bluuebunny/crossref_metadata_2025 huggingface dataset:
Triglyceride glucose-body mass index in identifying high-risk groups of pre-diabetes
Authors: Jiang Chunyuan , Yang Ruijuan , Kuang Maobin , Yu Meng , Zhong Mingchun , Zou Yang
Published: November 2021

Background

Triglyceride glucose-body mass index (TyG-BMI) has been recommended as an alternative indicator of insulin resistance. However, the association between TyG-BMI and pre-diabetes remains to be elucidated.

Methods

More than 100,000 subjects with normal glucose at baseline received follow-up. The main outcome event of concern was pre-diabetes defined according to the diagnostic criteria recommended by the American Diabetes Association (ADA) in 2018 and the World Health Organization (WHO) in 1999. A Cox proportional hazard regression model was used to evaluate the role of TyG-BMI in identifying people at high risk of pre-diabetes.

Results

At a mean observation period of 3.1 years, the incidence of pre-diabetes in the cohort was 3.70 and 12.31% according to the WHO and ADA diagnostic criteria for pre-diabetes, respectively. The multivariate Cox regression analysis demonstrated that TyG-BMI was independently positively correlated with pre-diabetes, and there was a special population dependence phenomenon. Among them, non-obese people, women and people under 50 years old had a significantly higher risk of TyG-BMI-related pre-diabetes (P-interaction< 0.05).

Conclusions

These findings suggest that a higher TyG-BMI significantly increases an individual’s risk of pre-diabetes, and this risk is significantly higher in women, non-obese individuals, and individuals younger than 50 years of age.
Job satisfaction among Syrian healthcare workers in refugee health centres
Authors: Zikusooka Monica , Elci Omur Cinar , Özdemir Habibe
Published: November 2021

Background

Achieving universal health coverage is subject to the availability, accessibility, acceptability, and quality of health workers. Countries that host refugees and migrants, such as Turkey, must strengthen the capacity of their health systems to increase access to services, especially for refugees and migrants. The Turkish Ministry of Health adapted Syrian refugee healthcare workers in the healthcare services to boost Syrian refugees’ access to healthcare. This study aimed to assess job satisfaction and the factors influencing job satisfaction among refugee physicians and nurses working in Refugee Healthcentres (RHCs) in Turkey.

Methods

A self-administered, cross-sectional survey targeted all Syrian physicians and nurses working in RHCs across Turkey. The short-form Minnesota Satisfaction Questionnaire(MSQ) was used to assess job satisfaction. In total, 555 nurse/midwives and 336 physicians responded, yielding a total response rate of 56.5%. Descriptive analyses and linear regression tests were conducted to determine the level of job satisfaction and to analyze determinant factors.

Results

Nurses/midwives reported the highest level of general job satisfaction, followed by specialist physicians and general physicians. Physicians who had worked as specialists in Syria but were now working as general physicians in Turkey had the lowest job satisfaction levels. Multiple regression analysis showed that professional status in Turkey, income, teamwork and team management were significantly associated with job satisfaction.

Conclusions

To maintain a high level of job satisfaction in refugee healthcare workers, human resources management should consider matching job placements with training specialization and support good leadership and good teamwork. Remuneration that accounts for the cost of living and non-financial incentives could also play a significant role in job satisfaction.
Duration of third stage labour and postpartum blood loss: a secondary analysis of the WHO CHAMPION trial data
Authors: Chikkamath Sumangala B. , Katageri Geetanjali M. , Mallapur Ashalata A. , Vernekar Sunil S. , Somannavar Manjunath S. , Piaggio Gilda , Carroli Guillermo , de Carvalho José Ferreira , Althabe Fernando , Hofmeyr G. Justus , Widmer Mariana , Gulmezoglu Ahmet Metin , Goudar Shivaprasad S.
Published: November 2021

Background

Obstetric haemorrhage continues to be a leading cause of maternal mortality, contributing to more than a quarter of the 2,443,000 maternal deaths reported between 2003 and 2009. During this period, about 70% of the haemorrhagic deaths occurred postpartum. In addition to other identifiable risk factors for greater postpartum blood loss, the duration of the third stage of labour (TSL) seems to be important, as literature shows that a longer TSL can be associated with more blood loss. To better describe the association between the duration of TSL and postpartum blood loss in women receiving active management of third stage of labour (AMTSL), this secondary analysis of the WHO CHAMPION trial data has been conducted.

Methods

This was a secondary analysis of the WHO CHAMPION trial conducted in twenty-three sites in ten countries. We studied the association between the TSL duration and blood loss in the sub cohort of women from the CHAMPION trial (all of whom received AMTSL), with TSL upto 60 min and no interventions for postpartum haemorrhage. We used a general linear model to fit blood loss as a function of TSL duration on the log scale, arm and center, using a normal distribution and the log link function. We showed this association separately for oxytocin and for Heat stable (HS) carbetocin.

Results

For the 10,040 women analysed, blood loss rose steeply with third stage duration in the first 10 min, but more slowly after 10 min. This trend was observed for both Oxytocin and HS carbetocin and the difference in the trends for both drugs was not statistically significant (p-value = 0.2070).

Conclusions

There was a positive association between postpartum blood loss and TSL duration with either uterotonic. Blood loss rose steeply with TSL duration until 10 min, and more slowly after 10 min.

