bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel risk score system of immune genes associated with prognosis in endometrial cancer
Authors: Zhou Hongyu , Zhang Chufan , Li Haoran , Chen Lihua , Cheng Xi
Published: June 2020

Background

Endometrial cancer was the commonest gynecological malignancy in developed countries. Despite striking advances in multimodality management, however, for patients in advanced stage, targeted therapy still remained a challenge. Our study aimed to investigate new biomarkers for endometrial cancer and establish a novel risk score system of immune genes in endometrial cancer.

Methods

The clinicopathological characteristics and gene expression data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) of immune genes between tumors and normal tissues were identified. Protein–protein interaction (PPI) network of immune genes and transcriptional factors was integrated and visualized in Cytoscape. Univariate and multivariate analysis were employed for key genes to establish a new risk score system. Receiver operating characteristic (ROC) curve and survival analysis were performed to investigate the prognostic value of the model. Association between clinical characteristics and the model was analyzed by logistic regression. For validation, we identified 34 patients with endometrial cancer from Fudan University Shanghai Cancer Center (FUSCC). We detected 14-genes mRNA expression and calculated the risk scores of each patients and we performed survival analysis between the high-risk group and the low-risk group.

Results

23 normal tissues and 552 tumor tissues were obtained from TCGA database. 410 immune-related DEGs was identified by difference analysis and correlation analysis. KEGG and GO analysis revealed these DEGs were enriched in cell adhesion, chemotaxis, MAPK pathways and PI3K-Akt signaling pathway, which might regulate tumor progression and migration. All genes were screened for risk model construction and 14 hub immune-related genes (HTR3E, CBLC, TNF, PSMC4, TRAV30, PDIA3, FGF8, PDGFRA, ESRRA, SBDS, CRHR1, LTA, NR2F1, TNFRSF18) were prognostic in endometrial cancer. The area under the curve (AUC) was 0.787 and the high-risk group estimated by the model possessed worse outcome (P < 0.001). Multivariate analysis suggested that the model was indeed an independent prognostic factor (high-risk vs. low-risk, HR = 1.14, P < 0.001). Meanwhile, the high-risk group was prone to have higher grade (P = 0.002) and advanced clinical stage (P = 0.018). In FUSCC validation set, the high-risk group had worse survival than the low-risk group (P < 0.001).

Conclusions

In conclusion, the novel risk model of immune genes had some merits in predicting the prognosis of endometrial cancer and had strong correlation with clinical outcomes. Furthermore, it might provide new biomarkers for targeted therapy in endometrial cancer.
Circ_LDLR promoted the development of papillary thyroid carcinoma via regulating miR-195-5p/LIPH axis
Authors: Gui Xiaolong , Li Yan , Zhang Xiaobin , Su Ka , Cao Wenlong
Published: June 2020

Background

Emerging studies have demonstrated that circular RNAs (circRNAs) are key regulators for tumorigenesis in cancers, including papillary thyroid carcinoma (PTC). In this study, we aimed to explore the effects of circ_LDLR on PTC.

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the levels of circ_LDLR, miR-195-5p and lipase H (LIPH). RNase R digestion assay and Actinomycin D assay were utilized to analyze the characteristics of circ_LDLR. Colony formation assay and 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay were conducted to evaluate cell proliferation. Western blot assay was used for the determination of protein levels. Flow cytometry analysis was applied to determine cell apoptosis. Transwell assay was performed to determine cell migration and invasion. Dual-luciferase reporter assay was used to verify the associations among circ_LDLR, miR-195-5p and LIPH. The murine xenograft model was constructed to explore the roles of circ_LDLR in vivo.

Results

Compared to normal tissues and cells, circ_LDLR was upregulated in PTC tissues and cells. Silencing of circ_LDLR suppressed PTC cell colony formation, proliferation, migration and invasion and promoted apoptosis in vitro and hampered tumor growth in vivo. For mechanism investigation, circ_LDLR could regulate LIPH expression via sponging miR-195-5p. Moreover, miR-195-5p inhibition restored the effects of circ_LDLR knockdown on the malignant behaviors of PTC cells. MiR-195-5p overexpression inhibited PTC cell colony formation, proliferation, migration and invasion and facilitated apoptosis by targeting LIPH.

Conclusion

Circ_LDLR knockdown decelerated PTC progression by regulating miR-195-5p/LIPH axis, which might provide a novel therapeutic target for PTC.
Antitumor efficacy of cytosine deaminase-armed vaccinia virus plus 5-fluorocytosine in colorectal cancers
Authors: Ding Yuedi , Fan Jun , Deng Lili , Huang Biao , Zhou Bin
Published: June 2020

Background

Vaccinia viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Cytosine deaminase (CD), which is derived from bacteria or yeast, can convert a relatively nontoxic prodrug 5-fluorocytosine (5-FC) into the active anticancer drug 5-Fluorouracil (5-FU). Vaccinia virus armed with the prodrug-activator CD gene would result in augmented antitumor effects that combined the effect of vaccinia virus and 5-FU together, and particularly limited the anticancer drug to tumor regions.

Methods

The attenuated vaccinia Tian Tan strain Guang 9 (VG9), with active yeast CD expression and thymidine kinase (TK) deficiency, was successfully constructed. Then, in vitro and in vivo antitumor efficacy of vaccinia VG9-CD plus 5-FC administration was evaluated in colorectal cancer cells.

