bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspiration of superabsorbent polymer beads resulting in focal lung damage: a case report
Authors: Alharbi Nasser , Dabbour Maryam
Published: May 2020

Background

Concerns have recently been raised about reported incidents of intestinal obstruction following ingestion of Superabsorbent polymer (SAP) beads. Texas Poison Centers reported 110 cases of superabsorbent polymer bead ingestions between 2011 and 2016 (Pediatr Emerg Care 35:426-7, 2019). Furthermore, cases of related auditory complications following the placement of SAP beads into the external auditory canal have also been reported. Here, we report the first case of significant airway damage secondary to the ingestion of a SAP bead (Orbeez), which was aspirated and then overlooked. Further, we hypothesized that the capability of the bead to expand in size once exposed to water from the respiratory mucous may contribute to airway damage.

Case presentation

A 3-year-old boy presented to our hospital with persistent cough and recurrent hospitalizations to the general ward and intensive care unit. The boy was diagnosed with focal lung bronchiectasis in the left lower lobe, which occurred after the patient aspirated an Orbeez bead before a year. The bead was removed using flexible bronchoscopy and a retrieval basket.

Conclusion

Orbeez beads are commonly ingested by young children resulting in gastrointestinal obstruction. The beads can easily be aspirated by children and overlooked by their caregivers and physicians for long periods of time due to their small size. The bead can cause significant airway damage after multiplying in size when coming into contact with respiratory mucus which consists of 95% water.
MiR-449b-5p targets lncRNA PSMG3-AS1 to suppress cancer cell proliferation in lung adenocarcinoma
Authors: Yue Na , Ye Ming , Zhang Ran , Guo Yunquan
Published: May 2020

Background

PSMG3-AS1 has been characterized as an oncogenic lncRNA in breast cancer, while its role in other cancers is unknown. This study investigated the role of PSMG3-AS1 in lung adenocarcinoma (LUAD).

Methods

This study included 64 LUAD patients (42 males and 22 females) who were enrolled between May 2012 and May 2014. RT-qPCR was used to evaluate the expression levels of lncRNA. Cell proliferation analysis was performed using CCK-8 kit.

Results

We found that upregulation of PSMG3-AS1 in LUAD predicted the poor survival of patients. MiR-449b-5p is downregulated in LUAD and the expression levels of LUAD were inversely correlated with the expression levels of PSMG3-AS1. MiR-449b-5p was predicted to target PSMG3-AS1, and overexpression of miR-449b-5p resulted in the downregulation of PSMG3-AS1 in LUAD cells. Cell proliferation analysis showed that overexpression of PSMG3-AS1 resulted in increased rate of cell proliferation. Overexpression of miR-449b-5p reduced the enhancing effects of PSMG3-AS1 on cell proliferation.

Conclusions

Therefore, miR-449b-5p may target PSMG3-AS1 in LUAD to suppress cancer cell proliferation.
The effect of tai chi and Qigong exercise on depression and anxiety of individuals with substance use disorders: a systematic review and meta-analysis
Authors: Liu Fang , Cui Jiabao , Liu Xuan , Chen Kevin W. , Chen Xiaorong , Li Ru
Published: May 2020

Background

Previous studies have acknowledged Tai Chi and Qigong exercise could be potential effective treatments for reducing depression and anxiety in both healthy and clinical populations. However, there is a scarcity of systematic reviews summarizing the clinical evidence conducted among individuals with substance use disorders. This study tries to fill up this gap.

Methods

A systematic search using Medline, EMbase, PsychINFO, Eric, SPORTDiscus, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese National Knowledge Infrastructure (CNKI), Wanfang, and the Chinese Scientific Journal (VIP) databases was initiated to identify randomized controlled trials (RCTs) and non-randomized comparison studies (NRS) assessing the effect of Tai Chi and Qigong versus various comparison groups on depression and anxiety related outcomes. Study quality was evaluated using a Checklist to Evaluate a Report of a Nonpharmacological Trial (CLEAR-NPT) designed for nonpharmacological trial.

Results

One RCT and six NRS with a total of 772 participants were identified. Some of them were meta-analyzed to examine the pooled effects based on different types of intervention and controls. The results of meta-analyses suggested the effect of Tai Chi was comparable to treatment as usual (TAU) on depression (standardized mean difference (SMD) = − 0.17[− 0.52, 0.17]). Qigong exercise appears to result in improvement on anxiety compared to that of medication (SMD = -1.12[− 1.47, − 0.78]), and no treatment control (SMD = -0.52[− 0.77, − 0.27]).

Conclusion

The findings suggest potentially beneficial effect of Qigong exercise on symptoms of anxiety among individuals with drug abuse. Considering the small number and overall methodological weakness of included studies and lack of RCTs, results should be interpreted with caution and future rigorously designed RCTs are warranted to provide more reliable evidence.
Self-evaluated ethical competence of a practicing physiotherapist: a national study in Finland
Authors: KULJU Kati , SUHONEN Riitta , PUUKKA Pauli , TOLVANEN Anna , LEINO-KILPI Helena
Published: May 2020

Background

Patients have the right to equal, respectful treatment. Nowadays, one third of patient complaints concern health care staff’s behavior towards patients. Ethically safe care requires ethical competence, which has been addressed as a core competence in physiotherapy. It has been defined in terms of character strength, ethical awareness, moral judgment skills in decision-making, and willingness to do good. The purpose of this study was to analyze the ethical competence of practicing physiotherapists.

