bluuebunny/crossref_metadata_2025 huggingface dataset:
A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol
Authors: Gao Lin-rui , Wang Xin , Han Weiming , Deng Wei , Li Chen , Wang Xiaomin , Zhao Yidian , Ni Wenjie , Chang Xiao , Zhou Zongmei , Deng Lei , Wang Wenqing , Liu Wenyang , Liang Jun , Zhang Tao , Bi Nan , Wang Jianyang , Zhai Yirui , Feng Qinfu , Lv Jima , Li Ling , Xiao Zefen
Published: September 2020

Background

Since the development of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT), no prospective study has investigated whether concurrent chemoradiotherapy (SIB-IMRT with 60 Gy) remains superior to radiotherapy (SIB-IMRT) alone for unresectable esophageal cancer (EC). Furthermore, the optimal therapeutic regimen for patients who cannot tolerate concurrent chemoradiotherapy is unclear. We recently completed a phase I/II radiation dose-escalation trial using simultaneous integrated boost (SIB), elective nodal irradiation, and concurrent chemotherapy for unresectable EC. We now intend to conduct a prospective, phase III, randomized study of SIB-IMRT with or without concurrent chemotherapy. We aim to find a safe, practical, and effective therapeutic regimen to replace the conventional segmentation (1.8–2.0 Gy) treatment mode (radiotherapy ± chemotherapy) for unresectable EC.

Methods

This two-arm, open, randomized, multicenter, phase III trial will recruit esophageal squamous cell carcinoma patients (stage IIA–IVB [UICC 2002]; IVB only with metastasis to the supraclavicular or celiac lymph nodes). In all, 164 patients will be randomized using a 1:1 allocation ratio, and stratified by study site and disease stage, especially the extent of lymph node metastasis. Patients in the SIB arm will receive definitive SIB radiotherapy (95% planning target volume/planning gross tumor volume, 50.4 Gy/59.92 Gy/28 f, equivalent dose in 2-Gy fractions = 60.62 Gy). Patients in the SIB + concurrent chemotherapy arm will receive definitive SIB radiotherapy with weekly paclitaxel and a platinum-based drug (5–6 weeks). Four cycles of consolidated chemoradiotherapy will also be recommended. The primary objective is to compare the 1-year, 2-year, and 3-year overall survival of the SIB + chemotherapy group and SIB groups. Secondary objectives include progression-free survival, local recurrence-free rate, completion rate, and adverse events. Detailed radiotherapy protocol and quality-assurance procedures have been incorporated into this trial.

Discussion

In unresectable, locally advanced EC, a safe and effective total radiotherapy dose and reasonable segmentation doses are required for the clinical application of SIB-IMRT + two-drug chemotherapy. Whether this protocol will replace the standard treatment regimen will be prospectively investigated. The effects of SIB-IMRT in patients with poor physical condition who cannot tolerate definitive chemoradiotherapy will also be investigated.

Trial registration

clinicaltrials.gov (NCT03308552, November 1, 2017).
Somatic mutation detection efficiency in EGFR: a comparison between high resolution melting analysis and Sanger sequencing
Authors: Joy Reenu Anne , Thelakkattusserry Sukrishna Kamalasanan , Vikkath Narendranath , Bhaskaran Renjitha , Krishnan Sajitha , Vasudevan Damodaran , Ariyannur Prasanth S.
Published: September 2020

Background

High resolution melting curve analysis is a cost-effective rapid screening method for detection of somatic gene mutation. The performance characteristics of this technique has been explored previously, however, analytical parameters such as limit of detection of mutant allele fraction and total concentration of DNA, have not been addressed. The current study focuses on comparing the mutation detection efficiency of High-Resolution Melt Analysis (HRM) with Sanger Sequencing in somatic mutations of the EGFR gene in non-small cell lung cancer.

Methods

The minor allele fraction of somatic mutations was titrated against total DNA concentration using Sanger sequencing and HRM to determine the limit of detection. The mutant and wildtype allele fractions were validated by multiplex allele-specific real-time PCR. Somatic mutation detection efficiency, for exons 19 & 21 of the EGFR gene, was compared in 116 formalin fixed paraffin embedded tumor tissues, after screening 275 tumor tissues by Sanger sequencing.

Results

The limit of detection of minor allele fraction of exon 19 mutation was 1% with sequencing, and 0.25% with HRM, whereas for exon 21 mutation, 0.25% MAF was detected using both methods. Multiplex allele-specific real-time PCR revealed that the wildtype DNA did not impede the amplification of mutant allele in mixed DNA assays. All mutation positive samples detected by Sanger sequencing, were also detected by HRM. About 28% cases in exon 19 and 40% in exon 21, detected as mutated in HRM, were not detected by sequencing. Overall, sensitivity and specificity of HRM were found to be 100 and 67% respectively, and the negative predictive value was 100%, while positive predictive value was 80%.