Study registration The main trial was registered with Australian New Zealand Clinical Trials Registry ACTRN12614000870651 and Clinical Trial Registry of India CTRI/2016/05/006969
Neutralization of interleukin-38 exacerbates coxsackievirus B3-induced acute myocarditis in mice
Authors: Xue Yimin , Chen Mingguang , Chen Qian , Huang Tingfeng , Fan Qiaolian , Lin Fenghui , Ke Jun , Chen Feng
Published: November 2021

Background

Interleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection. However, the expression and functional role of IL-38 in acute viral myocarditis (AVMC) have not been investigated.

Methods

Male BALB/c mice were treated with intraperitoneal (i.p.) injection of coxsackievirus B3 (CVB3) for establishing AVMC models. On day 7 post-injection, the expression of IL-38 and IL-36R (IL-36 receptor) were measured. Mice were then treated with i.p. injection of mouse Anti-IL-38 Antibodies (Abs) for neutralization of IL-38. The survival, bodyweight loss, cardiac function, and myocarditis severity of mice were recorded. The percentages of splenic Th1 and Th17 cells, the expression levels of Th1/Th17-related master transcription factors (T-bet and RORγt) and cytokines were determined by flow cytometry, RT-qPCR, and ELISA, respectively. Cardiac viral replication was further detected.

Results

The mRNA and protein expression levels of IL-38 in myocardium and serum, as well as cardiac IL-36R mRNA levels were significantly elevated in mice with AVMC. Increased IL-38 levels were negatively correlated with the severity of AVMC. Neutralization of IL-38 exacerbated CVB3-induced AVMC, as verified by the lower survival rate, impaired cardiac function, continuous bodyweight loss, and higher values of HW/BW and cardiac pathological scores. In addition, neutralization of IL-38 suppressed Th1 cells differentiation while promoted Th17 cells differentiation, accompanied by decreased T-bet mRNA expression and increased RORγt expression. Down-regulation of IFN-γ and up-regulation of IL-17, TNF-α, and IL-6 mRNA and protein expression levels in myocardium and serum were also observed in the IL-38 neutralization group. Furthermore, neutralization of IL-38 markedly promoted cardiac viral replication.

Conclusions

Neutralization of IL-38 exacerbates CVB3-induced AVMC in mice, which may be attributable to the imbalance of Th1/Th17 cells and increased CVB3 replication. Thus, IL-38 can be considered as a potential therapeutic target for AVMC.
The association between interferon lambda 3 and 4 gene single-nucleotide polymorphisms and the recovery of COVID-19 patients
Authors: Rahimi Pooneh , Tarharoudi Rahil , Rahimpour Alireza , Mosayebi Amroabadi Jalal , Ahmadi Iraj , Anvari Enayat , Siadat Seyed Davar , Aghasadeghi Mohammadreza , Fateh Abolfazl
Published: November 2021

Background

The recent pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has elevated several clinical and scientific questions. These include how host genetic factors influence the pathogenesis and disease susceptibility. Therefore, the aim of this study was to evaluate the impact of interferon lambda 3 and 4 (IFNL3/4) gene polymorphisms and clinical parameters on the resistance and susceptibility to coronavirus disease 2019 (COVID-19) infection.

Methods

A total of 750 SARS-CoV-2 positive patients (375 survivors and 375 nonsurvivors) were included in this study. All single-nucleotide polymorphisms (SNPs) on IFNL3 (rs12979860, rs8099917, and rs12980275) and IFNL4 rs368234815 were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method.

Results

In this study, a higher viral load (low PCR Ct value) was shown in nonsurvivor patients. In survivor patients, the frequency of the favorable genotypes of IFNL3/4 SNPs (rs12979860 CC, rs12980275 AA, rs8099917 TT, and rs368234815 TT/TT) was significantly higher than in nonsurvivor patients. Multivariate logistic regression analysis has shown that a higher low-density lipoprotein (LDL), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and PCR Ct value, and lower 25-hydroxyvitamin D, and also IFNL3 rs12979860 TT, IFNL3 rs8099917 GG, IFNL3 rs12980275 GG, and IFNL4 rs368234815 ∆G/∆G genotypes were associated with the severity of COVID-19 infection.

Conclusions

The results of this study proved that the severity of COVID-19 infection was associated with clinical parameters and unfavorable genotypes of IFNL3/IFNL4 SNPs. Further studies in different parts of the world are needed to show the relationship between severity of COVID-19 infection and host genetic factors.
Long non-coding RNA DUXAP8 elevates RCN2 expression and facilitates cell malignant behaviors and angiogenesis in cervical cancer via sponging miR-1297
Authors: Gu Jihui , Liu Yi , Qi Ting , Qian Weiwei , Hu Dongdong , Feng Wen
Published: November 2021

Background

Cervical cancer (CC) endangers women’s health in the world range. Accumulating studies have revealed the crucial regulatory role of long non-coding RNAs (lncRNAs) in multiple malignancies, including CC. Our study aimed to explore the role of lncRNA double homeobox A pseudogene 8 (DUXAP8) in cervical carcinogenesis.

Methods

Gene expressions in CC were assessed by RT-qPCR. Function experiments and tube formation assays were performed to evaluate the role of DUXAP8 in CC cells. Subcellular fractionation and FISH assays were conducted to determine the subcellular location of DUXAP8. Luciferase reporter, RNA pull down and RIP assays were conducted to investigate the mechanism of DUXAP8.

