate to dominance rank. Furthermore, the difference in repeatability estimates of baseline and response values was due to high within-individual variance of baseline cortisol concentration; the amount of between-individual variance was similar for baseline cortisol and the two measures of cortisol responsiveness.

Conclusions

Females occupying different dominance ranks did not have long-term differences in cortisol concentrations, and cortisol responsiveness does not seem to be significantly involved in the maintenance of dominance rank. Overall, this study reveals the remarkable stability of cortisol responsiveness and dominance rank in a female rodent, and it remains an open question whether the magnitude of cortisol responsiveness is adaptive in social contexts for females.
Identification of the most specific markers to differentiate primary pulmonary carcinoma from metastatic gastrointestinal carcinoma to the lung
Authors: Alabdullah Bachar , Hadji-Ashrafy Amir
Published: January 2022

Background

A number of biomarkers have the potential of differentiating between primary lung tumours and secondary lung tumours from the gastrointestinal tract, however, a standardised panel for that purpose does not exist yet. We aimed to identify the smallest panel that is most sensitive and specific at differentiating between primary lung tumours and secondary lung tumours from the gastrointestinal tract.

Methods

A total of 170 samples were collected, including 140 primary and 30 non-primary lung tumours and staining for CK7, Napsin-A, TTF1, CK20, CDX2, and SATB2 was performed via tissue microarray. The data was then analysed using univariate regression models and a combination of multivariate regression models and Receiver Operating Characteristic (ROC) curves.

Results

Univariate regression models confirmed the 6 biomarkers’ ability to independently predict the primary outcome (p < 0.001). Multivariate models of 2-biomarker combinations identified 11 combinations with statistically significant odds ratios (ORs) (p < 0.05), of which TTF1/CDX2 had the highest area under the curve (AUC) (0.983, 0.960–1.000 95% CI). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 75.7, 100, 100, and 37.5% respectively. Multivariate models of 3-biomarker combinations identified 4 combinations with statistically significant ORs (p < 0.05), of which CK7/CK20/SATB2 had the highest AUC (0.965, 0.930–1.000 95% CI). The sensitivity, specificity, PPV, and NPV were 85.1, 100, 100, and 41.7% respectively. Multivariate models of 4-biomarker combinations did not identify any combinations with statistically significant ORs (p < 0.05).

Conclusions

The analysis identified the combination of CK7/CK20/SATB2 to be the smallest panel with the highest sensitivity (85.1%) and specificity (100%) for predicting tumour origin with an ROC AUC of 0.965 (p < 0.001; SE: 0.018, 0.930–1.000 95% CI).
Urachal yolk sac tumor penetrating the bladder as a diagnostic challenge: a case report and review of the literature
Authors: Šámal Vladimír , Jirásek Tomáš , Paldus Vít , Richter Igor , Hes Ondřej
Published: January 2022

Background

Yolk sac tumor (YST) is a germ cell tumor. It is primarily located in the gonads but can also occur extragonadally (extragonadal yolk sac tumor - EGYST), most commonly in the pelvis, retroperitoneum or mediastinum. Only a few YSTs of the urachus have been described.

Case report

We present a rare case report of a 37-year-old male with episodes of macroscopic hematuria. The histological specimen obtained by transurethral resection showed a solid, and in some parts papillary infiltrative, high-grade tumor with numerous areas of marked nuclear atypia and clear invasion between the detrusor bundles. Glandular pattern has been observed in only minority of the tumor. Immunohistochemistry showed significant positivity for GPC3, SALL4 and cytokeratins AE1/AE3, while KRT7 and GATA3 were negative. We concluded that the biopsy findings were consistent with urothelial carcinoma with infrequent YST differentiation. In definitive surgical specimens we found a malignant epithelial, glandular and cystically arranged tumor of germinal appearance arising from urachus. The surrounding urothelium was free of invasive or in situ tumor changes. We reclassified the tumor as a urachal YST.