Conclusion

The comparative series study suggests that HRM is a modest initial screening test for somatic mutation detection of EGFR, which must further be confirmed by Sanger sequencing. With the modification of annealing temperature of initial PCR, the limit of detection of Sanger sequencing can be improved.
Combined and interaction effect of chlamydia pneumoniae infection and smoking on lung cancer: a case-control study in Southeast China
Authors: Xu Xin , Liu Zhiqiang , Xiong Weimin , Qiu Minglian , Kang Shuling , Xu Qiuping , Cai Lin , He Fei
Published: September 2020

Background

This case-control study investigated the role ofChlamydia pneumoniae(Cpn) infection in the pathogenesis of lung cancer and the combined and interaction effect of Cpn infection, smoking, and various environmental factors.

Methods

The study comprised 449 lung cancer patients and 512 age- and sex-matched healthy controls. All participants provided a 5 ml fasting peripheral venous blood sample for testing Cpn-specific IgG and IgA by using micro-immunofluorescence. Besides analyzing the associations between Cpn and lung cancer, combined effect analysis, logistic regression, and the Excel table made by Andersson were used to analyze the combined and interaction effects of Cpn and environmental factors on lung cancer.

Results

Compared to those with no evidence of serum Cpn IgA or Cpn IgG, those with both Cpn IgG+ and IgA+ had 2.00 times the risk (95% CI: 1.34–3.00) of developing lung cancer. Cpn IgG+ or IgA+ was associated with a significantly increased risk of lung cancer among smokers; the adjusted odds ratio (OR) was 1.79 (95% CI: 1.10–2.91) and 2.27 (95% CI: 1.38–3.72), respectively. Those exposed to passive smoking with Cpn IgG+ or IgA+ also showed an increased risk of lung cancer; the adjusted OR was 1.82 (95% CI: 1.20–2.77) or 1.87 (95% CI: 1.22–2.87), respectively. Similar results were also observed among alcohol drinkers. Multiplicative and additive interactions were not observed between Cpn infection and environmental factors. The combined effects of Cpn IgG+ or IgA+ with smoking, passive smoking, and family history of cancer on lung cancer were determined.

Conclusion

Cpn infection is potentially associated with primary lung cancer in the Chinese Han population and has combined effects with smoking, passive smoking, and family history of cancer.
Hypoketotic hypoglycemia in citrin deficiency: a case report
Authors: Wada Yoichi , Arai-Ichinoi Natsuko , Kikuchi Atsuo , Sakamoto Osamu , Kure Shigeo
Published: September 2020

Background

Citrin deficiency (CD) is a recessive metabolic disease caused by biallelic pathogenic variants in SLC25A13. Although previous studies have reported ketosis in CD, it was observed at the time of euglycemia or mild hypoglycemia. Blood ketone levels concomitant with symptomatic or severe hypoglycemia in CD have not been a topic of focus despite its importance in identifying the etiology of hypoglycemia and assessing the ability of fatty acid utilization. Herein, we describe a patient with CD who had repeated episodes of hypoglycemia with insufficient ketosis.

Case presentation

A 1-year-old boy with repetitive hypoglycemia was referred to us to investigate its etiology. The fasting load for 13 h led to hypoketotic hypoglycemia, indicating the possibility of partial β-oxidation dysfunction. A genetic test led to the diagnosis of CD. The hypoglycemic episodes disappeared after switching to a medium-chain triglyceride-containing formula.

Conclusions

This case report suggests that symptomatic or severe hypoglycemia in patients with CD could be associated with relatively low levels of ketone bodies, implying that β-oxidation in these patients might possibly be partially disrupted. When encountering a patient with hypoglycemia, clinicians should check blood ketone levels and bear in mind the possibility of CD because excessive intravenous administration of glucose can cause decompensated symptoms in patients with CD as opposed to other disorders presenting with hypoketotic hypoglycemia, such as fatty acid oxidation disorders. Further studies in a large-scale cohort are warranted to confirm our speculation.
Testing a physical education-delivered autonomy supportive intervention to promote leisure-time physical activity in lower secondary school students: the PETALS trial
Authors: Schneider Jekaterina , Polet Juho , Hassandra Mary , Lintunen Taru , Laukkanen Arto , Hankonen Nelli , Hirvensalo Mirja , Tammelin Tuija H. , Törmäkangas Timo , Hagger Martin S.
Published: September 2020

Background

Inadequate physical activity in young people is associated with several physical and mental health concerns. Physical education (PE) is a potentially viable existing network for promoting physical activity in this population. However, little research has been conducted on whether PE teachers can influence students’ engagement in leisure-time physical activity. The present study therefore examined the efficacy of an intervention aimed at increasing PE teachers’ autonomy support on students’ leisure-time physical activity (the PETALS trial). The intervention was guided by the trans-contextual model (TCM) explaining the processes by which PE teachers’ provision of autonomy support during PE promotes students’ motivation and engagement in physical activity in their leisure time.