Results

DUXAP8 was notably upregulated in CC cells. Downregulation of DUXAP8 repressed cell malignant behaviors and angiogenesis in CC. Mechanically, DUXAP8 boosted the expression of reticulocalbin-2 (RCN2) through relieving the binding of miR-1297 to RCN2 3’-UTR. Moreover, miR-1297 inhibition and RCN2 overexpression could counteract the inhibitory effects of DUXAP8 knockdown on the malignant phenotypes of CC cells. Besides, enhanced RCN2 expression restored the tumor growth in vivo that was inhibited by DUXAP8 repression.

Conclusions

DUXAP8 promotes malignant behaviors in CC cells via regulating miR-1297/RCN2 axis.

Graphical Abstract
Operating procedures, risk management and challenges during implementation of adaptive and non-adaptive MR-guided radiotherapy: 1-year single-center experience
Authors: Garcia Schüler Helena Isabel , Pavic Matea , Mayinger Michael , Weitkamp Nienke , Chamberlain Madalyne , Reiner Cäcilia , Linsenmeier Claudia , Balermpas Panagiotis , Krayenbühl Jerome , Guckenberger Matthias , Baumgartl Michael , Wilke Lotte , Tanadini-Lang Stephanie , Andratschke Nicolaus
Published: November 2021

Background

Main purpose was to describe procedures and identify challenges in the implementation process of adaptive and non-adaptive MR-guided radiotherapy (MRgRT), especially new risks in workflow due to the new technique. We herein report the single center experience for the implementation of (MRgRT) and present an overview on our treatment practice.

Methods

Descriptive statistics were used to summarize clinical and technical characteristics of treatment and patient characteristics including sites treated between April 2019 and end of March 2020 after ethical approval. A risk analysis was performed to identify risks of the online adaptive workflow.

Results

A summary of the processes on the MR-Linac including workflows, quality assurance and possible pitfalls is presented. 111 patients with 124 courses were treated during the first year of MR-guided radiotherapy. The most commonly treated site was the abdomen (42% of all treatment courses). 73% of the courses were daily online adapted and a high number of treatment courses (75%) were treated with stereotactic body irradiation. Only 4/382 fractions could not be treated due to a failing online adaptive quality assurance. In the risk analysis for errors, the two risks with the highest risk priority number were both in the contouring category, making it the most critical step in the workflow.

Conclusion

Although challenging, establishment of MRgRT as a routinely used technique at our department was successful for all sites and daily o-ART was feasible from the first day on. However, ongoing research and reports will have to inform us on the optimal indications for MRgRT because careful patient selection is necessary as it continues to be a time-consuming treatment technique with restricted availability. After risk analysis, the most critical workflow category was the contouring process, which resembles the need of experienced staff and safety check paths.
Oesophageal IGRT considerations for SBRT of LA-NSCLC: barium-enhanced CBCT and interfraction motion
Authors: Woodford Katrina , Panettieri Vanessa , Ruben Jeremy D. , Davis Sidney , Tran Le Trieumy , Miller Stephanie , Senthi Sashendra
Published: November 2021

Background

To determine the optimal volume of barium for oesophageal localisation on cone-beam CT (CBCT) for locally-advanced non-small cell lung cancers (NSCLC) and quantify the interfraction oesophageal movement relative to tumour.

Methods

Twenty NSCLC patients with mediastinal and/or hilar disease receiving radical radiotherapy were recruited. The first five patients received 25 ml of barium prior to their planning CT and alternate CBCTs during treatment. Subsequent five patient cohorts, received 15 ml, 10 ml and 5 ml. Six observers contoured the oesophagus on each of the 107 datasets and consensus contours were created. Overall 642 observer contours were generated and interobserver contouring reproducibility was assessed. The kappa statistic, dice coefficient and Hausdorff Distance (HD) were used to compare barium-enhanced CBCTs and non-enhanced CBCTs. Oesophageal displacement was assessed using the HD between consensus contours of barium-enhanced CBCTs and planning CTs.

Results

Interobserver contouring reproducibility was significantly improved in barium-enhanced CBCTs compared to non-contrast CBCTs with minimal difference between barium dose levels. Only 10 mL produced a significantly higher kappa (0.814, p = 0.008) and dice (0.895, p = 0.001). The poorer the reproducibility without barium, the greater the improvement barium provided. The median interfraction HD between consensus contours was 4 mm, with 95% of the oesophageal displacement within 15 mm.

Conclusions

10 mL of barium significantly improves oesophageal localisation on CBCT with minimal image artifact. The oesophagus moves substantially and unpredictably over a course of treatment, requiring close daily monitoring in the context of hypofractionation.
Biological dosiomic features for the prediction of radiation pneumonitis in esophageal cancer patients
Authors: Puttanawarut Chanon , Sirirutbunkajorn Nat , Khachonkham Suphalak , Pattaranutaporn Poompis , Wongsawat Yodchanan
Published: November 2021

Objective

The purpose of this study was to develop a model using dose volume histogram (DVH) and dosiomic features to predict the risk of radiation pneumonitis (RP) in the treatment of esophageal cancer with radiation therapy and to compare the performance of DVH and dosiomic features after adjustment for the effect of fractionation by correcting the dose to the equivalent dose in 2 Gy (EQD2).