Method

A self-evaluation instrument (Physiotherapist’s Ethical Competence Evaluation Tool) based on an analysis of a concept “ethical competence” was constructed in 2016 and physiotherapists (n = 839), working in public health services or private practice responded to the questionnaire.

Results

Based on the results, most of the physiotherapists evaluated themselves highly ethically competent in all areas of ethical competence, subscales being Strength, Awareness, Skills and Will. Willingness to do good was evaluated as highest, while character strength, including the strength to support ethical processes and speak on behalf of the patient, was evaluated the lowest. Physiotherapists most commonly consult a colleague when encountering an ethical problem. Other methods for problem solving are not very familiar, neither are the international or national ethical codes of conduct.

Conclusions

This was the first attempt to assess all aspects of ethical competence empirically in a clinical environment in physiotherapy, using a novel self-evaluation instrument. Even if physiotherapists evaluate themselves as competent in ethics, further exploration is needed for ethical awareness. Also the patients’ viewpoints about ethically competent care should be considered, to better ensure ethical safety of the patient.
Evidence of unexplained discrepancies between planned and conducted statistical analyses: a review of randomised trials
Authors: Cro Suzie , Forbes Gordon , Johnson Nicholas A. , Kahan Brennan C.
Published: May 2020

Background

Choosing or altering the planned statistical analysis approach after examination of trial data (often referred to as ‘p-hacking’) can bias the results of randomised trials. However, the extent of this issue in practice is currently unclear. We conducted a review of published randomised trials to evaluate how often a pre-specified analysis approach is publicly available, and how often the planned analysis is changed.

Methods

A review of randomised trials published between January and April 2018 in six leading general medical journals. For each trial, we established whether a pre-specified analysis approach was publicly available in a protocol or statistical analysis plan and compared this to the trial publication.

Results

Overall, 89 of 101 eligible trials (88%) had a publicly available pre-specified analysis approach. Only 22/89 trials (25%) had no unexplained discrepancies between the pre-specified and conducted analysis. Fifty-four trials (61%) had one or more unexplained discrepancies, and in 13 trials (15%), it was impossible to ascertain whether any unexplained discrepancies occurred due to incomplete reporting of the statistical methods. Unexplained discrepancies were most common for the analysis model (n = 31, 35%) and analysis population (n = 28, 31%), followed by the use of covariates (n = 23, 26%) and the approach for handling missing data (n = 16, 18%). Many protocols or statistical analysis plans were dated after the trial had begun, so earlier discrepancies may have been missed.

Conclusions

Unexplained discrepancies in the statistical methods of randomised trials are common. Increased transparency is required for proper evaluation of results.
High-yield production of l-serine through a novel identified exporter combined with synthetic pathway in Corynebacterium glutamicum
Authors: Zhang Xiaomei , Gao Yujie , Chen Ziwei , Xu Guoqiang , Zhang Xiaojuan , Li Hui , Shi Jinsong , Koffas Mattheos A. G. , Xu Zhenghong
Published: May 2020

Background

l-Serine has wide and increasing applications in industries with fast-growing market demand. Although strategies for achieving and improving l-serine production in Corynebacterium glutamicum (C. glutamicum) have focused on inhibiting its degradation and enhancing its biosynthetic pathway, l-serine yield has remained relatively low. Exporters play an essential role in the fermentative production of amino acids. To achieve higher l-serine yield, l-serine export from the cell should be improved. In C. glutamicum, ThrE, which can export l-threonine and l-serine, is the only identified l-serine exporter so far.

Results

In this study, a novel l-serine exporter NCgl0580 was identified and characterized in C. glutamicum ΔSSAAI (SSAAI), and named as SerE (encoded by serE). Deletion of serE in SSAAI led to a 56.5% decrease in l-serine titer, whereas overexpression of serE compensated for the lack of serE with respect to l-serine titer. A fusion protein with SerE and enhanced green fluorescent protein (EGFP) was constructed to confirm that SerE localized at the plasma membrane. The function of SerE was studied by peptide feeding approaches, and the results showed that SerE is a novel exporter for l-serine and l-threonine in C. glutamicum. Subsequently, the interaction of a known l-serine exporter ThrE and SerE was studied, and the results suggested that SerE is more important than ThrE in l-serine export in SSAAI. In addition, probe plasmid and electrophoretic mobility shift assays (EMSA) revealed NCgl0581 as the transcriptional regulator of SerE. Comparative transcriptomics between SSAAI and the NCgl0581 deletion strain showed that NCgl0581 is a positive regulator of NCgl0580. Finally, by overexpressing the novel exporter SerE, combined with l-serine synthetic pathway key enzyme serAΔ197, serC, and serB, the resulting strain presented an l-serine titer of 43.9 g/L with a yield of 0.44 g/g sucrose, which is the highest l-serine titer and yield reported so far in C. glutamicum.

Conclusions

This study provides a novel target for l-serine and l-threonine export engineering as well as a new global transcriptional regulator NCgl0581 in C. glutamicum.
HMGB1 mediates lipopolysaccharide-induced inflammation via interacting with GPX4 in colon cancer cells
Authors: Yang Yuhan , Yang Ling , Jiang Sheng , Yang Ting , Lan Jingbin , Lei Yun , Tan Hao , Pan Kejian
Published: May 2020

Background

Inflammation is one of a main reason for colon cancer progression and poor prognosis. The high-mobility group box-1 (HMGB1) and glutathione peroxidase 4 (GPX4) are responsible for inflammation, but the relationship between HMGB1 and GPX4 remains unknown about inflammation in colon cancer.