Conclusion

EGYST was suspected because glandular and hepatoid structures were found, but the presence of these structures should be verified by immunohistochemistry.
MicroRNA-625-3p improved proliferation and involved chemotherapy resistance via targeting PTEN in high grade ovarian serous carcinoma
Authors: Zhong Lili , Liu Xiumin , Wang Lixing , Liu Yu , Zhang Duohan , Zhao Yinlong
Published: January 2022

Objective

High-grade serous ovarian cancer (HGSOC) is an aggressive gynaecological malignancy and associated with poor prognosis. Here we examined the effects of miR-625-3p on proliferation, treatment, migration and invasion in HGSOC.

Methods

The proliferation of HGSOC cells was evaluated by MTT assay. Transwell assay was performed to examine migration and matrigel assay were used to assess invasion. The effect of miR-625-3p on cisplatin-induced apoptosis was investigated by Caspase-Glo3/7 assay. The dual-luciferase reporter assay was carried out to confirm the potential binding site.

Results

Overexpression of miR-625-3p promoted proliferation, and increased migration and invasion in HGSOC cells. MiR-625-3p significantly inhibited cisplatin sensitivity in HGSOC cells. Meanwhile, miR-625-3p decreased cisplatin-induced apoptosis by regulation of BAX and Bcl-2 expression. Furthermore, aberrant expression of miR-625-3p changed PTEN expression by directly binding to 3’UTR of PTEN. Further study showed miR-625-3p expression was higher in human HGSOC tissue than normal ovarian tissues and associated with higher clinical stage.

Conclusions

miR-625-3p promotes HGSOC growth, involves chemotherapy resistance and might serve as a potential biomarker to predict chemotherapy response and prognosis in HGSOC.
Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression
Authors: Jonkman Thomas H. , Dekkers Koen F. , Slieker Roderick C. , Grant Crystal D. , Ikram M. Arfan , van Greevenbroek Marleen M. J. , Franke Lude , Veldink Jan H. , Boomsma Dorret I. , Slagboom P. Eline , Consortium B. I. O. S. , Heijmans Bastiaan T.
Published: January 2022

Background

Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks.

Results

We perform a functional genomics analysis on four epigenetic clocks, including Hannum’s blood predictor and Horvath’s multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expressionin trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells.

Conclusions

The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes.
Human embryos in a dish – modeling early embryonic development with pluripotent stem cells
Authors: Wang Xiukun , Hu Guang
Published: January 2022

Stem cell-based embryo models present new opportunities to study early embryonic development. In a recent study, Kagawa et al. identified an approach to create human pluripotent stem cell-based blastoids that resemble the human blastocysts. These blastoids efficiently generated analogs of the EPI, TE, PrE lineages with transcriptomes highly similar to those found in vivo. Furthermore, the formation of these lineages followed the same sequence and pace of blastocyst development, and was also dependent on the same pathways required for lineage specification. Finally, the blastoids were capable of attaching to stimulated endometrial cells to mimic the process of implantation. While more comprehensive analysis is needed to confirm its validity and usefulness, this new blastoid system presents the latest development in the attempt to model early human embryogenesis in vitro.
Acceptance and use of complementary and alternative medicine among medical specialists: a 15-year systematic review and data synthesis
Authors: Phutrakool Phanupong , Pongpirul Krit
Published: January 2022

Background

Complementary and Alternative Medicine (CAM) has gained popularity among the general population, but its acceptance and use among medical specialists have been inconclusive. This systematic review aimed to identify relevant studies and synthesize survey data on the acceptance and use of CAM among medical specialists.

Methods

We conducted a systematic literature search in PubMed and Scopus databases for the acceptance and use of CAM among medical specialists. Each article was assessed by two screeners. Only survey studies relevant to the acceptance and use of CAM among medical specialists were reviewed. The pooled prevalence estimates were calculated using random-effects meta-analyses. This review followed both PRISMA and SWiM guidelines.