Materials and methods

DVH features and dosiomic features were extracted from the 3D dose distribution of 101 esophageal cancer patients. The features were extracted with and without correction to EQD2. A predictive model was trained to predict RP grade ≥ 1 by logistic regression with L1 norm regularization. The models were then evaluated by the areas under the receiver operating characteristic curves (AUCs).

Result

The AUCs of both DVH-based models with and without correction of the dose to EQD2 were 0.66 and 0.66, respectively. Both dosiomic-based models with correction of the dose to EQD2 (AUC = 0.70) and without correction of the dose to EQD2 (AUC = 0.71) showed significant improvement in performance when compared to both DVH-based models. There were no significant differences in the performance of the model by correcting the dose to EQD2.

Conclusion

Dosiomic features can improve the performance of the predictive model for RP compared with that obtained with the DVH-based model.
Buyang Huanwu Decoction protects against STZ-induced diabetic nephropathy by inhibiting TGF-β/Smad3 signaling-mediated renal fibrosis and inflammation
Authors: Wu Weifeng , Wang Yifan , Li Haidi , Chen Haiyong , Shen Jiangang
Published: November 2021

Background

Buyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD.

Methods

Mice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms.

Results

We found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells.

Conclusion

BHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy.
Myocardial protective effect and transcriptome profiling of Naoxintong on cardiomyopathy in zebrafish
Authors: Hu Mengyan , Liu Peirong , Lu Shuxian , Wang Zhihao , Lyu Zhaojie , Liu Hongkai , Sun Yuhong , Liu Feng , Tian Jing
Published: November 2021

Background

Cardiomyopathy is a kind of cardiovascular diseases, which makes it more difficult for the heart to pump blood to other parts of the body, eventually leading to heart failure. Naoxintong (NXT), as a traditional Chinese Medicine (TCM) preparation, is widely used in the treatment of cardiovascular diseases, including cardiomyopathy, while its underlying mechanism has not been fully elucidated. The purpose of this study is to investigate the therapeutic effect of NXT on cardiomyopathy and its molecular mechanism in zebrafish model.

Methods

The zebrafish cardiomyopathy model was established using terfenadine (TFD) and treated with NXT. The therapeutic effect of NXT on cardiomyopathy was evaluated by measuring the heart rate, the distance between the sinus venosus and bulbus arteriosus (SV-BA), the pericardial area, and the blood flow velocity of zebrafish. Then, the zebrafish hearts were isolated and collected; transcriptome analysis of NXT on cardiomyopathy was investigated. Moreover, the heg1 mutant of zebrafish congenital cardiomyopathy model was used to further validate the therapeutic effect of NXT on cardiomyopathy. Additionally, UPLC analysis combined with the zebrafish model investigation was performed to identify the bioactive components of NXT.

Results

In the TFD-induced zebrafish cardiomyopathy model, NXT treatment could significantly restore the cardiovascular malformations caused by cardiac dysfunction. Transcriptome and bioinformatics analyses of the TFD and TFD  +  NXT treated zebrafish developing hearts revealed that the differentially expressed genes were highly enriched in biological processes such as cardiac muscle contraction and heart development. As a cardiac development protein associated with cardiomyopathy, HEG1 had been identified as one of the important targets of NXT in the treatment of cardiomyopathy. The cardiovascular abnormalities of zebrafish heg1 mutant could be recovered significantly from NXT treatment, including the expanded atrial cavity and blood stagnation. qRT-PCR analysis further showed that NXT could restore cardiomyopathy phenotype in zebrafish through HEG1-CCM signaling. Among the seven components identified in NXT, paeoniflorin (PF) and salvianolic acid B (Sal B) were considered to be the main bioactive ones with myocardial protection.

Conclusion

NXT presented myocardial protective effect and could restore myocardial injury and cardiac dysfunction in zebrafish; the action mechanism was involved in HEG1-CCM signaling.
Healthcare resource utilization and costs associated with anogenital warts in Morocco
Authors: Berrada Myriam , Holl Ryan , Ndao Tidiane , Benčina Goran , Dikhaye Siham , Melhouf Abdelilah , Chiheb Soumiya , Guelzim Khalid
Published: November 2021

Background

Human papillomavirus (HPV), primarily genotypes 6 and 11, cause the majority of cases of anogenital warts (AGW). Although benign, AGW are associated with a substantial economic and psychosocial burden. Several vaccines have been developed to prevent HPV. The objective of this study was to describe the epidemiology and healthcare resource utilization of AGW in Morocco, as well as the associated costs of treatment from the public healthcare perspective.

Methods

This was a descriptive analysis of questionnaire data obtained via a Delphi panel. The panel consisted of 9 physicians practicing in public hospitals in Morocco (4 dermatologists and 5 obstetricians/gynecologists). The questionnaire collected data on physician and practice characteristics, diagnostic tests and procedures, treatments, and follow-up (including recurrence) of patients with AGW. Questionnaire items on which ≥ 70% of respondents agreed were considered as having consensus. Costs associated with diagnosis, treatment, and follow-up were calculated in Moroccan dirham (MAD) and converted to euros (€) based on official national price lists for public hospitals and the HCRU estimates from the questionnaire.