Methods

RT-qPCR was carried out to investigate the expression of IL1β, IL6 and TNFα in colon cancer cells stimulated with LPS or siHMGB1. To observe the relationship between HMGB1, GPX4 and inflammation or ROS, Western blot assays were adopted. Pull-down, CoIP and immunohistochemistry assays were performed to further investigate the molecular mechanisms of HMGB1 and GPX4 in colon cancer.

Results

We report that HMGB1 mediates lipopolysaccharide (LPS)-induced inflammation in colon cancer cells. Mechanistically, acetylated HMGB1 interacts with GPX4, negatively regulating GPX4 activity. Furthermore, by utilizing siHMGB1 and its inhibitor, our discoveries demonstrate that HMGB1 knockdown can inhibit inflammation and reactive oxygen species (ROS) accumulation via NF-kB.

Conclusion

Collectively, our findings first demonstrate that acetylated HMGB1 can interact with GPX4, leading to inflammation, and providing therapeutic strategies targeting HMGB1 and GPX4 for colon cancer.
Chronic vagus nerve stimulation for drug-resistant epilepsy may influence fasting blood glucose concentration
Authors: Liu Hongyun , Zhan Ping , Meng Fangang , Wang Weidong
Published: May 2020

Background

Cervical vagus nerve stimulation (VNS) has been widely accepted as adjunctive therapy for drug-resistant epilepsy and major depression. Its effects on glycemic control in humans were however poorly understood. The aim of our study was to investigate the potential effects of VNS on fasting blood glucose (FBG) in patients with drug-resistant epilepsy.

Methods

Patients with drug-resistant epilepsy who had received VNS implants at the same hospital were retrospectively studied. Effects on FBG, weight, body mass index and blood pressure were evaluated at 4, 8 and 12 months of follow-up.

Results

32 subjects (11 females/21 males, 19 ± 9 years, body mass index 22.2 ± 4.0 kg/m2) completed 12-month follow-up. At the 4 months, there were no significant changes in FBG concentrations from baseline to follow-up in both Sham-VNS (4.89 ± 0.54 vs. 4.56 ± 0.54 mmol/L, N = 13, p = 0.101) and VNS (4.80 ± 0.54 vs. 4.50 ± 0.56 mmol/L, N = 19, p = 0.117) groups. However, after 8 (4.90 ± 0.42 mmol/L, N = 32, p = 0.001) and 12 (4.86 ± 0.40 mmol/L, N = 32, p = 0.002) months of VNS, FBG levels significantly increased compared to baseline values (4.52 ± 0.54 mmol/L, N = 32). Changes in FBG concentrations at both 8 (R2 = 0.502, N = 32, p < 0.001) and 12 (R2 = 0.572, N = 32, p < 0.001) months were negatively correlated with baseline FBG levels.

Conclusions

Our study suggests that chronic cervical VNS elevates FBG levels with commonly used stimulation parameters in patients with epilepsy.

Trial registration VNSRE, NCT02378792. Registered 4 March 2015—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02378792
Health-related quality of life among 13–14 year old adolescents with overweight−a mixed methods approach
Authors: Sundar T. K. B. , Riiser K. , Småstuen M. C. , Opheim R. , Løndal K. , Glavin K. , Helseth S.
Published: May 2020

Background

Overweight and obesity are public concerns with risk of adverse health outcomes. Health-related quality of life (HRQoL) is lower in adolescents than children in general. An increase in body mass index (BMI) is associated with a decrease in HRQoL. The purpose of this study was to measure and explore the HRQoL among adolescents with overweight or obesity who had participated in an intervention study, Young & Active, with the aim of increasing physical activity (PA), reducing BMI and promoting HRQoL.

Methods

Mixed methods, with a convergent design, were used to investigate how different methodological approaches could expand our understanding of the adolescents’ HRQoL. Quantitative post-intervention data on HRQoL were collected among the 84 intervention participants, aged 13–14 years, using the KIDSCREEN 52 questionnaire. The data were compared with a Norwegian reference population of 244 individuals, and analysed using a non-parametric Mann-Whitney test. Qualitative semi-structured interviews were conducted with 21 adolescents from the intervention. A directed approach to content analysis was adopted, using the ten sub-scales from KIDSCREEN 52.

Results

HRQoL in the intervention sample was significantly reduced on the sub-scale of physical well-being compared to the reference population. The reference population scored significantly lower than the intervention sample on the sub-scale of parent relation and home life. No significant differences were found on the other sub-scales. The qualitative data supported the quantitative findings on the sub-scale of physical well-being, but showed that perceptions of fitness, energy level or health could vary. Regarding parent relations, the interviewees extended this to include relationships to other family members as equally important. Most of the interviewees expressed a negative view of their bodies, but not their clothing or accessories. This may explain why no statistically significant differences were found on these aspects in the results from the KIDSCREEN questionnaire.