Results

Vaccinia viruses displayed different oncolytic potency in vitro cells, no relationship with whether they were cancer cells or normal cells. In colorectal tumor models, mice treated with vaccinia VG9-TK− showed better tumor remission ability and prolonged survival. Moreover, vaccinia VG9-CD in combination with gavage administration of 5-FC displayed the best antitumor efficacy, especially for the prolongation of survival.

Conclusions

Vaccinia VG9-CD in combination with 5-FC plays combined effect of vaccinia virus and chemotherapy, and becomes a promising virotherapy for cancer.
Coronavirus disease 19 in minority populations of Newark, New Jersey
Authors: Okoh Alexis K. , Sossou Christoph , Dangayach Neha S. , Meledathu Sherin , Phillips Oluwakemi , Raczek Corinne , Patti Michael , Kang Nathan , Hirji Sameer A. , Cathcart Charles , Engell Christian , Cohen Marc , Nagarakanti Sandhya , Bishburg Eliahu , Grewal Harpreet S.
Published: June 2020

Background

The purpose of this study is to report the clinical features and outcomes of Black/African American (AA) and Latino Hispanic patients with Coronavirus disease 2019 (COVID-19) hospitalized in an inter-city hospital in the state of New Jersey.

Methods

This is a retrospective cohort study of AA and Latino Hispanic patients with COVID-19 admitted to a 665-bed quaternary care, teaching hospital located in Newark, New Jersey. The study included patients who had completed hospitalization between March 10, 2020, and April 10, 2020. We reviewed demographics, socioeconomic variables and incidence of in-hospital mortality and morbidity. Logistic regression was used to identify predictor of in-hospital death.

Results

Out of 416 patients, 251 (60%) had completed hospitalization as of April 10, 2020. The incidence of In-hospital mortality was 38.6% (n = 97). Most common symptoms at initial presentation were dyspnea 39% (n = 162) followed by cough 38%(n = 156) and fever 34% (n = 143). Patients were in the highest quartile for population’s density, number of housing units and disproportionately fell into the lowest median income quartile for the state of New Jersey. The incidence of septic shock, acute kidney injury (AKI) requiring hemodialysis and admission to an intensive care unit (ICU) was 24% (n = 59), 21% (n = 52), 33% (n = 82) respectively. Independent predictors of in-hospital mortality were older age, lower serum Hemoglobin < 10 mg/dl, elevated serum Ferritin and Creatinine phosphokinase levels > 1200 U/L and > 1000 U/L.

Conclusions

Findings from an inter-city hospital’s experience with COVID-19 among underserved minority populations showed that, more than one of every three patients were at risk for in-hospital death or morbidity. Older age and elevated inflammatory markers at presentation were associated with in-hospital death.
X-ray induced photodynamic therapy (PDT) with a mitochondria-targeted liposome delivery system
Authors: Gu Xuefan , Shen Chao , Li Hua , Goldys Ewa M. , Deng Wei
Published: June 2020

In this study, we constructed multifunctional liposomes with preferentially mitochondria-targeted feature and gold nanoparticles-assisted synergistic photodynamic therapy. We systemically investigated the in vitro X-ray triggered PDT effect of these liposomes on HCT 116 cells including the levels of singlet oxygen, mitochondrial membrane potential, cell apoptosis/necrosis and the expression of apoptosis-related proteins. The results corroborated that synchronous action of PDT and X-ray radiation enhance the generation of cytotoxic reactive oxygen species produced from the engineered liposomes, causing mitochondrial dysfunction and increasing the levels of apoptosis.
Oral health status and oral health-related quality of life among patients with type 2 diabetes mellitus in the United Arab Emirates: a matched case-control study
Authors: Khalifa Nadia , Rahman Betul , Gaintantzopoulou Marianna D. , Al-Amad Suhail , Awad Manal M.
Published: June 2020

Background

Nearly a quarter of the population in the UAE has type 2 diabetes mellitus (T2DM), and this medical condition is associated with poorer oral health. The effects on oral health-related quality of life (OHRQoL), however, have not been examined in this population. Therefore, the objective of this study was to assess the impact of oral health problems, such as caries and periodontitis, on OHRQoL among Arab patients with and without T2DM.

Methods

This matched case-control study included 88 diabetic and 88 non-diabetic participants recruited from University Dental Hospital Sharjah and University Hospital Sharjah, UAE. Participants completed a sociodemographic questionnaire as well as the Oral Health Impact Profile short form (OHIP-14), which measures OHRQoL. Clinical examinations were conducted to assess participants’ dental caries status, using the Decayed Missing Filled Teeth (DMFT) Index, and periodontal condition, via clinical attachment loss (CAL) dichotomized to CAL < 3 mm and CAL ≥3 mm. Linear regression models were used to identify the association among OHIP domains, clinical attachment loss, DMFT scores, and diabetes status.

Results

The mean age of participants was 43.0 years. A significantly (p = 0.01) higher proportion of diabetic patients (23%) had a CAL ≥3 mm than non-diabetic patients (10%). No significant differences in OHIP scores were observed between diabetic and non-diabetic patients. The results of the linear regression suggested that irrespective of diabetic status, DMFT scores were significantly associated with physical disability, physical pain, psychological discomfort, and psychological disability, as well as total OHIP scores. CAL was significantly associated with the handicap domain. Among non-diabetic patients, OHIP scores were significantly associated with DMFT scores in five OHIP domains (functional limitation, physical disability, physical pain, psychological discomfort, psychological disability), as well as total OHIP scores. Among diabetic patients, CAL was significantly associated with both the social disability and handicap domains, while only the handicap domain reached statistical significance among non-diabetic patients.

