bluuebunny/crossref_metadata_2025 huggingface dataset:
Bis-benzylidine Piperidone RA190 Treatment of Hepatocellular Carcinoma via Binding RPN13 and Inhibiting NF-κB Signaling
Authors: Soong Ruey-Shyang , Anchoori Ravi K. , Roden Richard B. S. , Cho Rou-Ling , Chen Yi-Chan , Tseng Sheng-Chieh , Huang Yun-Li , Liao Po-Cheng , Shyu Yu-Chiau
Published: April 2020

Background According to GLOBOSCAN, hepatocellular carcinoma (HCC) claimed 782,000 lives in 2018. The tyrosine kinase inhibitor sofafenib is used to treat HCC, but new anticancer agents targeting different pathways are urgently needed to improve outcomes for patients with advanced disease. The aberrant metabolism and aggressive growth of cancer cells can render them particularly susceptible to proteasome inhibition, as demonstrated by bortezomib treatment of multiple myeloma. However, resistance does emerge, and this 20S proteasome inhibitor has not proven active against HCC. The bis-benzylidine piperidone RA190 represents a novel class of proteasome inhibitor that covalently binds to cysteine 88 of RPN13, an ubiquitin receptor subunit of the proteasome’s 19S regulatory particle. RA190 treatment inhibits proteasome function, causing rapid accumulation of polyubiquitinated proteins. Considerable evidence suggests that nuclear factor κB (NF-κB) signaling, which is dependent upon the proteasome, is a major driver of inflammation-associated cancers, including HCC. Methods Human HCC cell lines were treated with titrations of RA190. The time course of endoplasmic reticulum stress and NF-κB-related mechanisms by which RA190 may trigger apoptosis were assessed. The therapeutic activity of RA190 was also determined in an orthotopic HCC xenograft mouse model. Results RA190 is toxic to HCC cells and synergizes with sofafenib. RA190 triggers rapid accumulation of polyubiquitinated proteins, unresolved endoplasmic reticulum stress, and cell death via apoptosis. RA190 blocks proteasomal degradation of IκBα and consequent release of NF-κB into the nuclei of HCC cells. Treatment of mice bearing an orthotopic HCC model with RA190 significantly reduced tumor growth. Conclusions RA190 has therapeutic activity in a xenograft model, and with sorafenib exhibited synergetic killing of HCC cells in vitro, suggesting further exploration of such a combination treatment of HCC is warranted.
Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation
Authors: Blasco Maria Pilar , Chauhan Anjali , Honarpisheh Pedram , Ahnstedt Hilda , d’Aigle John , Ganesan Arunkumar , Ayyaswamy Sriram , Blixt Frank , Venable Susan , Major Angela , Durgan David , Haag Anthony , Kofler Julia , Bryan Robert , McCullough Louise D , Ganesh Bhanu Priya
Published: April 2020

Background Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation and mast cells residing in the gut are a primary source of histamine. Methods Stroke was induced in male C57BL/6J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice, mice underwent MCAO surgery and were euthanized at 6h, 24h and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice was associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. Results We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of mast cells and histamine receptors in the gut. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24 hours post-stroke. Conclusion An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.
Serious Infections in People with Systemic sclerosis: A National U.S. Study
Authors: Singh Jasvinder , Cleveland John D.
Published: April 2020

Objective: To study incidence, time-trends and outcomes of serious infections in systemic sclerosis (SSc). Methods: We used the 1998-2016 U.S. National Inpatient Sample data. We examined the epidemiology, time-trends and outcomes of five serious infections (opportunistic infections (OI), skin and soft tissue infections (SSTI), urinary tract infection (UTI), pneumonia, and sepsis/bacteremia) in hospitalized people with SSc. We performed multivariable-adjusted logistic regression analyses to analyze independent association of factors with healthcare utilization (hospital charges, length of hospital stay, discharge to non-home setting), and in-hospital mortality. Results: There were 49,904,955 hospitalizations with serious infections in people without SSc and 61,615 in those with SSc. During 1998-2016, the most common serious infections in SSc were pneumonia (45%), sepsis (32%), SSTI (19%), UTI (3%) and OI (3%). In 2013-14, sepsis surpassed pneumonia as the most common serious infection; by 2015-16, sepsis was 1.8-times more common than pneumonia. Over the study period, hospital charges increased, while length of hospital stay and in-hospital mortality decreased, overall and for each serious infection. Multivariable-adjusted analyses showed that sepsis, age ≥80 years and Deyo-Charlson score ≥2 were associated with significantly higher odds of healthcare utilization and in-hospital mortality; and Medicare or Medicaid insurance payer, Northeast location, urban teaching or non-teaching hospital, and medium or large hospital bed size with significantly higher odds of healthcare utilization. Conclusions: Outcomes in people with SSc hospitalized with serious infections have improved over time, except higher hospital charges. Identification of factors associated with higher healthcare utilization and in-hospital mortality allows for developing interventions to improve outcomes.
The relationship between sleep duration and all-cause mortality in the older people: an updated and dose-response meta-analysis
Authors: He Mengyang , Deng Xiangling , Zhu Yuqing , Huan Luyao , Niu Wenquan
Published: April 2020