Results

Of 5628 articles published between 2002 and 2017, 25 fulfilled the selection criteria. Ten medical specialties were included: Internal Medicine (11 studies), Pediatrics (6 studies), Obstetrics and Gynecology (6 studies), Anesthesiology (4 studies), Surgery (3 studies), Family Medicine (3 studies), Physical Medicine and Rehabilitation (3 studies), Psychiatry and Neurology (2 studies), Otolaryngology (1 study), and Neurological Surgery (1 study). The overall acceptance of CAM was 52% (95%CI, 42–62%). Family Medicine reported the highest acceptance, followed by Psychiatry and Neurology, Neurological Surgery, Obstetrics and Gynecology, Pediatrics, Anesthesiology, Physical Medicine and Rehabilitation, Internal Medicine, and Surgery. The overall use of CAM was 45% (95% CI, 37–54%). The highest use of CAM was by the Obstetrics and Gynecology, followed by Family Medicine, Psychiatry and Neurology, Pediatrics, Otolaryngology, Anesthesiology, Internal Medicine, Physical Medicine and Rehabilitation, and Surgery. Based on the studies, meta-regression showed no statistically significant difference across geographic regions, economic levels of the country, or sampling methods.

Conclusion

Acceptance and use of CAM varied across medical specialists. CAM was accepted and used the most by Family Medicine but the least by Surgery. Findings from this systematic review could be useful for strategic harmonization of CAM and conventional medicine practice.

Systematic review registration

PROSPERO CRD42019125628

Graphical abstract
On approximation of Bernstein–Chlodowsky–Gadjiev type operators that fix $e^{-2x}$
Authors: Tanberk Okumuş Feyza , Akyiğit Mahmut , Ansari Khursheed J. , Usta Fuat
Published: January 2022

that fix the function$e^{-2x} $e−2xfor$x\geq 0 $x≥0. Then, we provide the approximation properties of these newly defined operators for different types of function spaces. In addition, we focus on the rate of convergence utilizing appropriate moduli of continuity. Then, we provide the Voronovskaya-type theorem for these new operators. Finally, in order to validate our theoretical results, we provide some numerical experiments that are produced by a MATLAB complier.
Measuring visual electrophysiological responses in individuals with low-functioning autism: a feasibility and pilot study
Authors: Sung Kyongje , Glazer Hanna , O’Grady Jessica , McEntee Mindy L. , Bosley Laura , Reich Dana Boatman , Gordon Barry
Published: January 2022

Background

Although visual abnormalities are considered common in individuals with autism spectrum disorders, the associated electrophysiological markers have remained elusive. One impediment has been that methodological challenges often preclude testing individuals with low-functioning autism (LFA).

Methods

In this feasibility and pilot study, we tested a hybrid visual evoked potential paradigm tailored to individuals with LFA that combines passively presented visual stimuli to elicit scalp-recorded evoked responses with a behavioral paradigm to maintain visual attention. We conducted a pilot study to explore differences in visual evoked response patterns across three groups: individuals with LFA, with high-functioning autism (HFA), and with typical development.

Results

All participants with LFA met criteria for study feasibility by completing the recordings and producing measurable cortical evoked waveform responses. The LFA group had longer (delayed) cortical response latencies on average as compared with the HFA and typical development groups. We also observed group differences in visually induced alpha spectral power: the LFA group showed little to no prestimulus alpha activity in contrast to the HFA and typical development groups that showed increased prestimulus alpha activity. This observation was confirmed by the bootstrapped confidence intervals, suggesting that the absence of prestimulus alpha power may be a potential electrophysiological marker of LFA.