Conclusions

Participants who had decayed teeth, irrespective of their diabetic status, reported substantial physical and psychological impacts on OHRQoL. CAL also had a significant impact on OHRQoL, being primarily associated with the OHIP handicap domain in both diabetic and non-diabetic patients.
Validation of the Greek translation of the multicultural quality of life index (MQLI-gr)
Authors: Kokaliari Effrosyni D. , Roy Ann W.
Published: June 2020

Background

The aim of the current study was to examine the internal structure and convergent and discriminant validity of theMulticultural Quality of Life Index(MQLI) in a Greek sample of community-dwelling adults in a major Greek city.

Methods

The authors developed a Greek version of theMulticultural Quality of Life Index(MQLI-Gr). It was translated following cross-cultural adaptation procedures for self-report measures and administered to community members (N = 884). Participants completed abrief demographic survey, theMQLI-Gr, and theDepression Anxiety Stress Scales(DASS-42).

Results

TheMQLI-Gris brief, easy to use, and demonstrates strong internal consistency (Cronbach alpha = .90). In terms of internal structure there were mixed results. In terms of discriminant validity, statistically significant differences in meanMQLI-Grscores were observed between two groups: those withnone-mildsymptoms versus those withsevere symptomsof depression, anxiety, and stress (p < .05). TheMQLI-Grwas also able to discriminate among groups assumed to vary on quality of life; marital status, income, and employment. In terms of convergent validity, results were in the expected direction, with participants reporting high levels of depression, anxiety, and stress, also reporting lower quality of life on theMQLI-Gr(p < .001).

Conclusion

Consistent with other translations, theMQLI-Grdemonstrated feasibility, strong internal consistency, and good convergent and discriminant validity. This is the first step in the development of a psychometrically sound measure to assessquality of lifein a community-dwelling population in Greece. With the addition of further validation studies, this measure will be a useful tool for assessing thequality of lifein the Greek community.
Analysis of adherence to HIV-positive quality of care indicators and their impact on service quality perceptions in patients: a Spanish cross-sectional study
Authors: Gimeno-García A. , Franco-Moreno A. , Montero-Hernández C. , Arponen S. , García-Carrasco E. , Alejos B. , Corps-Fernández D. , Gaspar-García E. , Galindo-Jara P. , García-Navarro M. , Varillas-Delgado D.
Published: June 2020

Background

Since the identification of human immunodeficiency virus (HIV) infection, there have been significant advances in its diagnosis and treatment, but there have been few contributions to the area of care quality. In 2010, the Spanish AIDS Study Group (GeSIDA) published the document “Health quality indicators of GeSIDA for the care of people infected with HIV/AIDS” in which standards are proposed for the purpose of improving and standardizing the assistance provided to people infected with HIV. The purpose of this study was to evaluate the degree of compliance with these indicators and to analyse whether adherence to the standards improves patient perception of care quality in terms of their satisfaction with the health care they have received.

Methods

Compliance with GeSIDA indicators was analysed within a cohort of people living with HIV (PLHIV) in a hospital in the Madrid region. To evaluate patient perception, the External Consultation User Satisfaction Questionnaire (SUCE) was used, which is a tool that was previously validated in the Spanish population.

Results

A total of 334 patients were included. The level of adherence to the indicators was 74.46%. The score on the SUCE questionnaire was 9.04 out of 10 (CI 95%: 8.90–9.19). Of the 47 indicators assessed, only 4 were related to satisfaction with health care.

Conclusions

The levels of compliance with the indicators and patient satisfaction with health care were high. Adherence to quality indicators showed little relation to patient-reported satisfaction.
Validity and reliability of subjective methods to assess sedentary behaviour in adults: a systematic review and meta-analysis
Authors: Bakker Esmée A. , Hartman Yvonne A. W. , Hopman Maria T. E. , Hopkins Nicola D. , Graves Lee E. F. , Dunstan David W. , Healy Genevieve N. , Eijsvogels Thijs M. H. , Thijssen Dick H. J.
Published: June 2020

Background

Subjective measures of sedentary behaviour (SB) (i.e. questionnaires and diaries/logs) are widely implemented, and can be useful for capturing type and context of SBs. However, little is known about comparative validity and reliability. The aim of this systematic review and meta-analysis was to: 1) identify subjective methods to assess overall, domain- and behaviour-specific SB, and 2) examine the validity and reliability of these methods.

Methods

The databases MEDLINE, EMBASE and SPORTDiscus were searched up to March 2020. Inclusion criteria were: 1) assessment of SB, 2) evaluation of subjective measurement tools, 3) being performed in healthy adults, 4) manuscript written in English, and 5) paper was peer-reviewed. Data of validity and/or reliability measurements was extracted from included studies and a meta-analysis using random effects was performed to assess the pooled correlation coefficients of the validity.