Results

The physician-estimated prevalence of AGW in Morocco was 1.6%-2.6% in women and 2.0%-5.3% in men. A mean (median) of 6.4 (4) patients per month per physician sought medical attention for AGW. Simple observation was the most common diagnostic method for AGW in both men and women, and excision was the most prescribed therapy (75%), requiring a mean of 2 visits. Recurrence occurred in approximately 27% of patients. The cost per case of managing AGW, including recurrence, was estimated at 2182–2872 MAD (€207–272) for women and 2170–2450 MAD (€206–233) for men. The total annual cost of medical consultations for AGW in Morocco ranged from 3,271,877 MAD to 4,253,703 MAD (€310,828–404,102).

Conclusions

Expert consensus indicates that AGW represent a significant burden to the Moroccan public healthcare system. These data can inform policy makers regarding this vaccine-preventable disease.
Metagenomic analysis to identify novel infectious agents in systemic anaplastic large cell lymphoma
Authors: Mahale Parag , Nomburg Jason , Song Joo Y. , Steinberg Mia , Starrett Gabriel , Boland Joseph , Lynch Charles F. , Chadburn Amy , Rubinstein Paul G. , Hernandez Brenda Y. , Weisenburger Dennis D. , Bullman Susan , Engels Eric A.
Published: November 2021

Systemic anaplastic large cell lymphoma (ALCL) is a rare CD30-expressing T-cell non-Hodgkin lymphoma. Risk of systemic ALCL is highly increased among immunosuppressed individuals. Because risk of cancers associated with viruses is increased with immunosuppression, we conducted a metagenomic analysis of systemic ALCL to determine whether a known or novel pathogen is associated with this malignancy. Total RNA was extracted and sequenced from formalin-fixed paraffin-embedded tumor specimens from 19 systemic ALCL cases (including one case from an immunosuppressed individual with human immunodeficiency virus infection), 3 Epstein-Barr virus positive diffuse large B-cell lymphomas (DLBCLs) occurring in solid organ transplant recipients (positive controls), and 3 breast cancers (negative controls). We used a pipeline based on the Genome Analysis Toolkit (GATK)-PathSeq algorithm to subtract out human RNA reads and map the remaining RNA reads to microbes. No microbial association with ALCL was identified, but we found Epstein-Barr virus in the DLBCL positive controls and determined the breast cancers to be negative. In conclusion, we did not find a pathogen associated with systemic ALCL, but because we analyzed only one ALCL tumor from an immunosuppressed person, we cannot exclude the possibility that a pathogen is associated with some cases that arise in the setting of immunosuppression.
The terpenes camphene and alpha-bisabolol inhibit inflammatory and neuropathic pain via Cav3.2 T-type calcium channels
Authors: Gadotti Vinicius M. , Huang Sun , Zamponi Gerald W.
Published: November 2021

T-type calcium channels are known molecular targets of certain phytocannabinoids and endocannabinoids. Here we explored the modulation of Cav3.2 T-type calcium channels by terpenes derived from cannabis plants. A screen of eight commercially available terpenes revealed that camphene and alpha-bisabolol mediated partial, but significant inhibition of Cav3.2 channels expressed in tsA-201 cells, as well as native T-type channels in mouse dorsal root ganglion neurons. Both compounds inhibited peak current amplitude with IC50s in the low micromolar range, and mediated an additional small hyperpolarizing shift in half-inactivation voltage. When delivered intrathecally, both terpenes inhibited nocifensive responses in mice that had received an intraplantar injection of formalin, with alpha-bisabolol showing greater efficacy. Both terpenes reduced thermal hyperalgesia in mice injected with Complete Freund’s adjuvant. This effect was independent of sex, and absent in Cav3.2 null mice, indicating that these compounds mediate their analgesic properties by acting on Cav3.2 channels. Both compounds also inhibited mechanical hypersensitivity in a mouse model of neuropathic pain. Hence, camphene and alpha-bisabolol have a wide spectrum of analgesic action by virtue of inhibiting Cav3.2 T-type calcium channels.
Avoidance memory requires CaMKII activity to persist after recall
Authors: Radiske Andressa , Gonzalez Maria Carolina , Rossato Janine I. , Apolinário Gênedy , de Oliveira João R. , Bevilaqua Lia R. M. , Cammarota Martín
Published: November 2021

Avoidance memory is destabilized when recalled concurrently with conflicting information, and must undergo a hippocampus-dependent restabilization process called reconsolidation to persist. CaMKII is a serine/threonine protein kinase essential for memory processing; however, its possible involvement in avoidance memory reconsolidation has not yet been studied. Using pharmacological, electrophysiological and optogenetic tools, we found that in adult male Wistar rats hippocampal CaMKII is necessary to reconsolidate avoidance memory, but not to keep it stored while inactive, and that blocking reconsolidation via CaMKII inhibition erases learned avoidance responses.
Necrotizing enterocolitis in the preterm: newborns medical and nutritional Management in a Single-Center Study
Authors: Savarino Giovanni , Carta Maurizio , Cimador Marcello , Corsello Antonio , Giuffrè Mario , Schierz Ingrid Anne Mandy , Serra Gregorio , Corsello Giovanni
Published: November 2021