Methods

The study adopted a cluster-randomized, waitlist control intervention design with randomization by school. Participants were PE teachers (N = 29, 44.83%female; M age = 42.83, SD = 9.53 yrs) and their lower secondary school students (N = 502, 43.82%female; M age = 14.52, SD = 0.71 yrs). We measured TCM constructs, including perceived autonomy support, autonomous motivation in PE and leisure time, beliefs and intentions towards leisure-time physical activity, and physical activity behavior at baseline, post-intervention, and at one-, three-, and six-months. Study hypotheses were tested through a series of ANOVAs and structural equation models using post-intervention and one-month follow-up data.

Results

We found no changes in TCM constructs or physical activity behavior in either group at post-intervention or at 1 month. Path analyses supported two propositions of the TCM as change variables: perceived autonomy support had a significant effect on autonomous motivation in PE and autonomous motivation in PE had a significant effect on autonomous motivation in leisure time. Although we found a direct effect of autonomous motivation in leisure time on physical activity, we did not find support for the third premise of the TCM that autonomous motivation in leisure time indirectly affects physical activity through beliefs and intentions.

Conclusions

Current findings did not support the efficacy of the PETALS intervention at changing physical activity behavior and TCM constructs. More research is required to determine whether the TCM predictive validity is supported when other model variables are manipulated through experimental and intervention studies.

Trial registration

ISRCTN, ISRCTN39374060. Registered 19 July 2018. Prospectively registered.
Predictors of Poor Postoperative Outcomes in Pediatric Surgery Patients in Rural Ghana
Authors: Peiffer Sarah , Ssentongo Anna E. , Keeney Laura , Amponsah-Manu Forster , Yeboako Richard , Ofosu-Akromah Richard , Arkorful Temitope Ebenezer , Agyemang Eric , Tsai Anthony , Oh John , Ssentongo Paddy
Published: September 2020

Background/Purpose

Perioperative complications cause significant pediatric morbidity and mortality in low- and lower middle -income countries. This study investigates factors associated with prolonged length of stay, 90-day readmission and in-hospital mortality among pediatric patients at Eastern Regional Hospital (ERH) in Ghana.

Methods

This is a retrospective review of perioperative morbidity and mortality in children < 18 years at ERH in Koforidua, Ghana. All pediatric surgeries performed between January 2015 and December 2017 were included in this study. Univariate analysis was performed using Pearson’s chi-square tests or Fisher’s exact tests. Variables that were significant on univariate analysis were included in multivariable logistic regression models adjusted for age and gender.

Results

We analyzed 468 patients < 18 years of age with a median length of stay (LOS) of 3 days. The 90-day readmission and in-hospital mortality rates were 138 and 17 per 1000 patients, respectively. The most common procedures were herniorrhaphy (19 %) and appendectomy (15 %). Gastrointestinal surgery, surgical trauma, surgical infection and lack of insurance were significantly associated with prolonged LOS. Young age and female gender were significantly associated with in-hospital mortality. Malaria was significantly associated with 90-day readmission.

Conclusions

Malaria infection is a significant risk factor for readmission, which should be investigated and treated in pediatric surgical patients in rural Ghana. Ensuring that all patients have insurance may result in shorter hospital stays. Provision of laparoscopic equipment may reduce hospital stays for patients undergoing gastrointestinal surgery. Expansion of the surgical work force, particularly pediatric surgeons, could improve perioperative survival in the very young population.

Level of Evidence

Retrospective comparative study.
Weight gain in patients with severe atopic dermatitis treated with dupilumab: a cohort study
Authors: Johansson Emma Kristin , Ivert Lina Ulrika , Bradley Baltzar , Lundqvist Maria , Bradley Maria
Published: September 2020

Background

Dupilumab, targeting the interleukin-4α receptor and inhibiting the action of interleukin-4 and interleukin-13, was recently approved for treatment of moderate to severe atopic dermatitis. There is limited data on long-term effects and safety among patients with severe atopic dermatitis treated with dupilumab. Weight gain was observed among patients treated with dupilumab in our clinic. The aim was to describe weight change in a cohort study of patients with severe atopic dermatitis treated with dupilumab from baseline to follow-up after 12 months, and to analyze if weight change was associated with effect of treatment, reported appetite, and/or disturbed night sleep due to itching.

Methods

All patients with atopic dermatitis receiving systemic treatment at the Unit of Dermatology, Karolinska University Hospital, have been registered and monitored consecutively since January 2017. This cohort constituted all patients who started treatment on dupilumab or methotrexate between 10 January 2017 and 30 June 2019 with at least 6 months of follow-up within the study period. The following variables were monitored at start of and during treatment: Eczema Severity Score Index, Patient-Oriented Eczema Measure, visual analogue scale for pruritus 10 cm, Montgomery-Åsberg Depression Rating Scale, Dermatology Life Quality Index, and weight. Data analyses were performed using two-sample Wilcoxon-Mann-Whitney rank-sum test, or the Wilcoxon matched-pairs sign-rank test with ap-value < 0.05 considered as statistically significant.