Results

The systematic search resulted in 2423 hits. After excluding duplicates and screening on title and abstract, 82 studies were included with 75 self-reported measurement tools. There was wide variability in the measurement properties and quality of the studies. The criterion validity varied between poor-to-excellent (correlation coefficient [R] range − 0.01- 0.90) with logs/diaries (R = 0.63 [95%CI 0.48–0.78]) showing higher criterion validity compared to questionnaires (R = 0.35 [95%CI 0.32–0.39]). Furthermore, correlation coefficients of single- and multiple-item questionnaires were comparable (1-item R = 0.34; 2-to-9-items R = 0.35; ≥10-items R = 0.37). The reliability of SB measures was moderate-to-good, with the quality of these studies being mostly fair-to-good.

Conclusion

Logs and diaries are recommended to validly and reliably assess self-reported SB. However, due to time and resources constraints, 1-item questionnaires may be preferred to subjectively assess SB in large-scale observations when showing similar validity and reliability compared to longer questionnaires.

Registration number

CRD42018105994.
Orexin A alleviates neuroinflammation via OXR2/CaMKKβ/AMPK signaling pathway after ICH in mice
Authors: Li Tao , Xu Weilin , Ouyang Jinsong , Lu Xiaoyang , Sherchan Prativa , Lenahan Cameron , Irio Giselle , Zhang John H. , Zhao Jianhua , Zhang Yongfa , Tang Jiping
Published: June 2020

Background

Orexins are two neuropeptides (orexin A, OXA; orexin B, OXB) secreted mainly from the lateral hypothalamus, which exert a wide range of physiological effects by activating two types of receptors (orexin receptor 1, OXR1; orexin receptor 2, OXR2). OXA has equal affinity for OXR1 and OXR2, whereas OXB binds preferentially to OXR2. OXA rapidly crosses the blood-brain barrier by simple diffusion. Many studies have reported OXA’s protective effect on neurological diseases via regulating inflammatory response which is also a fundamental pathological process in intracerebral hemorrhage (ICH). However, neuroprotective mechanisms of OXA have not been explored in ICH.

Methods

ICH models were established using stereotactic injection of autologous arterial blood into the right basal ganglia of male CD-1 mice. Exogenous OXA was administered intranasally; CaMKKβ inhibitor (STO-609), OXR1 antagonist (SB-334867), and OXR2 antagonist (JNJ-10397049) were administered intraperitoneally. Neurobehavioral tests, hematoma volume, and brain water content were evaluated after ICH. Western blot and ELISA were utilized to evaluate downstream mechanisms.

Results

OXA, OXR1, and OXR2 were expressed moderately in microglia and astrocytes and abundantly in neurons. Expression of OXA decreased whereas OXR1 and OXR2 increased after ICH. OXA treatment significantly improved not only short-term but also long-term neurofunctional outcomes and reduced brain edema in ipsilateral hemisphere. OXA administration upregulated p-CaMKKβ, p-AMPK, and anti-inflammatory cytokines while downregulated p-NFκB and pro-inflammatory cytokines after ICH; this effect was reversed by STO-609 or JNJ-10397049 but not SB-334867.

Conclusions

OXA improved neurofunctional outcomes and mitigated brain edema after ICH, possibly through alleviating neuroinflammation via OXR2/CaMKKβ/AMPK pathway.
Impact of elastic ankle exoskeleton stiffness on neuromechanics and energetics of human walking across multiple speeds
Authors: Nuckols Richard W. , Sawicki Gregory S.
Published: June 2020

Background

Elastic ankle exoskeletons with intermediate stiffness springs in parallel with the human plantarflexors can reduce the metabolic cost of walking by ~ 7% at 1.25 m s− 1. In a move toward ‘real-world’ application, we examined whether the unpowered approach has metabolic benefit across a range of walking speeds, and if so, whether the optimal exoskeleton stiffness was speed dependent. We hypothesized that, for any walking speed, there would be an optimal ankle exoskeleton stiffness - not too compliant and not too stiff - that minimizes the user’s metabolic cost. In addition, we expected the optimal stiffness to increase with walking speed.

Methods

Eleven participants walked on a level treadmill at 1.25, 1.50, and 1.75 m s− 1 while we used a state-of-the-art exoskeleton emulator to apply bilateral ankle exoskeleton assistance at five controlled rotational stiffnesses (kexo = 0, 50, 100, 150, 250 Nm rad− 1). We measured metabolic cost, lower-limb joint mechanics, and EMG of muscles crossing the ankle, knee, and hip.

Results

Metabolic cost was significantly reduced at the lowest exoskeleton stiffness (50 Nm rad− 1) for assisted walking at both 1.25 (4.2%; p = 0.0162) and 1.75 m s− 1 (4.7%; p = 0.0045). At these speeds, the metabolically optimal exoskeleton stiffness provided peak assistive torques of ~ 0.20 Nm kg− 1 that resulted in reduced biological ankle moment of ~ 12% and reduced soleus muscle activity of ~ 10%. We found no stiffness that could reduce the metabolic cost of walking at 1.5 m s− 1. Across all speeds, the non-weighted sum of soleus and tibialis anterior activation rate explained the change in metabolic rate due to exoskeleton assistance (p < 0.05; R2 > 0.56).