Necrotizing enterocolitis (NEC) is a typical disorder of preterm newborns, with a high mortality and morbidity rate. The therapeutic and nutritional management of disease depends on several factors. Its prognosis is linked, in addition to the severity of the disease and the need for surgery, to a correct enteral feeding in these patients. This study aims to identify the clinical characteristics of 18 patients with NEC, evaluating the different therapeutic paths undertaken, the type of formula used and the survival rate of this population. Average time of enteral nutrition before the NEC onset was 11,3 ± 11,6 days, with an average fasting period since the onset of 24 ± 18.9 days. 77.8% of patients received surgery and resumed enteral nutrition 17.7 ± 17.9 days after the intervention. The overall survival rate of our cohort was 55.5%. More prospective studies are needed to evaluate the long-term outcomes of survived children with NEC.
Targeted high mean arterial pressure aggravates cerebral hemodynamics after extracorporeal resuscitation in swine
Authors: Levy Yael , Hutin Alice , Lidouren Fanny , Polge Nicolas , Fernandez Rocio , Kohlhauer Matthias , Leger Pierre-Louis , Debaty Guillaume , Lurie Keith , Lamhaut Lionel , Ghaleh Bijan , Tissier Renaud
Published: November 2021

Background

Extracorporeal cardiopulmonary resuscitation (E-CPR) is used for the treatment of refractory cardiac arrest. However, the optimal target to reach for mean arterial pressure (MAP) remains to be determined. We hypothesized that MAP levels critically modify cerebral hemodynamics during E-CPR and tested two distinct targets (65–75 vs 80–90 mmHg) in a porcine model.

Methods

Pigs were submitted to 15 min of untreated ventricular fibrillation followed by 30 min of E-CPR. Defibrillations were then delivered until return of spontaneous circulation (ROSC). Extracorporeal circulation was initially set to an average flow of 40 ml/kg/min. The dose of epinephrine was set to reach a standard or a high MAP target level (65–75 vs 80–90 mmHg, respectively). Animals were followed during 120-min after ROSC.

Results

Six animals were included in both groups. During E-CPR, high MAP improved carotid blood flow as compared to standard MAP. After ROSC, this was conversely decreased in high versus standard MAP, while intra-cranial pressure was superior. The pressure reactivity index (PRx), which is the correlation coefficient between arterial blood pressure and intracranial pressure, also demonstrated inverted patterns of alteration according to MAP levels during E-CPR and after ROSC. In standard-MAP, PRx was transiently positive during E-CPR before returning to negative values after ROSC, demonstrating a reversible alteration of cerebral autoregulation during E-CPR. In high-MAP, PRx was negative during E-CPR but became sustainably positive after ROSC, demonstrating a prolonged alteration in cerebral autoregulation after ROSC. It was associated with a significant decrease in cerebral oxygen consumption in high- versus standard-MAP after ROSC.

Conclusions

During early E-CPR, MAP target above 80 mmHg is associated with higher carotid blood flow and improved cerebral autoregulation. This pattern is inverted after ROSC with a better hemodynamic status with standard versus high-MAP.
Early prediction of hemodynamic interventions in the intensive care unit using machine learning
Authors: Rahman Asif , Chang Yale , Dong Junzi , Conroy Bryan , Natarajan Annamalai , Kinoshita Takahiro , Vicario Francesco , Frassica Joseph , Xu-Wilson Minnan
Published: November 2021

Background

Timely recognition of hemodynamic instability in critically ill patients enables increased vigilance and early treatment opportunities. We develop the Hemodynamic Stability Index (HSI), which highlights situational awareness of possible hemodynamic instability occurring at the bedside and to prompt assessment for potential hemodynamic interventions.

Methods

We used an ensemble of decision trees to obtain a real-time risk score that predicts the initiation of hemodynamic interventions an hour into the future. We developed the model using the eICU Research Institute (eRI) database, based on adult ICU admissions from 2012 to 2016. A total of 208,375 ICU stays met the inclusion criteria, with 32,896 patients (prevalence = 18%) experiencing at least one instability event where they received one of the interventions during their stay. Predictors included vital signs, laboratory measurements, and ventilation settings.

Results

HSI showed significantly better performance compared to single parameters like systolic blood pressure and shock index (heart rate/systolic blood pressure) and showed good generalization across patient subgroups. HSI AUC was 0.82 and predicted 52% of all hemodynamic interventions with a lead time of 1-h with a specificity of 92%. In addition to predicting future hemodynamic interventions, our model provides confidence intervals and a ranked list of clinical features that contribute to each prediction. Importantly, HSI can use a sparse set of physiologic variables and abstains from making a prediction when the confidence is below an acceptable threshold.

Conclusions

The HSI algorithm provides a single score that summarizes hemodynamic status in real time using multiple physiologic parameters in patient monitors and electronic medical records (EMR). Importantly, HSI is designed for real-world deployment, demonstrating generalizability, strong performance under different data availability conditions, and providing model explanation in the form of feature importance and prediction confidence.
Accurate long-read de novo assembly evaluation with Inspector
Authors: Chen Yu , Zhang Yixin , Wang Amy Y. , Gao Min , Chong Zechen
Published: November 2021

Long-read de novo genome assembly continues to advance rapidly. However, there is a lack of effective tools to accurately evaluate the assembly results, especially for structural errors. We present Inspector, a reference-free long-read de novo assembly evaluator which faithfully reports types of errors and their precise locations. Notably, Inspector can correct the assembly errors based on consensus sequences derived from raw reads covering erroneous regions. Based on in silico and long-read assembly results from multiple long-read data and assemblers, we demonstrate that in addition to providing generic metrics, Inspector can accurately identify both large-scale and small-scale assembly errors.
Fluoroquinolone susceptibility in first-line drug-susceptible M. tuberculosis isolates in Lima, Peru
Authors: Schwalb Alvaro , Cachay Rodrigo , Meza Ericka , Cáceres Tatiana , Blackman Amondrea , Maruri Fernanda , Sterling Timothy R. , Gotuzzo Eduardo
Published: November 2021

Objective

To determine at two distinct time points the prevalence of resistance to ofloxacin (OFX), the representative class drug of fluoroquinolones (FQs), in M. tuberculosis isolates susceptible to first-line drugs.