Conclusion

The use of the KIDSCREEN 52 instrument gave important indications about the adolescents’ HRQoL and need for additional follow up. The qualitative data provided an in-depth understanding that nuanced the findings and widened our knowledge of the adolescents HRQoL. Combining methods enabled a comprehensive approach to research on HRQoL.
Evaluation of metastatic lymph nodes in cN0 thoracic esophageal cancer patients with inconsistent pathological lymph node diagnosis
Authors: Wakita Akiyuki , Motoyama Satoru , Sato Yusuke , Kawakita Yuta , Nagaki Yushi , Terata Kaori , Imai Kazuhiro , Minamiya Yoshihiro
Published: May 2020

Background

Preoperative clinical diagnosis of lymph node (LN) metastasis and subsequent pathological diagnosis are often not in agreement. Detection of false-negative LNs is essential in selecting an optimal treatment strategy, and most importantly, the presence of false-negative LN is itself a significant prognostic indicator. Therefore, at present, there is an urgent need to establish more accurate and individualized evaluation methods for LN metastasis.

Methods

Of 213 cN0 patients who underwent curative esophagectomy without preoperative neoadjuvant treatment, 60 (28%) had LN metastasis diagnosed pathologically. There were 129 false-negative LNs, of which 85 were detectable by preoperative computed tomography (CT). We retrospectively investigated the distribution, frequency, and characteristics of pathologically positive nodes in patients with clinically N0 esophageal cancer.

Results

The paracardial region was the most frequent region of false-negative LNs, accounting for 26% (22 LNs) of the total incidence. False-negative LNs distributed widely from the neck to the abdomen in patients with a primary tumor in the middle thoracic esophagus. In patients with a primary tumor in the lower thoracic esophagus, four false-negative LNs were detected in the superior mediastinum. When the short-axis diameter, shape, and attenuation patterns of the LNs were used as criteria for metastasis diagnosis, they were insufficient for an accurate diagnosis. However, false-negative LNs in the most frequently occurring sites are characterized by smaller short-axis, suggesting that accurate diagnosis cannot be made unless the diagnostic criteria for the short-axis are reduced in addition to shape and attenuation.

Conclusions

Although restrictive to the most frequent regions of false-negative LNs occur, reducing size criterion and consideration of their shape and attenuation may contribute to improved diagnosis.
CCL2/CCR2 signaling in cancer pathogenesis
Authors: Hao Qiongyu , Vadgama Jaydutt V. , Wang Piwen
Published: May 2020

Chemokines are a family of small cytokines, which guide a variety of immune/inflammatory cells to the site of tumor in tumorigenesis. A dysregulated expression of chemokines is implicated in different types of cancer including prostate cancer. The progression and metastasis of prostate cancer involve a complex network of chemokines that regulate the recruitment and trafficking of immune cells. The chemokine CCL2 and its main receptor CCR2 have been receiving particular interest on their roles in cancer pathogenesis. The up-regulation of CCL2/CCR2 and varied immune conditions in prostate cancer, are associated with cancer advancement, metastasis, and relapse. Here we reviewed recent findings, which link CCL2/CCR2 to the inflammation and cancer pathogenesis, and discussed the therapeutic potential of CCL2/CCR2 axis in cancer treatment based on results from our group and other investigators, with a major focus on prostate cancer.
Whole blood transcriptomic investigation identifies long non-coding RNAs as regulators in sepsis
Authors: Cheng Lixin , Nan Chuanchuan , Kang Lin , Zhang Ning , Liu Sheng , Chen Huaisheng , Hong Chengying , Chen Youlian , Liang Zhen , Liu Xueyan
Published: May 2020

Background

Sepsis is a fatal disease referring to the presence of a known or strongly suspected infection coupled with systemic and uncontrolled immune activation causing multiple organ failure. However, current knowledge of the role of lncRNAs in sepsis is still extremely limited.

Methods

We performed an in silico investigation of the gene coexpression pattern for the patients response to all-cause sepsis in consecutive intensive care unit (ICU) admissions. Sepsis coexpression gene modules were identified using WGCNA and enrichment analysis. lncRNAs were determined as sepsis biomarkers based on the interactions among lncRNAs and the identified modules.

Results

Twenty-three sepsis modules, including both differentially expressed modules and prognostic modules, were identified from the whole blood RNA expression profiling of sepsis patients. Five lncRNAs, FENDRR, MALAT1, TUG1, CRNDE, and ANCR, were detected as sepsis regulators based on the interactions among lncRNAs and the identified coexpression modules. Furthermore, we found that CRNDE and MALAT1 may act as miRNA sponges of sepsis related miRNAs to regulate the expression of sepsis modules. Ultimately, FENDRR, MALAT1, TUG1, and CRNDE were reannotated using three independent lncRNA expression datasets and validated as differentially expressed lncRNAs.

Conclusion

The procedure facilitates the identification of prognostic biomarkers and novel therapeutic strategies of sepsis. Our findings highlight the importance of transcriptome modularity and regulatory lncRNAs in the progress of sepsis.
TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain
Authors: Dai Shih-Ping , Hsieh Wei-Shan , Chen Chien-Hua , Lu Yueh-Hao , Huang Hsu-Shan , Chang Der-Ming , Huang Shir-Ly , Sun Wei-Hsin
Published: May 2020

Background

The autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of pro-inflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear.