Conclusions

Elastic ankle exoskeletons with low rotational stiffness reduce users’ metabolic cost of walking at slow and fast but not intermediate walking speed. The relationship between the non-weighted sum of soleus and tibialis activation rate and metabolic cost (R2 > 0.56) indicates that muscle activation may drive metabolic demand. Future work using simulations and ultrasound imaging will get ‘under the skin’ and examine the interaction between exoskeleton stiffness and plantarflexor muscle dynamics to better inform stiffness selection in human-machine systems.
Hepatitis E virus infection during pregnancy
Authors: Wu Chunchen , Wu Xiaoxue , Xia Jianbo
Published: June 2020

Background

Hepatitis E virus (HEV) generally causes self-limiting viral hepatitis. However, in pregnant women, HEV infection can be severe and has been associated with up to 30% mortality in the third trimester. Additionally, HEV infection in pregnancy is also associated with high rates of preterm labor and vertical transmission.

Main body

HEV is now recognized as a global health problem in both developing and industrialized countries. HEV can be transmitted via the fecal-oral route, zoonotic route, and blood transfusion route. An altered immune status, hormonal levels, and viral factors may be related to the severity of the disease. Currently, no established treatment is available for HEV in pregnant women. A Chinese vaccine has been demonstrated to be protective against HEV in the general population and seems to be safe in pregnancy; however, its safety and efficacy in a large population of pregnant women remain to be determined.

Conclusion

This review summarizes the current knowledge about HEV infection during pregnancy and focuses on the epidemiology, clinical manifestations, mechanisms underlying severe liver injury, and management and prevention of HEV infection during pregnancy. Considering that HEV infection during pregnancy may result in poor outcomes, screening for and monitoring HEV infection early in pregnancy should be taken into account. In addition, a better understanding of the pathogenesis will help to develop potential treatment strategies targeting HEV infection in pregnancy.
WSES guidelines updates
Authors: Ceresoli Marco , Coccolini Federico , Biffl Walter L. , Sartelli Massimo , Ansaloni Luca , Moore Ernest E. , Di Saverio Salomone , Kluger Yoram , Catena Fausto
Published: June 2020

The World Society of Emergency Surgery promotes training and continuing medical education in the field of emergency surgery and trauma. One of the most important activities of the society is the development of guidelines. The debate about the process of developing and updating guidelines is very active with no clear consensus and different policies among scientific societies. The present commentary provides the position of the World Society of Emergency Surgery on guideline development process and their update.
Characterization of clinical and genetic spectrum of Chinese patients with cystic fibrosis
Authors: Liu Keqiang , Xu Wenshuai , Xiao Meng , Zhao Xinyue , Bian Chun , Zhang Qianli , Song Jiaxing , Chen Keqi , Tian Xinlun , Liu Yaping , Xu Kai-Feng , Zhang Xue
Published: June 2020

Background

Cystic fibrosis (CF) is a rare autosomal recessive disorder caused by biallelic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The clinical features and mutation spectrum of CF have been well characterized in Caucasians, while limited studies were conducted in Chinese patients.

Subjects and methods

A total of 20 individuals from 19 families were diagnosed with CF in this study. We analyzed the clinical features and screened all coding exons of CFTR using a combination of Sanger sequencing and multiplex ligation-dependent probe amplification analysis.

Results

The median age at onset was 9.3 years in our cohort, while the median age at diagnosis was 19 years. The respiratory system was most frequently affected in this study: all patients (100%, 19/19) presented diffuse bronchiectasis and 61.1% (11/18) of patients showed a forced expiratory volume in 1 s below 80% predicted. Six patients (6/20, 30%) exhibited allergic bronchopulmonary aspergillosis (ABPA). Only 4 (4/20, 20%) patients presented pancreatic exocrine insufficiency (PI). Three adult male patients receiving examinations for congenital bilateral absence of the vas deferens were all found positive for the condition. A total of 22 distinct mutations were detected in this cohort, with the variant p.G970D as the most common variant (12/38 alleles, 31.6%). Four variants (p.Y109D, p.I203F, p.D572E, and exon 2–3 deletion) were novel, which expanded the mutation spectrum of Chinese CF patients.

Conclusions

Chinese CF patients showed different clinical features and a distinct CFTR mutation spectrum compared with Caucasians. There is a significant diagnosis delay, suggesting the current underdiagnosis of CF in China.
Self-rated worry is associated with hospital admission in out-of-hours telephone triage – a prospective cohort study
Authors: Gamst-Jensen Hejdi , Frischknecht Christensen Erika , Lippert Freddy , Folke Fredrik , Egerod Ingrid , Huibers Linda , Brabrand Mikkel , Tolstrup Janne Schurmann , Thygesen Lau Caspar
Published: June 2020

Objective

Telephone triage manages patient flow in acute care, but a lack of visual cues and vague descriptions of symptoms challenges clinical decision making. We aim to investigate the association between the caller’s subjective perception of illness severity expressed as “degree-of-worry” (DOW) and hospital admissions within 48 h.

Design and setting

A prospective cohort study was performed from January 24th to February 9th, 2017 at the Medical Helpline 1813 (MH1813) in Copenhagen, Denmark. The MH1813 is a primary care out-of-hours service.

Participants

Of 38,787 calls received at the MH1813, 11,338 met the inclusion criteria (caller being patient or close friend/relative and agreement to participate). Participants rated their DOW on a 5-point scale (1 = minimum worry, 5 = maximum worry) before talking to a call handler.