Results

Patients treated with dupilumab (n = 12) gained weight (mean 6.1 kg, range [0.1–18.0],p = 0.002) after 1 year on treatment. The majority of patients showed a good response to treatment with dupilumab (n = 11); at follow-up at 6, 9, or 12 months, they reached EASI-90 (n = 6), EASI-75 (n = 4), or EASI-50 (n = 1). There was no significant association between weight gain and treatment response, reported appetite, or disturbed night-sleep due to itch. Patients treated with methotrexate showed no significant weight change (n = 8).

Conclusions

To our knowledge, this is the first report on a possible association between weight gain and dupilumab treatment; the extent of the association is yet to be seen, as is the mechanism behind this finding.
Variability of residents’ ratings of faculty’s teaching performance measured by five- and seven-point response scales
Authors: Debets Maarten P. M. , Scheepers Renée A. , Boerebach Benjamin C. M. , Arah Onyebuchi A. , Lombarts Kiki M. J. M. H.
Published: September 2020

Background

Medical faculty’s teaching performance is often measured using residents’ feedback, collected by questionnaires. Researchers extensively studied the psychometric qualities of resulting ratings. However, these studies rarely consider the number of response categories and its consequences for residents’ ratings of faculty’s teaching performance. We compared the variability of residents’ ratings measured by five- and seven-point response scales.

Methods

This retrospective study used teaching performance data from Dutch anaesthesiology residency training programs. Questionnaires with five- and seven-point response scales from the extensively studied System for Evaluation of Teaching Qualities (SETQ) collected the ratings. We inspected ratings’ variability by comparing standard deviations, interquartile ranges, and frequency (percentage) distributions. Relevant statistical tests were used to test differences in frequency distributions and teaching performance scores.

Results

We examined 3379 residents’ ratings and 480 aggregated faculty scores. Residents used the additional response categories provided by the seven-point scale – especially those differentiating between positive performances. Residents’ ratings and aggregated faculty scores showed a more even distribution on the seven-point scale compared to the five-point scale. Also, the seven-point scale showed a smaller ceiling effect. After rescaling, the mean scores and (most) standard deviations of ratings from both scales were comparable.

Conclusions

Ratings from the seven-point scale were more evenly distributed and could potentially yield more nuanced, specific and user-friendly feedback. Still, both scales measured (almost) similar teaching performance outcomes. In teaching performance practice, residents and faculty members should discuss whether response scales fit their preferences and goals.
The psychometric properties of the respectful maternity care (RMC) for an Iranian population
Authors: Hajizadeh Khadije , Asghari Jafarabadi Mohammad , Vaezi Maryam , Meedya Shahla , Mohammad-Alizadeh-Charandabi Sakineh , Mirghafourvand Mojgan
Published: September 2020

Background

The absence of Respectful Maternity Care (RMC) deters mothers from seeking maternity care services. Given the importance of RMC and the lack of a standard tool for its assessment in Iran, the present study was conducted to translate and assess the psychometric properties of the RMC questionnaire in Iranian women.

Methods

Forward-backward method was used for translating the questionnaire from English into Persian. A total of 265 postpartum women entered the study by simple random sampling from public and private hospitals in Tabriz, Iran. The validity of the questionnaire was confirmed through the face, content and construct validity. Construct validity was assessed through exploratory and confirmatory factor analyses. The internal consistency and test-retest reliability were used to confirm the reliability of the questionnaire. Internal consistency was examined by measuring the Cronbach’s alpha in a sample of 20 mothers, and test-retest stability by calculating the Intraclass Correlation Coefficient (ICC) in the same group of mothers, who had completed the questionnaire twice with a two-week interval.

Results

The exploratory factor analysis led to the extraction of one factor. Item 12 was eliminated due to its low factor loading. X2/df was less than 5, and RMSEA was less than 0.08, which confirms the validity of this model. The Cronbach’s alpha coefficient was obtained as 0.93 and ICC (with 95% confidence interval) as 0.98 (0.96 to 0.99).

Conclusion

The results of the study demonstrated that the Iranian RMC scale can be used as a valid and reliable instrument to assess RMC in Iran.
Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes: retrospective cohort study
Authors: Lee Da Young , Han Kyungdo , Park Sanghyun , Yu Ji Hee , Seo Ji A. , Kim Nam Hoon , Yoo Hye Jin , Kim Sin Gon , Choi Kyung Mook , Baik Sei Hyun , Park Yong Gyu , Kim Nan Hee
Published: September 2020

Background

Previous research regarding long-term glucose variability over several years which is an emerging indicator of glycemic control in diabetes showed several limitations. We investigated whether variability in long-term fasting plasma glucose (FG) can predict the development of stroke, myocardial infarction (MI), and all-cause mortality in patients with diabetes.

Methods

This is a retrospective cohort study using the data provided by the Korean National Health Insurance Corporation. A total of 624,237 Koreans ≥ 20 years old with diabetes who had undergone health examinations at least twice from 2005 to 2008 and simultaneously more than once from 2009 to 2010 (baseline) without previous histories of stroke or MI. As a parameter of variability of FG, variability independent of mean (VIM) was calculated using FG levels measured at least three times during the 5 years until the baseline. Study endpoints were incident stroke, MI, and all-cause mortality through December 31, 2017.