Methods

To address this question, we intra-articularly injected complete Freund’s adjuvant (CFA) into TDAG8+/+, TDAG8−/− or wild-type mice, followed by pain behavioral tests. Joints and dorsal root ganglia were taken, sectioned, and stained with antibodies to observe the number of immune cells, macrophages, and satellite glial cells (SGCs). For compound treatments, compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection.

Results

We demonstrated that TDAG8 deletion slightly reduced RA pain in the early phase but dramatically attenuated RA progression and pain in the chronic phase (> 7 weeks). TDAG8 deletion inhibited an increase in SGC number and inhibition of SGC function attenuated chronic phase of RA pain, so TDAG8 could regulate SGC number to control chronic pain. TDAG8 deletion also reduced M1 pro-inflammatory macrophage number at 12 weeks, contributing to the attenuation of chronic RA pain. Such results were further confirmed by using salicylanilide derivatives, CCL-2d or LCC-09, to suppress TDAG8 expression and function.

Conclusions

This study demonstrates that TDAG8 deletion reduced SGC and M1 macrophage number to relieve RA disease severity and associated chronic pain. M1 macrophages are critical for the development and maintenance of RA disease and pain, but glial activation is also required for the chronic phase of RA pain.
Automated quantitative analysis of Ki-67 staining and HE images recognition and registration based on whole tissue sections in breast carcinoma
Authors: Feng Min , Deng Yang , Yang Libo , Jing Qiuyang , Zhang Zhang , Xu Lian , Wei Xiaoxia , Zhou Yanyan , Wu Diwei , Xiang Fei , Wang Yizhe , Bao Ji , Bu Hong
Published: May 2020

Background

The scoring of Ki-67 is highly relevant for the diagnosis, classification, prognosis, and treatment in breast invasive ductal carcinoma (IDC). Traditional scoring method of Ki-67 staining followed by manual counting, is time-consumption and inter−/intra observer variability, which may limit its clinical value. Although more and more algorithms and individual platforms have been developed for the assessment of Ki-67 stained images to improve its accuracy level, most of them lack of accurate registration of immunohistochemical (IHC) images and their matched hematoxylin-eosin (HE) images, or did not accurately labelled each positive and negative cell with Ki-67 staining based on whole tissue sections (WTS). In view of this, we introduce an accurate image registration method and an automatic identification and counting software of Ki-67 based on WTS by deep learning.

Methods

We marked 1017 breast IDC whole slide imaging (WSI), established a research workflow based on the (i) identification of IDC area, (ii) registration of HE and IHC slides from the same anatomical region, and (iii) counting of positive Ki-67 staining.

Results

The accuracy, sensitivity, and specificity levels of identifying breast IDC regions were 89.44, 85.05, and 95.23%, respectively, and the contiguous HE and Ki-67 stained slides perfectly registered. We counted and labelled each cell of 10 Ki-67 slides as standard for testing on WTS, the accuracy by automatic calculation of Ki-67 positive rate in attained IDC was 90.2%. In the human-machine competition of Ki-67 scoring, the average time of 1 slide was 2.3 min with 1 GPU by using this software, and the accuracy was 99.4%, which was over 90% of the results provided by participating doctors.

Conclusions

Our study demonstrates the enormous potential of automated quantitative analysis of Ki-67 staining and HE images recognition and registration based on WTS, and the automated scoring of Ki67 can thus successfully address issues of consistency, reproducibility and accuracy. We will provide those labelled images as an open-free platform for researchers to assess the performance of computer algorithms for automated Ki-67 scoring on IHC stained slides.
Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription
Authors: Zheng Jing-Jie , He Yue , Liu Yang , Li Feng-Shuang , Cui Zhen , Du Xiao-Meng , Wang Chun-Peng , Wu Yu-Mei
Published: May 2020

Background

Radiosensitivity is limited in cervical cancer (CC) patients due to acquired radiation resistance. In our previous studies, we found that immediate-early response 5 (IER5) is upregulated in CC cells upon radiation exposure and decreases cell survival by promoting apoptosis. The details on the transcriptional regulation of radiation-induced IER5 expression are unknown. Studies in recent years have suggested that Pol II-associated factor 1 (PAF1) is a pivotal transcription factor for certain genes “induced” during tumor progression. In this study, we investigated the role of PAF1 in regulating IER5 expression during CC radiotherapy.

Methods

PAF1 expression in CC cells was measured by western blotting, immunohistochemistry, and qRT-PCR, and the localization of PAF1 and IER5 was determined by immunofluorescence. The effect of PAF1 and IER5 knockdown by siRNA in Siha and Hela cells was studied by western blotting, qRT-PCR, CCK-8 assay, and flow cytometry. The physical interaction of PAF1 with the IER5 promoter and enhancers was confirmed using chromatin immunoprecipitation and qPCR with or without enhancers knockout by CRISPR/Cas9.

Results

We confirmed that PAF1 was highly expressed in CC cells and that relatively low expression of IER5 was observed in cells with highly expressed PAF1 in the nucleus. PAF1 knockdown in Siha and Hela cells was associated with increased expression of IER5, reduced cell viability and higher apoptosis rate in response to radiation exposure, while simultaneous PAF1 and IER5 knockdown had little effect on the proportion of apoptotic cells. We also found that PAF1 hindered the transcription of IER5 by promoting Pol II pausing at the promoter-proximal region, which was primarily due to the binding of PAF1 at the enhancers.