Main outcome measure

Information on hospitalization within 48 h after the call, was obtained from the Danish National Patient Register. The association was assessed using logistic regression in three models: 1) crude, 2) age-and-gender adjusted and 3) age, gender, co-morbidity, reason for calling and caller status adjusted.

Results

A total of 581 participants (5.1%) were admitted to the hospital, of whom 170 (11.3%) presented with a maximum DOW, with a crude odds ratio (OR) for hospitalization of 6.1 (95% confidence interval (CI) 3.9 to 9.6) compared to minimum DOW. Estimates showed dose-response relationship between DOW and hospitalization. In the fully adjusted model, the ORs decreased to 3.1 (95%CI 2.0 to 5.0) for DOW = 5, 3.2 (2.0 to 5.0) for DOW = 4, 1.6 (1.0 to 2.6) for DOW = 3 and 0.8 (0.5 to 1.4) for DOW = 2 compared to minimum DOW.

Conclusion

Patients’ self-assessment of illness severity as DOW was associated with subsequent hospital admission. Further, it may be beneficial in supporting clinical decision making in telephone triage. Finally, it might be useful as a measure to facilitate patient participation in the triage process.
Dynamic rewiring of the human interactome by interferon signaling
Authors: Kerr Craig H. , Skinnider Michael A. , Andrews Daniel D. T. , Madero Angel M. , Chan Queenie W. T. , Stacey R. Greg , Stoynov Nikolay , Jan Eric , Foster Leonard J.
Published: June 2020

Background

The type I interferon (IFN) response is an ancient pathway that protects cells against viral pathogens by inducing the transcription of hundreds of IFN-stimulated genes. Comprehensive catalogs of IFN-stimulated genes have been established across species and cell types by transcriptomic and biochemical approaches, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to describe the effects of IFN signaling on the human proteome, and apply protein correlation profiling to map IFN-induced rearrangements in the human protein-protein interaction network.

Results

We identify > 26,000 protein interactions in IFN-stimulated and unstimulated cells, many of which involve proteins associated with human disease and are observed exclusively within the IFN-stimulated network. Differential network analysis reveals interaction rewiring across a surprisingly broad spectrum of cellular pathways in the antiviral response. We identify IFN-dependent protein-protein interactions mediating novel regulatory mechanisms at the transcriptional and translational levels, with one such interaction modulating the transcriptional activity of STAT1. Moreover, we reveal IFN-dependent changes in ribosomal composition that act to buffer IFN-stimulated gene protein synthesis.

Conclusions

Our map of the IFN interactome provides a global view of the complex cellular networks activated during the antiviral response, placing IFN-stimulated genes in a functional context, and serves as a framework to understand how these networks are dysregulated in autoimmune or inflammatory disease.
Efficacy, safety, and economic assessment of hominis placental pharmacopuncture for chronic temporomandibular disorder: a protocol for a multicentre randomised controlled trial
Authors: Kim Jongho , Park Kyoung Sun , Lee Yoon Jae , Kim Koh-Woon , Cho Jae-Heung , Ha In-Hyuk
Published: June 2020

Background

Temporomandibular disorder (TMD) is a condition encompassing clinical symptoms of the temporomandibular joint, masseter muscle, and surrounding structures. Hominis placental pharmacopuncture (HPP), consisting of human placental extract, has been reported as effective for treating chronic musculoskeletal disorders, but a lack of well-designed randomised controlled trial s (RCTs) mean there is insufficient evidence to prove the efficacy of HPP.

Methods

This study is a two-arm parallel, assessor-blinded, multi-centre, randomised controlled trial. We will enrol 82 chronic TMD patients from rwo Korean Medicine hospitals in Axis 1, Group I according to RDC/TMD diagnostic criteria, and randomly allocate 41 patients each to an HPP group and a physical therapy (PT) group. Treatment will be administered in 10 rounds, after which there will be four follow-up visits 6, 9, 13, and 25 weeks from baseline. The primary end point is 6 weeks after baseline, and the primary outcome is the difference in Visual Analogue Scale (VAS) score for temporomandibular pain between baseline and week 6. Secondary outcomes will be Numeric Rating Scale (NRS) scores for temporomandibular pain and discomfort, temporomandibular joint range of motion, the Korean version of Beck’s Depression Index-II (K-BDI-II), Jaw Functional Limitation Scale (JFLS), Patient Global Impression of Change (PGIC) scores, and quality of life. Using data on adverse events and cost-effectiveness in the two groups, we will perform a safety assessment and a cost-effectiveness analysis (economic assessment).

Discussion

This study will assess the efficacy and safety of HPP for chronic TMD compared with PT. This RCT will provide evidence for the efficacy, safety, and economics of HPP.

Trial registration

clinicaTrials.gov(NCT04087005) / Clinical Research Information Service (CRIS) (KCT0004437) / IRB (JASENG 2017–09–002-002, KHNMCOH 2019–08-002) / Ministry of Food and Drug Safety (No. 31886).
Engineering Pichia pastoris with surface-display minicellulosomes for carboxymethyl cellulose hydrolysis and ethanol production
Authors: Dong Ce , Qiao Jie , Wang Xinping , Sun Wenli , Chen Lixia , Li Shuntang , Wu Ke , Ma Lixin , Liu Yi
Published: June 2020

Backgrounds

Engineering yeast as a consolidated bioprocessing (CBP) microorganism by surface assembly of cellulosomes has been aggressively utilized for cellulosic ethanol production. However, most of the previous studies focused onSaccharomyces cerevisiae, achieving efficient conversion of phosphoric acid-swollen cellulose (PASC) or microcrystalline cellulose (Avicel) but not carboxymethyl cellulose (CMC) to ethanol, with an average titer below 2 g/L.