Results

During follow-up, 25,038 cases of stroke, 15,832 cases of MI, and 44,716 deaths were identified. As the quartile of FG VIM increased, the risk of clinical outcomes serially increased after adjustment for confounding factors including duration and medications of diabetes and the mean FG. Adjusted hazard ratios (95% confidence intervals) of FG VIM quartile 4 compared with quartile 1 were 1.20 (1.16–1.24), 1.20 (1.15–1.25), and 1.32 (1.29–1.36) for stroke, MI and all-cause mortality, respectively. The impact of FG variability was higher in the elderly and those with a longer duration of diabetes and lower FG levels.

Conclusions

In diabetes, long-term glucose variability showed a dose–response relationship with the risk of stroke, MI, and all-cause mortality in this nationwide observational study.
Transcriptomic characterization and innovative molecular classification of clear cell renal cell carcinoma in the Chinese population
Authors: Zhao Qiang , Xue Jia , Hong Baoan , Qian Wubin , Liu Tiezhu , Fan Bin , Cai Jie , Ji Yongpeng , Liu Jia , Yang Yong , Li Qixiang , Guo Sheng , Zhang Ning
Published: September 2020

Background

Large-scale initiatives like The Cancer Genome Atlas (TCGA) performed genomics studies on predominantly Caucasian kidney cancer. In this study, we aimed to investigate genomics of Chinese clear cell renal cell carcinoma (ccRCC).

Methods

We performed whole-transcriptomic sequencing on 55 tumor tissues and 11 matched normal tissues from Chinese ccRCC patients. We systematically analyzed the data from our cohort and comprehensively compared with the TCGA ccRCC cohort.

Results

It found that PBRM1 mutates with a frequency of 11% in our cohort, much lower than that in TCGA Caucasians (33%). Besides, 31 gene fusions including 5 recurrent ones, that associated with apoptosis, tumor suppression and metastasis were identified. We classified our cohort into three classes by gene expression. Class 1 shows significantly elevated gene expression in the VEGF pathway, while Class 3 has comparably suppressed expression of this pathway. Class 2 is characterized by increased expression of extracellular matrix organization genes and is associated with high-grade tumors. Applying the classification to TCGA ccRCC patients revealed better distinction of tumor prognosis than reported classifications. Class 2 shows worst survival and Class 3 is a rare subtype ccRCC in the TCGA cohort. Furthermore, computational analysis on the immune microenvironment of ccRCC identified immune-active and tolerant tumors with significant increased macrophages and depleted CD4 positive T-cells, thus some patients may benefit from immunotherapies.

Conclusion

In summary, results presented in this study shed light into distinct genomic expression profiles in Chinese population, modified the stratification patterns by new molecular classification, and gave practical guidelines on clinical treatment of ccRCC patients.
Measuring inequalities in the selected indicators of National Health Accounts from 2008 to 2016: evidence from Iran
Authors: Mehrolhassani Mohammad Hossein , Yazdi-Feyzabadi Vahid , Lashkari Marzieh
Published: September 2020

Background

Increase in total health expenditures is one of the main challenges of health systems worldwide, and its inequality is considered as a concern in global arena especially developing countries. This study aims to measure inequality in the distribution of selected indicators of national health accounts across the Iranian provinces.

Methods

In this study, the data on health financing agents from provincial health accounts from 2008 to 2016 were collected. Gini coefficient (GC) was used to measure inequality. The population and the number of service providers in each province were the bases to measure the GC. The Coefficient of Variation (CV) and the Rate Ratio (RR) were used to determine the dispersion and variation across the provinces. Disparity index was employed to measure the average deviation of the out-of-pocket (OOP) proportion from the desired OOP proportion presented in national development plans (NDPs) of Iran.

Results

The distribution of resources using both bases were unequal, especially in OOP, with the highest rate over the years studied, ranging from 0.50 to 0.59. The inequality in public resources was lower, with Health Insurance Organization dropping from 0.42 to 0.40 over the years. CV and RR also confirmed the inequality in health resources distribution. In the years 2014 and 2015, the lowest and highest levels were 0.22 and 0.39, respectively. The values of disparity index for OOP had a fluctuating trend ranging from 37.01 to 65.85%.

Conclusion

Inequality in the distribution of public health expenditures was moderate to high. Moreover, inequality in private health expenditures was higher than public one. Distribution of OOP spent by households at provincial level showed a high inequality. It is suggested that inequality measures to be considered in NDPs to illustrate how resources are distributed at the geographical level. NHA framework can help to provide robust evidence base for policymaking.
Site-specific opening of the blood-brain barrier by extracellular histones
Authors: Villalba Nuria , Baby Sheon , Cha Byeong J. , Yuan Sarah Y.
Published: September 2020

Background

Increased extracellular histones in the bloodstream are known as a biomarker for vascular dysfunction associated with severe trauma or sepsis. There is limited information regarding the pathogenic role of circulating histones in neuroinflammation and cerebrovascular endothelial injury. Particularly, it remains unclear whether histones affect the blood-brain barrier (BBB) permeability function.