Conclusions

PAF1 reduces CC radiosensitivity by inhibiting IER5 transcription, at least in part by regulating its enhancers. PAF1 might be a potential therapeutic target for overcoming radiation resistance in CC patients.
Single approach to double-channel core decompression and bone grafting with structural bone support for treating osteonecrosis of the femoral head in different stages
Authors: Yue Ju’an , Guo Xiaozhong , Wang Randong , Li Bing , Sun Qiang , Liu Wangyan , Chen Jiao , Li Yingnan
Published: May 2020

Background

We created a novel method—single approach to double-channel core decompression and bone grafting with structural bone support (SDBS)—to treat early-stage osteonecrosis of the femoral head (ONFH) by improving the Phemister technique. This study aimed to evaluate the results of SDBS for early-stage ONFH.

Methods

Altogether, 53 patients (73 hips) were treated using SDBS during 2016–2018. Bilateral (20 patients) and unilateral (33 patients = 18 left hips, 15 right hips) ONFH was diagnosed. According to the Association Research Circulation Osseous classification stages, the femoral heads were staged as IIB (n = 15), IIC (n = 19), IIIA (n = 34), IIIB (n = 4), and IIIC (n = 1). The Harris hip score was used to evaluate the hips’ clinical function, computed tomography to evaluate subchondral fractures, and plain radiography to assess the extent of femoral head collapse.

Results

The average follow-up was 20.71 ± 6.65 months (6–36 months). At the patients’ last follow-up, 4 hips were found to require arthroplasty. Thus, the overall femoral head survival rate was 94.52% (69/73). Also, the overall Harris score (84.44 ± 14.57) was significantly higher than that preoperatively (77.67 ± 14.37) (P = 0.000). The combined excellent and good rate (76.71%) was significantly higher than that preoperatively (38.36%) (P = 0.000). Imaging showed that 16 femoral heads had some ONFH progression. The average length of stay was 6.15 ± 0.86 days. The average incision measured 2.69 ± 0.30 cm. Intraoperative blood loss was 61.20 ± 4.81 ml. There were no complications during or after the operation.

Conclusion

SDBS is an effective method for treating early-stage ONFH. It is a hip-preserving surgical approach to slow/prevent ONFH progression.
Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances
Authors: Wang Wenzhang , Zhao Fanpeng , Ma Xiaopin , Perry George , Zhu Xiongwei
Published: May 2020

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss of neurons in the brain. Under the microscope, neuronal accumulation of abnormal tau proteins and amyloid plaques are two pathological hallmarks in affected brain regions. Although the detailed mechanism of the pathogenesis of AD is still elusive, a large body of evidence suggests that damaged mitochondria likely play fundamental roles in the pathogenesis of AD. It is believed that a healthy pool of mitochondria not only supports neuronal activity by providing enough energy supply and other related mitochondrial functions to neurons, but also guards neurons by minimizing mitochondrial related oxidative damage. In this regard, exploration of the multitude of mitochondrial mechanisms altered in the pathogenesis of AD constitutes novel promising therapeutic targets for the disease. In this review, we will summarize recent progress that underscores the essential role of mitochondria dysfunction in the pathogenesis of AD and discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.
Correction to: Canine breeds associated with gastric carcinoma, metaplasia and dysplasia diagnosed by histopathology of endoscopic biopsy samples
Authors: Candido Marcus Vinicius , Syrjä Pernilla , Kilpinen Susanne , Spillmann Thomas
Published: May 2020

An amendment to this paper has been published and can be accessed via the original article.
The link between varicella and immune system: which children will develop acute cerebellitis?
Authors: Bozzola Elena , Carsetti Rita , Piano Mortari Eva , Masci Marco , Spina Giulia , Villani Alberto
Published: May 2020

Introduction

Varicella may complicate with cerebellitis in previously healthy children, requiring hospitalization. Aim of our study was to define whether children who experienced varicella cerebellitis have a normal immune system.

Methods

Patients over 3 years of age admitted at Bambino Gesù Children from January 2006 till June 2016 for cerebellitis in varicella were asked to participate to the follow-up study. The immune status was evaluated clinically and by laboratory investigations.

Results

Twenty-five patients were included in the study. At follow up, at least one immunological alteration was detected in 80% of patients. To avoid bias due to possible effects of the recent disease, we separately analyzed patients who had the follow-up control at least 1 year (Group 1) or between 1 month and 1 year (Group 2) after the hospitalization for acute varicella cerebellitis. The results were similar in both groups with immunological alterations detected in 84,6 and 75% of the patients, respectively.

Conclusions

Our preliminary results indicate that sub-clinical immunological defects may correlate to cerebellitis in varicella.
Patient-reported outcome measures for monitoring primary care patients with depression (PROMDEP): study protocol for a randomised controlled trial
Authors: Kendrick Tony , Moore Michael , Leydon Geraldine , Stuart Beth , Geraghty Adam W. A. , Yao Guiqing , Lewis Glyn , Griffiths Gareth , May Carl , Dewar-Haggart Rachel , Williams Samantha , Zhu Shihua , Dowrick Christopher
Published: May 2020

Background

Benefits to patients from reduced depression have been shown from monitoring progress with patient-reported outcome measures (PROMs) in psychological therapy and mental health settings. This approach has not yet been researched in the United Kingdom for primary care, which is where most people with depression are treated in the United Kingdom.