Conclusion

Our results confirm the utility of tailoring visual electrophysiology paradigms to individuals with LFA in order to facilitate inclusion of individuals across the autism spectrum in studies of visual processing.
Care Outcomes for Chiropractic Outpatient Veterans (COCOV): a qualitative study with veteran stakeholders from a pilot trial of multimodal chiropractic care
Authors: Salsbury Stacie A. , Twist Elissa , Wallace Robert B. , Vining Robert D. , Goertz Christine M. , Long Cynthia R.
Published: January 2022

Background

Low back pain (LBP) is common among military veterans seeking treatment in Department of Veterans Affairs (VA) healthcare facilities. As chiropractic services within VA expand, well-designed pragmatic trials and implementation studies are needed to assess clinical effectiveness and program uptake. This study evaluated veteran stakeholder perceptions of the feasibility and acceptability of care delivery and research processes in a pilot trial of multimodal chiropractic care for chronic LBP.

Methods

The qualitative study was completed within a mixed-method, single-arm, pragmatic, pilot clinical trial of chiropractic care for LBP conducted in VA chiropractic clinics. Study coordinators completed semi-structured, in person or telephone interviews with veterans near the end of the 10-week trial. Interviews were audiorecorded and transcribed verbatim. Qualitative content analysis using a directed approach explored salient themes related to trial implementation and delivery of chiropractic services.

Results

Of 40 participants, 24 completed interviews (60% response; 67% male gender; mean age 51.7 years). Overall, participants considered the trial protocol and procedures feasible and reported that the chiropractic care and recruitment methods were acceptable. Findings were organized into 4 domains, 10 themes, and 21 subthemes. Chiropractic service delivery domain encompassed 3 themes/8 subthemes: scheduling process (limited clinic hours, scheduling future appointments, attendance barriers); treatment frequency (treatment sufficient for LBP complaint, more/less frequent treatments); and chiropractic clinic considerations (hire more chiropractors, including female chiropractors; chiropractic clinic environment; patient-centered treatment visits). Outcome measures domain comprised 3 themes/4 subthemes: questionnaire burden (low burden vs. time-consuming or repetitive); relevance (items relevant for LBP study); and timing and individualization of measures (questionnaire timing relative to symptoms, personalized approach to outcomes measures). The online data collection domain included 2 themes/4 subthemes: user concerns (little difficulty vs. form challenges, required computer skills); and technology issues (computer/internet access, junk mail). Clinical trial planning domain included 2 themes/5 subthemes: participant recruitment (altruistic service by veterans, awareness of chiropractic availability, financial compensation); and communication methods (preferences, potential barriers).

Conclusions

This qualitative study highlighted veteran stakeholders’ perceptions of VA-based chiropractic services and offered important suggestions for conducting a full-scale, veteran-focused, randomized trial of multimodal chiropractic care for chronic LBP in this clinical setting.

Trial registration

ClinicalTrials.govNCT03254719
Can vena cava ultrasound-guided volume repletion prevent general induced hypotension in elderly patients? A mini-fluid challenge
Authors: Amin Samar Rafik , Mahdy Enas W.
Published: January 2022

Background

Hypotension is often occurring after induction of general anesthesia (IGA) and can cause organ hypoperfusion and ischemia which associated with adverse outcomes in patients having both cardiac and non-cardiac surgery. Elderly patients are particularly more vulnerable and at increased risk to the depressant effect of anesthetic drugs. So, recognition and prevention of such event are of clinical importance. This study recruited patients aged above 60 years, with ASA physical status classification I-II-III who were scheduled for surgery under general anesthesia with the aim to assess the effectiveness of preoperative IVC ultrasonography in predicting hypotension which develops following IGA and its association with the volume status in elderly patients receiving general anesthesia, through measurements of the maximum inferior vena cava diameter (dIVCmax), minimum inferior vena cava diameter (dIVCmin), inferior vena cava collapsibility index (IVC-CI), and basal and post-induction mean arterial pressure (MAP).