Methods

The direct effects of unfractionated histones on endothelial barrier properties were first assessed in brain microvascular endothelial cell monolayers by measuring transendothelial electrical resistance and solute flux. This was followed by in vivo mouse experiments, where BBB function was assessed by quantifying brain tissue accumulation of intravenously injected tracers of different molecular sizes, and comparison was made in mice receiving a sublethal dose of histones versus sterile saline. In parallel, the endothelial barrier ultrastructure was examined in histone- and saline-injected animals under transmission electron microscopy, corresponding to the expression of tight junction and adherens junction proteins.

Results

Histones increased paracellular permeability to sodium fluorescein and reduced barrier resistance at 100 μg/mL; these responses were accompanied by discontinuous staining of the tight junction proteins claudin-5 and zona ocludens-1. Interestingly, the effects of histones did not seem to result from cytotoxicity, as evidenced by negative propidium iodide staining. In vivo, histones increased the paracellular permeability of the BBB to small tracers of < 1-kDa, whereas tracers larger than 3-kDa remained impermeable across brain microvessels. Further analysis of different brain regions showed that histone-induced tracer leakage and loss of tight junction protein expression mainly occurred in the hippocampus, but not in the cerebral cortex. Consistently, opening of tight junctions was found in hippocampal capillaries from histone-injected animals. Protein expression levels of GFAP and iBA1 remained unchanged in histone-injected mice indicating that histones did not affect reactive gliosis. Moreover, cell membrane surface charge alterations are involved in histone-induced barrier dysfunction and tight junction disruption.

Conclusions

Extracellular histones cause a reversible, region-specific increase in BBB permeability to small molecules by disrupting tight junctions in the hippocampus. We suggest that circulating histones may contribute to cerebrovascular injury or brain dysfunction by altering BBB structure and function.
Uric acid is associated with adiposity factors, especially with fat mass reduction during weight loss in obese children and adolescents
Authors: Niu Yang , Zhao Xue-lin , Ruan Hui-juan , Mao Xiao-meng , Tang Qing-ya
Published: September 2020

Background

Current adult studies suggest that uric acid (UA) is associated with body fat, but the relationship in obese children is unclear. Thus, we aim to evaluate the association between uric acid and body composition of obese children.

Methods

A total of 79 obese children were included in this study, and 52 children (34 boys and 18 girls) underwent a 6-week weight loss camp, including 34 boys and 18 girls. Six-week weight-loss interventions were performed on all participants through aerobic exercise and appropriate dietary control. Laboratory tests and body composition were collected before and after the intervention.

Results

Before the intervention, correlation analysis demonstrated that uric acid was positively correlated with height, weight, body mass index (BMI), waist circumference, hip circumference, fat mass (FM), and free fat mass (FFM) with adjusting for age and gender (P < 0.05). After 6 weeks of intervention, the participants gained 3.12 ± 0.85 cm in height, body fat percentage decreased by 7.23 ± 1.97%, and lost 10.30 ± 2.83 kg in weight. Univariate and multivariate analysis indicated that uric acid at baseline was associated with FM reduction during weight loss (P < 0.05).

Conclusions

This study is the first report that uric acid is associated with BMI and FM, and may play an important role in the reduction of FM during weight loss in obese children and adolescents. The interaction between UA and adiposity factors and its underlying mechanisms need to be further explored.

Trial registration

This study was registered in Clinical Trials.gov (NCT03490448) and approved by the Ethics Committee of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.
Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia
Authors: Giraud Sophie , Bardel Claire , Dupuis-Girod Sophie , Carette Marie-France , Gilbert-Dussardier Brigitte , Riviere Sophie , Saurin Jean-Christophe , Eyries Mélanie , Patri Sylvie , Decullier Evelyne , Calender Alain , Lesca Gaëtan
Published: September 2020

Background

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in theENG (HHT1),ACVRL1 (HHT2)and, to a lesser extentMADH4andGDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role ofENG,ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.

Methods

We selected 354 patients from the French HHT patient database who had one disease causing variant in eitherENGorACVRL1and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14andADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.

Results

The proportion of patients with germlineACVRL1variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 inACVRL1, 1 inENG, 1 inSMAD5, and 1 inADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).

Conclusions

In this large association study, we confirmed the strong relationship betweenACVRL1and the development of HAVMs. Common polymorphisms ofACVRL1may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.
Management of ocular involvement in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: french national audit of practices, literature review, and consensus agreement
Authors: Thorel D. , Ingen-Housz-Oro S. , Royer G. , Delcampe A. , Bellon N. , Bodemer C. , Welfringer-Morin A. , Bremond-Gignac D. , Robert M. P. , Tauber M. , Malecaze F. , Dereure O. , Daien V. , Colin A. , Bernier C. , Couret C. , Vabres B. , Tetart F. , Milpied B. , Cornut T. , Ben Said B. , Burillon C. , Cordel N. , Beral L. , de Prost N. , Wolkenstein P. , Muraine M. , Gueudry J.
Published: September 2020

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) can lead to severe ophthalmologic sequelae. The main risk factor is the severity of the initial ocular involvement. There are no recommendations for ocular management during acute phase.