Methods

This is a parallel-group cluster randomised trial with 1:1 allocation to intervention and control. Patients who are age 18+ years, with a new episode of depressive disorder/symptoms, meet the inclusion criteria. Patients with current depression treatment, comorbid dementia/psychosis/substance misuse/suicidal ideas are excluded. The intervention includes the Administration of Patient Health Questionnaire (PHQ-9) as a PROM within 2 weeks of diagnosis and at follow-up 4 weeks later. General practitioners are trained in interpreting scores and asked to take them into account in their treatment decisions. Patients are given written feedback on scores and suggested treatments. The primary outcome measure is Depression on the Beck Depression Inventory BDI-II at 12 weeks. Secondary outcomes include BDI-II at 26 weeks, changes in drug treatments and referrals, social functioning (Work & Social Adjustment Scale) and quality of life (EQ-5D) at 12 and 26 weeks, service use over 26 weeks (modified Client Services Receipt Inventory) to calculate NHS costs, and patient satisfaction at 26 weeks (Medical Informant Satisfaction Scale). The sample includes 676 total participants from 113 practices across three centres. Randomisation is achieved by computerised sequence generation. Blinding is impossible given the nature of the intervention (self-report outcome measures prevent rating bias). Differences at 12 and 26 weeks between intervention and controls in depression, social functioning and quality of life are analysed using linear mixed models, adjusted for socio-demographics, baseline depression, anxiety, and clustering, while including practice as a random effect. Patient satisfaction, quality of life (QALYs) and costs over 26 weeks will be compared between arms. Qualitative process analysis includes interviews with 15–20 GP/NPs and 15–20 patients per arm to reflect trial results and implementation issues, using Normalization Process Theory as a theoretical framework.

Discussion

If PROMs are helpful in improving patient outcomes for depression even to a small extent, then they are likely to be good value for money, given their low cost. The benefits could be considerable, given that depression is common, disabling, and costly.

Trial registration

ISRCTN no: 17299295. Registered 1st October 2018.
Evaluation of an intervention to support decisions on disclosure in the employment setting (DECIDES): study protocol of a longitudinal cluster-randomized controlled trial
Authors: Janssens K. M. E. , van Weeghel J. , Henderson C. , Joosen M. C. W. , Brouwers E. P. M.
Published: May 2020

Background

Unemployment rates are higher among people with mental health issues/illness (MHI) than in the general working population, and many of them face the dilemma of whether or not to disclose their MHI when searching for employment. Disclosure can lead to rejection and discrimination, but alternatively can also have important advantages that may be necessary to retain employment. Whether disclosure decisions lead to sustainable employment depends on many factors, of which unemployed people themselves can only influence their decision to disclose or not and the way in which they communicate. This study evaluates the cost-effectiveness of an intervention to support unemployed people with MHI in their disclosure decision and communication.

Methods

This is a two-armed, clustered, randomized controlled trial with longitudinal design and randomization at organization level. An intervention will be examined, which consists of a disclosure decision aid tool (CORAL.NL) for unemployed people and workplace stigma-awareness training especially designed for employment specialists, which focusses on how to support unemployed people in their disclosure decisions. Participants in the intervention group are unemployed people who receive support from trained employment specialists from organizations allocated to the intervention group, and receive the CORAL.NL decision aid after baseline. The control group consists of unemployed people who receive support as usual from employment specialists from different organizations allocated to the control group. Primary outcomes are: cost-effectiveness of the intervention, e.g. healthcare costs, having employment, days until start of employment, independency of social security, having other forms of employment and decision making about disclosing MHI. Secondary outcomes are mental health and wellbeing, stigma and discrimination and work-related factors. Financial income data are collected via the registration systems of Dutch municipalities and Statistics Netherlands, and by questionnaires at baseline, and at 3, 6 and 12 months.

Discussion

If using a decision aid to decide about disclosure of MHI leads to people finding and retaining employment more often, this study will contribute to lowering healthcare and societal costs.

Trial registration

Netherlands Trial Register: NL7798. Registered on 4 June 2019.
High-flow nasal cannula versus standard oxygen therapy assisting sedation during endoscopic retrograde cholangiopancreatography in high risk cases (OTHER): study protocol of a randomised multicentric trial
Authors: Thiruvenkatarajan Venkatesan , Dharmalingam Ashok , Arenas Gilberto , Wahba Medhat , Steiner Reinhard , Kadam Vasanth Rao , Tran Andre , Currie John , Van Wijk Roelof , Quail Anthony , Ludbrook Guy
Published: May 2020

Background

Endoscopic retrograde cholangiopancreatography (ERCP) is an increasingly common intervention in the treatment of pancreaticobiliary disorders. Patients are often elderly with complex co-morbidities. While monitored anaesthesia care with sedation is commonly used for most cases, few would require general anaesthesia with an endotracheal tube. Both low-flow and high-flow nasal cannulas (HFNC) are established ways of delivering supplemental oxygen, but it is unclear whether one technique is better than the other. HFNC seems a promising tool for advanced procedures but evidence to support its application in high-risk ERCP cases is limited. The rate of oxygen desaturation during endoscopy has been reported to be as high as 11%–50% and the method of oxygen delivery for ERCP merits further study.