Results

Thirty-nine (44.3%) of the 88 patients developed hypotension after IGA, and it was significantly more in patients who did not receive preoperative fluid (p = 0.045). The cut-off for dIVCmax was found as 16.250 mm with the ROC analysis. Specificity and sensitivity for the cut-off value of 16.250 mm were calculated as 61.2% and 76.9%, respectively. The cut-off for IVC-CI was found as 33.600% with the ROC analysis. Specificity and sensitivity for the cut-off value of 33.600% were calculated as 68.7% and 87.2%, respectively.

Conclusions

IVC ultrasonography may be helpful in the prediction of preoperative hypovolemia in elderly patients in the form of high IVC-CI and low dIVCmax. The incidence of hypotension was lower in patients who received fluid infusion before IGA.
Cognitive impairment in recipients of liver transplantation and relation to hepatic encephalopathy
Authors: Mohamed Ahmad Saad , Elmeteini Mahmoud Ahmed , Mohamed Ghada Abd Elrazek , Elserafy Doha Mostafa , Elmadani Alaa Adel , Hashem Reem Elsayed
Published: January 2022

Background

Liver transplantation (LT) helped to save the life of end stage liver disease (ESLD) patients; however, there is a debate on the persistence of cognitive impairment. The study aimed to evaluate cognitive functions in patients with ESLD before and after liver transplantation and to assess its relation to hepatic encephalopathy (HE). Thirty recipients 47.6 ± 11 years undergone living donor liver transplantation at the transplantation center of both Ain Shams Center for Organ Transplant and Egypt air organ transplant unit were prospectively assessed by Trail Making Test, Wechsler Memory Scale–Revised, Benton Visual Retention—for the evaluation of cognitive functions before and 3 months after transplantation.

Results

The mean age of the patients was 47.6 ± 11 years, 17 males and 13 females. Eight out of 30 (26.7%) had past history of hepatic encephalopathy. The study reported significant improvement in the post-operative 3 months scores of Trail Making Test part (A), the digit span forward test, digit span backward test and the correct score difference of the Benton Visual Retention, as p value was (0.02), (0.01) (0.02), and (0.01) respectively, compared to the pre-operative scores. However, there was no difference in the scores of part (B), verbal association I, II, information subtest of WMS. Cognitive performance showed no significant difference between patients with or without history of HE.

Conclusions

Patients with ESLD have significant cognitive impairment that showed improvement after LT; HE did not correlate with cognitive function. Hence, transplantation has a favorable outcome on the cognitive impairment.
The effect of non-invasively obtained central blood pressure on cardiovascular outcome in diabetic patients in Assiut University Hospitals
Authors: El Toony Lobna F. , Ramzy Andrew N. , Abozaid Mohamed A. A.
Published: January 2022

Background

The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by the presence of hypertension. Therefore, proper control of BP in diabetic hypertensive patients is essential. Few studies have specifically investigated the prognostic significance of central BP in Egyptian populations with diabetes and hypertension and its relation with cardiovascular outcome. This study aims to evaluate relation between central BP and diabetic composite cardiovascular complications.

Results

Diabetic patients with CVD were significantly older (p value < 0.01), obese (p value < 0.01) with long duration of diabetes (p value < 0.001) and had significantly higher peripheral and central systolic and diastolic BP and higher AIx@75(p values < 0.01) than those without CVD. Regarding the metabolic parameters, they had significantly higher fasting blood glucose, HbA1c, and higher blood cholesterol levels (p values < 0.001), higher LDL (p value < 0.01), triglycerides levels (p value = 0.014), and microalbuminuria (p value = 0.028). Logistic regression analysis found increased BMI, central systolic BP, and AIx@75 were independent predictors of composite CVD (p values < 0.05).