We conducted a national audit of current practice in the 11 sites of the French reference center for toxic bullous dermatoses and a review of the literature to establish therapeutic consensus guidelines. We sent a questionnaire on ocular management practices in SJS/ TEN during acute phase to ophthalmologists and dermatologists. The survey focused on ophthalmologist opinion, pseudomembrane removal, topical ocular treatment (i.e. corticosteroids, antibiotics, antiseptics, artificial tear eye drops, vitamin A ointment application), amniotic membrane transplantation, symblepharon ring use, and systemic corticosteroid therapy for ophthalmologic indication. Nine of 11 centers responded. All requested prompt ophthalmologist consultation. The majority performed pseudomembrane removal, used artificial tears, and vitamin A ointment (8/9, 90%). Combined antibiotic-corticosteroid or corticosteroid eye drops were used in 6 centers (67%), antibiotics alone and antiseptics in 3 centers (33%). Symblepharon ring was used in 5 centers (55%) if necessary. Amniotic membrane transplantation was never performed systematically and only according to the clinical course. Systemic corticosteroid therapy was occasionally used (3/9, 33%) and discussed on a case-by-case basis.

The literature about ocular management practice in SJS/ TEN during acute phase is relatively poor. The role of specific treatments such as local or systemic corticosteroid therapy is not consensual. The use of preservatives, often present in eye drops and deleterious to the ocular surface, is to be restricted. Early amniotic membrane transplantation seems to be promising.
A study of the mechanism of lncRNA-CR594175 in regulating proliferation and invasion of hepatocellular carcinoma cells in vivo and in vitro
Authors: Liu Quan , Yu Xuxu , Yang Minjie , Li Xiangke , Zhai Xuejia , Lian Yujin , Chen Zhong , Fan Qingxia , Song Lijie , Li Wencai
Published: September 2020

Background

Hepatocellular carcinoma (HCC) is one of the cancers of highest incidence and mortality worldwide. The proliferation and invasion of tumor cells are the main reason for poor prognosis after HCC surgery. Long non-coding RNA (lncRNA) has been shown to play a key role in the progression of HCC. LncRNA-CR594175 is one of the highly expressed lncRNAs in HCC tumors and their metastatic tumors that we have obtained by the High-throughput screening method.

Methods

To elucidate the role of lncRNA-CR594175 in regulating the proliferation and invasion of human hepatoma cell line, HepG2, we operated through lncRNA-CR594175 silencing to inhibit the progression of HCC, either through in vitro or in vivo experiments.

Results

We found that lncRNA-CR594175 was lower in adjacent non-cancerous tissues than in primary HCC, and was lower in primary HCC than in its metastasis. Silencing of lncRNA-CR594175 inhibited the proliferation and invasion of HepG2 cells and growth of subcutaneous tumors. The results revealed that lncRNA-CR594175, as a RNA sponge, broke the negative regulation of hsa-miR-142-3p on Catenin, beta-1 (CTNNB1), and once lncRNA-CR594175 was silenced, the hsa-miR142-3p regained its negative regulation on CTNNB1 which can promote HCC progression by activating the wnt pathway.

Conclusions

Our present study demonstrated for the first time that lncRNA-CR594175 silencing suppressed proliferation and invasion of HCC cells in vivo and in vitro by restoring the negative regulation of hsa-miR-142-3p on CTNNB1, laying a solid theoretical base for using lncRNA-CR594175 as genetic target therapy for HCC and offering a reasonable explanation for inactivation of miRNA in different tumors or in the tumor at different stages.
The attitudes and feelings of mental health nurses towards adolescents and young adults with nonsuicidal self-injuring behaviors
Authors: Pintar Babič Matejka , Bregar Branko , Drobnič Radobuljac Maja
Published: September 2020

Background

Attitudes towards patients with self-harm behaviors are decisive for the quality of the relationship of healthcare professionals towards them, which is further linked to successful treatment. In mental health settings, nurses are the ones spending the longest time caring for these patients. Nurses often experience negative emotions while delivering care which may lead to professional burnout and suboptimal patient care. The purpose of this study was to explore the feelings and attitudes of nurses working in different psychiatric hospital settings toward adolescents and young adults with non-suicidal self-injury (NSSI).

Subjects and methods

The subjects were nurses from the tertiary psychiatric hospital who deliver mental health care to patients with NSSI on a daily basis (n = 76; 20 males, 56 females; average age 42 ± 8 years; average working experience 20 ± 9 years). Data were collected via a self-report questionnaire consisting of three parts (sociodemographic data, Emotional Burden, Adapted Self-Harm Antipathy-Scale). In the latter two parts of the questionnaire, the subjects rated their level of agreement with the emotions and statements on a five-point Likert scale. Nonparametric tests were used for statistical analysis. The statistical significance was set to p < 0.05.