Methods/design

This is a prospective, randomised, multicentre trial comparing the efficacy of oxygen supplementation through HFNC versus low-flow nasal cannula during ERCP, in a cohort of patients at risk of adverse respiratory events. A total of 132 patients will be recruited across three sites and randomly assigned to either the low-flow or the HFNC group. The primary outcome is the proportion of patients experiencing hypoxia, defined by any event of SpO2 < 90%. The secondary outcomes include parameters centred on oxygenation, requirement of airway manoeuvres, successful completion of procedure, perioperative complications, patient satisfaction and cost analysis of the consumables. An intention-to-treat principle will be applied while analysing.

Discussion

The demand for ERCPs is likely to increase in the future with the aging population. Our study results may lead to improved outcomes and reduce airway-related complications in patients undergoing ERCPs. The results will be presented at national and international meetings and published in peer-reviewed journals.

Trial registration

www.ANZCTR.org.au, CTRN12619000397112. Registered on 12 March 2019.
An under-represented and underserved population in trials: methodological, structural, and systemic barriers to the inclusion of adults lacking capacity to consent
Authors: Shepherd Victoria
Published: May 2020

Background

There is increasing international recognition that populations included in trials should adequately represent the population treated in clinical practice; however, adults who lack the capacity to provide informed consent are frequently excluded from trials. Addressing the under-representation of groups such as those with impaired capacity to consent is essential to develop effective interventions and provide these groups with the opportunity to benefit from evidence-based care. While the spotlight has been on ensuring only appropriate and justifiable exclusion criteria are used in trials, barriers to the inclusion of adults lacking capacity are multifactorial and complex, and addressing their under-representation will require more than merely widening eligibility criteria. This commentary draws on the literature exploring the inclusion of adults lacking the capacity to consent in research and a number of recent studies to describe the methodological, structural, and systemic factors that have been identified.

Main text

A number of potentially modifiable factors contributing to the under-representation of adults lacking the capacity to consent in trials have been identified. In addition to restrictive eligibility criteria, methodological issues include developing appropriate interventions and outcome measures for populations with impaired capacity. Structurally determined factors include the resource-intensive nature of these trials, the requirement for more appropriate research infrastructure, and a lack of interventions to inform and support proxy decision-makers. Systemic factors include the complexities of the legal frameworks, the challenges of ethical review processes, and paternalistic attitudes towards protecting adults with incapacity from the perceived harms of research.

Conclusions

Measures needed to address under-representation include greater scrutiny of exclusion criteria by those reviewing study proposals, providing education and training for personnel who design, conduct, and review research, ensuring greater consistency in the reviews undertaken by research ethics committees, and extending processes for advance planning to include prospectively appointing a proxy for research and documenting preferences about research participation. Negative societal and professional attitudes towards the inclusion of adults with impaired capacity in research should also be addressed, and the development of trials that are more person-centred should be encouraged. Further work to conceptualise under-representation in trials for such populations may also be helpful.
Configuration of active site segments in lytic polysaccharide monooxygenases steers oxidative xyloglucan degradation
Authors: Sun Peicheng , Laurent Christophe V. F. P. , Scheiblbrandner Stefan , Frommhagen Matthias , Kouzounis Dimitrios , Sanders Mark G. , van Berkel Willem J. H. , Ludwig Roland , Kabel Mirjam A.
Published: May 2020

Background

Lytic polysaccharide monooxygenases (LPMOs) are powerful enzymes that oxidatively cleave plant cell wall polysaccharides. LPMOs classified as fungal Auxiliary Activities family 9 (AA9) have been mainly studied for their activity towards cellulose; however, various members of this AA9 family have been also shown to oxidatively cleave hemicelluloses, in particularly xyloglucan (XG). So far, it has not been studied in detail how various AA9 LPMOs act in XG degradation, and in particular, how the mode-of-action relates to the structural configuration of these LPMOs.

Results

Two Neurospora crassa (Nc) LPMOs were found to represent different mode-of-action towards XG. Interestingly, the configuration of active site segments of these LPMOs differed as well, with a shorter Segment 1 (−Seg1) and a longer Segment 2 (+Seg2) present in NcLPMO9C and the opposite for NcLPMO9M (+Seg1−Seg2). We confirmed that NcLPMO9C cleaved the non-reducing end of unbranched glucosyl residues within XG via the oxidation of the C4-carbon. In contrast, we found that the oxidative cleavage of the XG backbone by NcLPMO9M occurred next to both unbranched and substituted glucosyl residues. The latter are decorated with xylosyl, xylosyl–galactosyl and xylosyl–galactosyl–fucosyl units. The relationship between active site segments and the mode-of-action of these NcLPMOs was rationalized by a structure-based phylogenetic analysis of fungal AA9 LPMOs. LPMOs with a −Seg1+Seg2 configuration clustered together and appear to have a similar XG substitution-intolerant cleavage pattern. LPMOs with the +Seg1−Seg2 configuration also clustered together and are reported to display a XG substitution-tolerant cleavage pattern. A third cluster contained LPMOs with a −Seg1−Seg2 configuration and no oxidative XG activity.

Conclusions

The detailed characterization of XG degradation products released by LPMOs reveal a correlation between the configuration of active site segments and mode-of-action of LPMOs. In particular, oxidative XG-active LPMOs, which are tolerant and intolerant to XG substitutions are structurally and phylogenetically distinguished from XG-inactive LPMOs. This study contributes to a better understanding of the structure–function relationship of AA9 LPMOs.