Results

There were 279 M. tuberculosis isolates from the two cohorts (2004–2005: 238 isolates; 2017: 41 isolates) that underwent OFX drug-susceptibility testing (critical concentration: 2 µg/ml). Of 238 isolates in Cohort 1, no resistance to OFX was detected (95% CI 0–0.016); likewise, in Cohort 2, no resistance to OFX was detected in 41 isolates (95% CI 0–0.086). Our findings suggest that FQ use remains a viable option for the treatment of first-line drug-susceptible TB in Peru.
Examining the effect of a wearable, anxiety detection technology on improving the awareness of anxiety signs in autism spectrum disorder: a pilot randomized controlled trial
Authors: Nguyen Jenny , Cardy Robyn E. , Anagnostou Evdokia , Brian Jessica , Kushki Azadeh
Published: November 2021

Background

Anxiety is prevalent in autism spectrum disorder (ASD) and can negatively impact physical and mental health. Self-awareness of anxiety signs is a key barrier to success of anxiety interventions for many children.

Methods

To address this, we conducted a randomized controlled trial to assess whether the Anxiety Meter, a wearable, real-time anxiety detection technology, can improve awareness of anxiety symptoms and the initiation of relaxation techniques in children with ASD. Twenty-eight children with ASD were trained on the use of the Anxiety Meter and taught a diaphragmatic breathing relaxation technique over three visits. On the fourth visit, participants were randomized to either receive feedback of their anxiety level or no feedback from the Anxiety Meter while completing a stress-eliciting task (public speaking) and asked to engage in deep breathing if anxious.

Results

Feedback from the Anxiety Meter was associated with increased likelihood of initiating deep breathing in response to anxiety.

Limitations

Limitations include the small sample size, imbalanced group matching for IQ and sex, and the controlled-laboratory settings which limit the statistical power and generalizability of the results to real-world settings.

Conclusions

Although these results are limited by the relatively small sample size, they support the feasibility of using a wearable device and real-time feedback to improve anxiety symptom awareness.

Trial Registration ClinicalTrials.gov Identifier: NCT02160691, registration date: 06/05/2014.
Bone regeneration in rat calvarial defects using dissociated or spheroid mesenchymal stromal cells in scaffold-hydrogel constructs
Authors: Shanbhag Siddharth , Suliman Salwa , Mohamed-Ahmed Samih , Kampleitner Carina , Hassan Mohamed Nageeb , Heimel Patrick , Dobsak Toni , Tangl Stefan , Bolstad Anne Isine , Mustafa Kamal
Published: November 2021

Background

Three-dimensional (3D) spheroid culture can promote the osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSC). 3D printing offers the possibility to produce customized scaffolds for complex bone defects. The aim of this study was to compare the potential of human BMSC cultured as 2D monolayers or 3D spheroids encapsulated in constructs of 3D-printed poly-L-lactide-co-trimethylene carbonate scaffolds and modified human platelet lysate hydrogels (PLATMC-HPLG) for bone regeneration.

Methods

PLATMC-HPLG constructs with 2D or 3D BMSC were assessed for osteogenic differentiation based on gene expression and in vitro mineralization. Subsequently, PLATMC-HPLG constructs with 2D or 3D BMSC were implanted in rat calvarial defects for 12 weeks; cell-free constructs served as controls. Bone regeneration was assessed via in vivo computed tomography (CT), ex vivo micro-CT and histology.

Results

Osteogenic gene expression was significantly enhanced in 3D versus 2D BMSC prior to, but not after, encapsulation in PLATMC-HPLG constructs. A trend for greater in vitro mineralization was observed in constructs with 3D versus 2D BMSC (p > 0.05). In vivo CT revealed comparable bone formation after 4, 8 and 12 weeks in all groups. After 12 weeks, micro-CT revealed substantial regeneration in 2D BMSC (62.47 ± 19.46%), 3D BMSC (51.01 ± 24.43%) and cell-free PLATMC-HPLG constructs (43.20 ± 30.09%) (p > 0.05). A similar trend was observed in the histological analysis.

Conclusion

Despite a trend for superior in vitro mineralization, constructs with 3D and 2D BMSC performed similarly in vivo. Regardless of monolayer or spheroid cell culture, PLATMC-HPLG constructs represent promising scaffolds for bone tissue engineering applications.
Nanog/NFATc1/Osterix signaling pathway-mediated promotion of bone formation at the tendon–bone interface after ACL reconstruction with De-BMSCs transplantation
Authors: Tie Kai , Cai Jinghang , Qin Jun , Xiao Hao , Shangguan Yangfan , Wang Hui , Chen Liaobin
Published: November 2021

Background

Bone formation plays an important role in early tendon–bone healing after anterior cruciate ligament reconstruction (ACLR). Dedifferentiated osteogenic bone marrow mesenchymal stem cells (De-BMSCs) have enhanced osteogenic potential. This study aimed to investigate the effect of De-BMSCs transplantation on the promotion of bone formation at the tendon–bone interface after ACLR and to further explore the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.