Conclusions

There is a pattern of favorability towards central rather than peripheral BP indices to predict the occurrence of CVD in diabetic patients.
Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib forBRAFV600–Mutant Unresectable or Metastatic Melanoma
Authors: Dummer Reinhard , Long Georgina V. , Robert Caroline , Tawbi Hussein A. , Flaherty Keith T. , Ascierto Paolo A. , Nathan Paul D. , Rutkowski Piotr , Leonov Oleg , Dutriaux Caroline , Mandalà Mario , Lorigan Paul , Ferrucci Pier Francesco , Grob Jean Jacques , Meyer Nicolas , Gogas Helen , Stroyakovskiy Daniil , Arance Ana , Brase Jan C. , Green Steven , Haas Tomas , Masood Aisha , Gasal Eduard , Ribas Antoni , Schadendorf Dirk
Published: January 2022

PURPOSE

Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma.

METHODS

Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692 ).

RESULTS

At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.

CONCLUSION

The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
Resonating delay equation
Authors: Ohira K.
Published: January 2022

We propose here a delay differential equation that exhibits a new type of resonating oscillatory dynamics. The oscillatory transient dynamics appear and disappear as the delay is increased between zero to asymptotically large delay. The optimal height of the power spectrum of the dynamical trajectory is observed with the suitably tuned delay. This resonant behavior contrasts itself against the general behaviors where an increase of the delay parameter leads to the persistence of oscillations or more complex dynamics.
Anti-gravity technology by non-positive equivalent mass revealing UFO flying secrets
Authors: Wu Jiu Hui , Yang Shao Kun
Published: January 2022

In this paper, a novel kind of anti-gravity technology by non-positive equivalent mass of aircraft is presented to try to reveal UFO flying secrets. Starting with a two-degree-of-freedom system, it is found that the system could produce an infinite acceleration under the condition of zero dynamic equivalent mass, and also provide a movement opposite to the direction of the external force under the negative equivalent mass. These two cases with non-positive equivalent mass could both be regarded as a novel kind of anti-gravity technology, which is also verified by a designed dynamic simulation experiment. For any aircraft that can be regarded as a multi-degree-of-freedom system driven by engine or other external forces, the non-positive equivalent mass could be figured out once the external input including gravity and engine exciting forces is known. Thus the anti-gravity technology for any aircraft could be realized, which could also be extended to matters related to flight, such as space ships, missiles, airplanes, etc.
Steroid Hormone Profiles and Molecular Diagnostic Tools in Pediatric Patients With non-CAH Primary Adrenal Insufficiency
Authors: Seven Menevse Tuba , Kendir Demirkol Yasemin , Gurpinar Tosun Busra , Bayramoglu Elvan , Yildiz Melek , Acar Sezer , Erisen Karaca Seda , Orbak Zerrin , Onder Asan , Sobu Elif , Anık Ahmet , Atay Zeynep , Bugrul Fuat , Derya Bulus Ayse , Demir Korcan , Dogan Durmus , Cihan Emeksiz Hamdi , Kirmizibekmez Heves , Ozcan Murat Nurhan , Yaman Akan , Turan Serap , Bereket Abdullah , Guran Tulay
Published: January 2022

Context

There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology.

Objective

This work aimed to investigate the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin.

Methods

Pediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targeted-gene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography–mass spectrometry and compared to that of controls. This study comprised 18 pediatric endocrinology clinics with 41 patients (17 girls, median age: 3 mo, range: 0-8 y) with non-CAH PAI of unknown etiology.

Results

A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to a healthy control group, patients showed lower steroid concentrations, most statistically significantly in cortisone, cortisol, and corticosterone (P < .0001, area under the receiver operating characteristic curve: .96, .88, and .87, respectively). Plasma cortisol of less than 4 ng/mL, cortisone of less than 11 ng/mL, and corticosterone of less than 0.11 ng/mL had a greater than 95% specificity to ensure the diagnosis of non-CAH PAI of unknown etiology.

Conclusion

Steroid hormone profiles are highly sensitive for the diagnosis of non-CAH PAI of unknown etiology, but they are unlikely to point to a specific molecular diagnosis. TPS is an optimal approach in the molecular diagnosis of these patients with high efficacy, whereas little additional benefit is expected from WES.