Results

Harnessing an ultra-high-affinity IM7/CL7 protein pair, here we describe a method to engineerPichia pastoriswith minicellulosomes by in vitro assembly of three recombinant cellulases including an endoglucanase (EG), an exoglucanase (CBH) and a β-glucosidase (BGL), as well as a carbohydrate-binding module (CBM) on the cell surface. For the first time, the engineered yeasts enable efficient and direct conversion of CMC to bioethanol, observing an impressive ethanol titer of 5.1 g/L.

Conclusions

The research promotes the application ofP. pastorisas a CBP cell factory in cellulosic ethanol production and provides a promising platform for screening the cellulases from different species to construct surface-assembly celluosome.
Favorable efficacy of rituximab in ANCA-associated vasculitis patients with excessive B cell differentiation
Authors: Miyazaki Yusuke , Nakayamada Shingo , Kubo Satoshi , Ishikawa Yuichi , Yoshikawa Maiko , Sakata Kei , Iwata Shigeru , Miyagawa Ippei , Nakano Kazuhisa , Tanaka Yoshiya
Published: June 2020

Objectives

B cell depletion by rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, peripheral B cell phenotypes and the selection criteria for RTX therapy in AAV remain unclear.

Methods

Phenotypic characterization of circulating B cells was performed by 8-color flow cytometric analysis in 54 newly diagnosed AAV patients (20 granulomatosis with polyangiitis and 34 microscopic polyangiitis). Patients were considered eligible to receive intravenous cyclophosphamide pulse (IV-CY) or RTX. All patients also received high-dose glucocorticoids (GC). We assessed circulating B cell phenotypes and evaluated the efficacy after 6 months of treatment.

Results

There were no significant differences in the rate of clinical improvement, relapses, or serious adverse events between patients receiving RTX and IV-CY. The rate of Birmingham Vasculitis Activity Score (BVAS) improvement at 6 months tended to be higher in the RTX group than in the IV-CY group. The proportion of effector or class-switched memory B cells increased in 24 out of 54 patients (44%). The proportions of peripheral T and B cell phenotypes did not correlate with BVAS at baseline. However, among peripheral B cells, the proportion of class-switched memory B cells negatively correlated with the rate of improvement in BVAS at 6 months after treatment initiation (r = − 0.28, p = 0.04). Patients with excessive B cell differentiation were defined as those in whom the proportion of class-switched memory B cells or IgD−CD27− B cells among all B cells was > 2 SDs higher than the mean in the HCs. The rate of BVAS remission in patients with excessive B cell differentiation was significantly lower than that in patients without. In patients with excessive B cell differentiation, the survival rate, the rate of BVAS-remission, and dose reduction of GC were significantly improved in the RTX group compared to those in the IV-CY group after 6 months of treatment.

Conclusions

The presence of excessive B cell differentiation was associated with treatment resistance. However, in patients with circulating B cell abnormality, RTX was effective and increased survival compared to IV-CY. The results suggest that multi-color flow cytometry may be useful to determine the selection criteria for RTX therapy in AAV patients.
Application of median lethal concentration (LC50) of pathogenic microorganisms and their antigens in vaccine development
Authors: Saganuwan Saganuwan Alhaji
Published: June 2020

Objective

Lack of ideal mathematical models to qualify and quantify both pathogenicity, and virulence is a dreadful setback in development of new antimicrobials and vaccines against resistance pathogenic microorganisms. Hence, the modified arithmetical formula of Reed and Muench has been integrated with other formulas and used to determine bacterial colony forming unit/viral concentration, virulence and immunogenicity.

Results

Microorganisms’ antigens tested are Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa in mice and rat, Edwardsiella ictaluri, Aeromonas hydrophila, Aeromonas veronii in fish, New Castle Disease virus in chicken, Sheep Pox virus, Foot-and-Mouth Disease virus and Hepatitis A virus in vitro, respectively. The LC50s for the pathogens using different routes of administrations are 1.93 × 103(sheep poxvirus) and 1.75 × 1010 for Staphylococcus aureus (ATCC29213) in rat, respectively. Titer index (TI) equals N log10 LC50 and provides protection against lethal dose in graded fashion which translates to protection index. N is the number of vaccine dose that could neutralize the LC50. Hence, parasite inoculum of 103 to 1011 may be used as basis for determination of LC50 and median bacterial concentrations (BC50).Pathogenic dose for immune stimulation should be sought at concentration about LC10.
Methylome profiling of young adults with depression supports a link with immune response and psoriasis
Authors: Lapsley Coral R. , Irwin Rachelle , McLafferty Margaret , Thursby Sara Jayne , O’Neill Siobhan M. , Bjourson Anthony J. , Walsh Colum P. , Murray Elaine K.
Published: June 2020

Background

Currently the leading cause of global disability, clinical depression is a heterogeneous condition characterised by low mood, anhedonia and cognitive impairments. Its growing incidence among young people, often co-occurring with self-harm, is of particular concern. We recently reported very high rates of depression among first year university students in Northern Ireland, with over 25% meeting the clinical criteria, based on DSM IV. However, the causes of depression in such groups remain unclear, and diagnosis is hampered by a lack of biological markers. The aim of this exploratory study was to examine DNA methylation patterns in saliva samples from individuals with a history of depression and matched healthy controls.