Methods

BMSCs from the femurs and tibias of New Zealand white rabbits were subjected to osteogenic induction and then cultured in medium without osteogenic factors; the obtained cell population was termed De-BMSCs. De-BMSCs were induced to undergo osteo-, chondro- and adipo-differentiation in vitro to examine the characteristics of primitive stem cells. An ACLR model with a semitendinosus tendon was established in rabbits, and the animals were divided into a control group, BMSCs group, and De-BMSCs group. At 12 weeks after surgery, the rabbits in each group were sacrificed to evaluate tendon–bone healing by histologic staining, micro-computed tomography (micro-CT) examination, and biomechanical testing. During osteogenic differentiation of De-BMSCs, an siRNA targeting nuclear factor of activated T-cells 1 (NFATc1) was used to verify the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.

Results

De-BMSCs exhibited some properties similar to BMSCs, including multiple differentiation potential and cell surface markers. Bone formation at the tendon–bone interface in the De-BMSCs group was significantly increased, and biomechanical strength was significantly improved. During the osteogenic differentiation of De-BMSCs, the expression of Nanog and NFATc1 was synergistically increased, which promoted the interaction of NFATc1 and Osterix, resulting in increased expression of osteoblast marker genes such as COL1A, OCN, and OPN.

Conclusions

De-BMSCs transplantation could promote bone formation at the tendon–bone interface after ACLR and improve the biomechanical strength of the reconstruction. The Nanog/NFATc1/Osterix signaling pathway mediated the enhanced osteogenic differentiation efficiency of De-BMSCs.
Human dental pulp stem cells attenuate streptozotocin-induced parotid gland injury in rats
Authors: Al-Serwi Rasha H. , El-Kersh Ahmed Othman Fathy Othman , El-Akabawy Gehan
Published: November 2021

Objective

Diabetes mellitus causes deterioration in the body, including serious damage of the oral cavity related to salivary gland dysfunction, characterised by hyposalivation and xerostomia. Human dental pulp stem cells (hDPSCs) represent a promising therapy source, due to the easy, minimally invasive surgical access to these cells and their high proliferative capacity. It was previously reported that the trophic support mediated by these cells can rescue the functional and structural alterations of damaged salivary glands. However, potential differentiation and paracrine effects of hDPSCs in diabetic-induced parotid gland damage have not been investigated. Our study aimed to investigate the therapeutic effects of intravenous transplantation of hDPSCs on parotid gland injury in a rat model of streptozotocin (STZ)-induced type 1 diabetes.

Methods

Thirty Sprague–Dawley male rats were randomly categorised into three groups: control, diabetic (STZ), and transplanted (STZ + hDPSCs). The hDPSCs or the vehicles were injected into the rats’ tail veins, 7 days after STZ injection. Fasting blood glucose levels were monitored weekly. A glucose tolerance test was performed, and the parotid gland weight, salivary flow rate, oxidative stress indices, parotid gland histology, and caspase-3, vascular endothelial growth factor, proliferating cell nuclear antigen, neuronal nitric oxide synthase, endothelial nitric oxide synthase, and tetrahydrobiopterin biosynthetic enzyme expression levels in parotid tissues were assessed 28 days post-transplantation.

Results

Transplantation of hDPSCs decreased blood glucose, improved parotid gland weight and salivary flow rate, and reduced oxidative stress. The cells migrated to the STZ-injured parotid gland and differentiated into acinar, ductal, and myoepithelial cells. Moreover, hDPSCs downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and proliferating cell nuclear antigen, likely exerting pro-angiogenic and anti-apoptotic effects and promoting endogenous regeneration. In addition, the transplanted cells enhanced the parotid nitric oxide-tetrahydrobiopterin pathway.

Conclusions

Our results showed that hDPSCs migrated to and survived within the STZ-injured parotid gland, where functional and morphological damage was prevented due to the restoration of normal glucose levels, differentiation into parotid cell populations, and stimulation of paracrine-mediated regeneration. Thus, hDPSCs may have potential in the treatment of diabetes-induced parotid gland injury.
Molecular generation by Fast Assembly of (Deep)SMILES fragments
Authors: Berenger Francois , Tsuda Koji
Published: November 2021

Background

In recent years, in silico molecular design is regaining interest. To generate on a computer molecules with optimized properties, scoring functions can be coupled with a molecular generator to design novel molecules with a desired property profile.

Results

In this article, a simple method is described to generate only valid molecules at high frequency ($$>300,000$$

>
300
,
000

molecule/s using a single CPU core), given a molecular training set. The proposed method generates diverse SMILES (or DeepSMILES) encoded molecules while also showing some propensity at training set distribution matching. When working with DeepSMILES, the method reaches peak performance ($$>340,000$$

>
340
,
000

molecule/s) because it relies almost exclusively on string operations. The “Fast Assembly of SMILES Fragments” software is released as open-source at https://github.com/UnixJunkie/FASMIFRA. Experiments regarding speed, training set distribution matching, molecular diversity and benchmark against several other methods are also shown.