Results

The emotions of nurses towards patients with NSSI were not very negative and the attitudes were positive. Powerlessness was the most prevalent (3.55 ± 1.038) of the studied emotions, followed by uncertainty (3.21 ± 1.225). The subjects disagreed with feeling anger (2.34 ± 1.17) and despair (2.07 ± 1.09) and were undecided about being afraid (3.07 ± 1.2). The nurses with higher education felt more negative emotions than those with medium education. Education did not affect nurses’ attitudes. The nurses from non-psychotherapeutic units felt more negative emotions and less positive attitudes than those from psychotherapeutic units. Gender did not affect the emotions felt towards patients, but the female nurses held more positive and less negative attitudes.

Conclusions

The respondents expressed low levels of negative emotions and positive and caring attitudes towards patients with NSSI, indicating a good predisposition for empathetic work and long-term burnout prevention. However, the differences observed with regards to education, gender and especially working environment indicate the different needs for environmental, educational and supervisory support.
MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy
Authors: Yao Hang-Ping , Tong Xiang-Min , Hudson Rachel , Wang Ming-Hai
Published: September 2020

Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease. However, these therapeutic modalities and approaches achieve only limited success. Thus, there is a pharmaceutical need to discover new targets and develop novel therapeutics for CRAC therapy. MET and RON receptor tyrosine kinases have been implicated in CRAC pathogenesis. Clinical studies have revealed that aberrant MET and/or RON expression and signaling are critical in regulating CRAC progression and malignant phenotypes. Increased MET and/or RON expression also has prognostic value for CRAC progression and patient survival. These features provide the rationale to target MET and RON for clinical CRAC intervention. At present, the use of small molecule kinase inhibitors targeting MET for CRAC treatment has achieved significant progress with several approvals for clinical application. Nevertheless, antibody-based biotherapeutics, although under clinical trials for more than 8 years, have made very little progress. In this review, we discuss the importance of MET and/or RON in CRAC tumorigenesis and development of anti-MET, anti-RON, and MET and RON-dual targeting antibody-drug conjugates for clinical application. The findings from both preclinical studies and clinical trials highlight the potential of this novel type of biotherapeutics for CRAC therapy in the future.
Correction to: The tree that hides the forest: cryptic diversity and phylogenetic relationships in the Palaearctic vector Obsoletus/Scoticus complex (Diptera: Ceratopogonidae) at the European level
Authors: Mignotte Antoine , Garros Claire , Gardès Laetitia , Balenghien Thomas , Duhayon Maxime , Rakotoarivony Ignace , Tabourin Laura , Poujol Léa , Mathieu Bruno , Ibañez-Justicia Adolfo , Deniz Ahmet , Cvetkovikj Aleksandar , Purse Bethan V. , Ramilo David W. , Stougiou Despoina , Werner Doreen , Pudar Dubravka , Petrić Dušan , Veronesi Eva , Jacobs Frans , Kampen Helge , da Fonseca Isabel Pereira , Lucientes Javier , Navarro Javier , la Puente Josue Martinez-de , Stefanovska Jovana , Searle Kate R. , Khallaayoune Khalid , Lorna Culverwell C. , Larska Magdalena , Bourquia Maria , Goffredo Maria , Bisia Marina , England Marion , Robin Matthew , Quaglia Michela , Miranda-Chueca Miguel Ángel , Bødker René , Estrada-Peña Rosa , Carpenter Simon , Tchakarova Simona , Boutsini Sofia , Sviland Ståle , Schäfer Stefanie M. , Ozoliņa Zanda , Segliņa Zanda , Vatansever Zati , Huber Karine
Published: September 2020

An amendment to this paper has been published and can be accessed via the original article.
Correction to: N6‑Adenosine methylation on mRNA is recognized by YTH2 domain protein of human malaria parasite Plasmodium falciparum
Authors: Govindaraju Gayathri , Kadumuri Rajashekar Varma , Sethumadhavan Devadathan Valiyamangalath , Jabeena C. A. , Chavali Sreenivas , Rajavelu Arumugam
Published: September 2020

An amendment to this paper has been published and can be accessed via the original article.
Simulation data for the analysis of Bayesian posterior significance and effect size indices for the two-sample t-test to support reproducible medical research
Authors: Kelter Riko
Published: September 2020

Objectives

The data presented herein represents the simulated datasets of a recently conducted larger study which investigated the behaviour of Bayesian indices of significance and effect size as alternatives to traditional p-values. The study considered the setting of Student’s and Welch’s two-sample t-test often used in medical research. It investigated the influence of the sample size, noise, the selected prior hyperparameters and the sensitivity to type I errors. The posterior indices used included the Bayes factor, the region of practical equivalence, the probability of direction, the MAP-based p-value and the e-value in the Full Bayesian Significance Test. The simulation study was conducted in the statistical programming language R.

Data description

The R script files for simulation of the datasets used in the study are presented in this article. These script files can both simulate the raw datasets and run the analyses. As researchers may be faced with different effect sizes, noise levels or priors in their domain than the ones studied in the original paper, the scripts extend the original results by allowing to recreate all analyses of interest in different contexts. Therefore, they should be relevant to other researchers.