Results

From our student subjects who showed evidence of a total lifetime major depressive event (MDE, n = 186) we identified a small but distinct subgroup (n = 30) with higher risk scores on the basis of co-occurrence of self-harm and attempted suicide. Factors conferring elevated risk included being female or non-heterosexual, and intrinsic factors such as emotional suppression and impulsiveness. Saliva samples were collected and a closely matched set of high-risk cases (n = 16) and healthy controls (n = 16) similar in age, gender and smoking status were compared. These showed substantial differences in DNA methylation marks across the genome, specifically in the late cornified envelope (LCE) gene cluster. Gene ontology analysis showed highly significant enrichment for immune response, and in particular genes associated with the inflammatory skin condition psoriasis, which we confirmed using a second bioinformatics approach. We then verified methylation gains at the LCE gene cluster at the epidermal differentiation complex and at MIR4520A/B in our cases in the laboratory, using pyrosequencing. Additionally, we found loss of methylation at the PSORSC13 locus on chromosome 6 by array and pyrosequencing, validating recent findings in brain tissue from people who had died by suicide. Finally, we could show that similar changes in immune gene methylation preceded the onset of depression in an independent cohort of adolescent females.

Conclusions

Our data suggests an immune component to the aetiology of depression in at least a small subgroup of cases, consistent with the accumulating evidence supporting a relationship between inflammation and depression. Additionally, DNA methylation changes at key loci, detected in saliva, may represent a valuable tool for identifying at-risk subjects.
Anaphylaxis to three humanized antibodies for severe asthma: a case study
Authors: Jingo Koichi , Harada Norihiro , Nishioki Toshihiko , Torasawa Masahiro , Yamada Tomoko , Asao Tetsuhiko , Takagi Haruhi , Takeshige Tomohito , Ito Jun , Takahashi Kazuhisa
Published: June 2020

Background

Omalizumab, mepolizumab, benralizumab, and dupilumab are the currently available biologics used to treat asthma in Japan. Anaphylaxis following treatment with mepolizumab or benralizumab is considered rare.

Case presentation

We report the case of a 35-year-old woman with severe asthma, who experienced anaphylaxis following the administration of benralizumab, mepolizumab, and omalizumab, separately. The therapy with biologics was chosen to avoid the repeated use of systemic corticosteroids for asthma exacerbations. The mechanisms underlying anaphylaxis caused by these three biologics remain unclear. The patient’s asthma symptoms and lung function improved after treatment with bronchial thermoplasty.

Conclusions

To our knowledge, this is the first report of an asthmatic patient developing anaphylaxis after commencement of benralizumab, mepolizumab, and omalizumab therapy. These three biologics should be administered carefully, and patients should be monitored for anaphylaxis.
Defining clusters of young autistic and typically developing children based on loudness-dependent auditory electrophysiological responses
Authors: Dwyer Patrick , Wang Xiaodong , De Meo-Monteil Rosanna , Hsieh Fushing , Saron Clifford D. , Rivera Susan M.
Published: June 2020

Background

Autistic individuals exhibit atypical patterns of sensory processing that are known to be related to quality of life, but which are also highly heterogeneous. Previous investigations of this heterogeneity have ordinarily used questionnaires and have rarely investigated sensory processing in typical development (TD) alongside autism spectrum development (ASD).

Methods

The present study used hierarchical clustering in a large sample to identify subgroups of young autistic and typically developing children based on the normalized global field power (GFP) of their event-related potentials (ERPs) to auditory stimuli of four different loudness intensities (50, 60, 70, 80 dB SPL): that is, based on an index of the relative strengths of their neural responses across these loudness conditions.

Results

Four clusters of participants were defined. Normalized GFP responses to sounds of different intensities differed strongly across clusters. There was considerable overlap in cluster assignments of autistic and typically developing participants, but autistic participants were more likely to display a pattern of relatively linear increases in response strength accompanied by a disproportionately strong response to 70 dB stimuli. Autistic participants displaying this pattern trended towards obtaining higher scores on assessments of cognitive abilities. There was also a trend for typically developing participants to disproportionately fall into a cluster characterized by disproportionately/nonlinearly strong 60 dB responses. Greater auditory distractibility was reported among autistic participants in a cluster characterized by disproportionately strong responses to the loudest (80 dB) sounds, and furthermore, relatively strong responses to loud sounds were correlated with auditory distractibility. This appears to provide evidence of coinciding behavioral and neural sensory atypicalities.

Limitations

Replication may be needed to verify exploratory results. This analysis does not address variability related to classical ERP latencies and topographies. The sensory questionnaire employed was not specifically designed for use in autism. Hearing acuity was not measured. Variability in sensory responses unrelated to loudness is not addressed, leaving room for additional research.

Conclusions

Taken together, these data demonstrate the broader benefits of using electrophysiology to explore individual differences. They illuminate different neural response patterns and suggest relationships between sensory neural responses and sensory behaviors, cognitive abilities, and autism diagnostic status.