Background: Short or long sleep duration is proposed as a potential risk factor for all-cause mortality in the older people, yet the results of published studies are not often reproducible. Objectives: We aimed to investigate whether short or long sleep duration was associated with an increased risk of all-cause mortality in the older people via a comprehensive meta-analysis. Methods: Literature retrieval, study selection and data extraction were completed independently and in duplicate. Effect-size estimates are expressed as relative risk (RR) and its 95% confidence interval (CI). Results: Summary data from 35 articles, involving a total of 106990 older people, were meta-analyzed. Overall analyses revealed a significant association between long sleep duration and all-cause mortality (RR=1.27, 95% CI: 1.19-1.35, P <.001), whereas marginal significance was observed for short sleep duration (RR=1.05; 95% CI: 1.00-1.09; P =.045). There was a low probability of publication bias as indicated by Egger’s test for the association between sleep duration and all-cause mortality. In subgroup analyses, the association between long sleep duration and all-cause mortality was relatively strong in women (RR=1.48, 95% CI: 1.18-1.85, P =.002) relative to men (RR=1.30, 95% CI: 1.10-1.50, P =.001) (Two-sample Z test P = .219). Further dose-response regression analyses showed that trend estimation was not obvious for short sleep duration ( P = .016) compared with long sleep duration ( P < .001), indicating a J-shaped relationship between sleep duration and all-cause mortality. Conclusions: Our findings indicate a J-shaped relationship between sleep duration and all-cause mortality in the older people, with long sleep duration significantly associating with all-cause mortality, especially in women.
Repair of alveolar cleft bone defects by bone collagen particles combined with human umbilical cord mesenchymal stem cells in rabbit
Authors: Sun Xue-Cheng , Wang Hu , Li Jian-Hui , Zhang Dan , Ma Xu , Xia Hong-Fei
Published: April 2020

Background: Alveolar cleft is a kind of cleft lip and palate, which seriously affects the physical and mental health of patients. In this study ， the model of the alveolar cleft phenotype was established in rabbits to evaluate the effect of bone collagen particles combined with human umbilical cord mesenchymal stem cells (HUC-MSCs) on the repair of alveolar cleft bone defects. Methods : The model of alveolar clefts in rabbits was established by removing the incisors on the left side of the upper jaw. Bone collagen particles combined with hUC-MSCs were implanted in the defect area. Blood biochemical analysis was performed after 3 months. Skull tissues were harvested for gross observation, and micro-focus computerized tomography (micro-CT) analysis. Tissues were harvested for histological and immunohistochemical staining. The experiments were repeated 6 months after surgery. Results: The bone collagen particles and HUC-MSCs have good biological safety. In addition, both can promote the regeneration of incisor. Bone collagen particles combined with hUC-MSCs were much better than those used alone in inducing bone repair and regeneration. Conclusions: The method of HUC-MSCs combined with bone collagen particle material to fill a bone defect site is simple, rapid and suitable for the treatment of alveolar cleft bone defects.
Lipoprotein (a) is a residual risk of atherosclerotic renal artery stenosis in hypertensive patients: a hospital-based cross-sectional study
Authors: Hu Xiangming , Yang Xing , Li Xida , Luo Demou , Zhou Yingling , Dong Haojian
Published: April 2020

Background Low-density lipoprotein cholesterol (LDL-c) has been proven to be a risk factor for atherosclerotic cardiovascular disease (CVD), while lipoprotein (a) (Lp(a)) is a residual risk factor for CVD, even though LDL-c is well controlled by statin use. Importantly, the role of Lp(a) in atherosclerotic renal artery stenosis (ARAS) is still unknown. Methods For this hospital-based cross-sectional study, patients who simultaneously underwent coronary and renal angiography were examined. ARAS was defined as a 50% reduction in the cross-sectional (two-dimensional plane) area of the renal artery. Data were collected and compared between ARAS and non-ARAS groups, including clinical history and metabolite profiles. Univariate analysis, three tertile LDL-c-based stratified analysis, and multivariate-adjusted logistic analysis were conducted, revealing a correlation between Lp(a) and ARAS. Results A total of 170 hypertensive patients were included in this study, 85 with ARAS and 85 with non-RAS. Baseline information indicated comparability between the two groups. In the univariate and multivariate analysis, common risk factors for atherosclerosis were not significantly different. Stratified analysis of LDL-c revealed a significant increase in the incidence of ARAS in patients who had high Lp(a) concentrations at low LDL-c levels (odds ratio (OR): 4.77, 95% confidence interval (CI): 1.04-21.79, P = 0.044). Further logistic analysis with adjusted covariates also confirmed the result, indicating that high Lp(a) levels were independently associated with ARAS (adjusted OR (aOR): 6.14, 95%CI: 1.03-36.47, P = 0.046). This relationship increased with increasing Lp(a) concentration based on a curve fitting graph. These results were not present in the low and intermediate LDL-c-level groups. Conclusion In hypertensive patients who present low LDL-c, high Lp(a) was significantly associated with atherosclerotic renal artery stenosis and thus is a residual risk factor.
The Efficacy of Surgery in Advanced Hepatocellular Carcinoma: A Cohort Study
Authors: Chen Lei , Sun Tao , Chen Shi , Ren Yanqiao , Yang Fan , Zheng Chuansheng
Published: April 2020

Background It is still controversial that whether hepatocellular carcinoma (HCC) patients with lymph node invasion should receive surgery treatment. This study aimed to evaluate the efficacy of surgery (liver resection and local tumor destruction treatments[l陈1] ) in HCC patients with regional lymph node metastasis.Methods The study utilized data from the Surveillance, Epidemiology, and End Results-18 (SEER-18) cancer registry. Patients for whom the treatment type was not clear or those with distant metastasis or without regional lymph nodules invasion were excluded. For survival analysis, patients with the survival months coded as 0 and 999 were excluded. [l陈2] All 1434 patients were included in the analysis. Among them, 168 patients were treated surgically and the other 1266 received non-surgery therapy. Propensity Score Matching (PSM) model was used to reduce selection bias.Results Before PSM, the median overall survival (mOS) and median cancer-specific survival (mCSS) of patients treated surgically were longer than that of receiving non-surgery treatment (mOS: 20 months, 95%CI: 15.3-24.7 vs. 7 months, 95%CI: 6.4-7.6, P<0.001; mCSS: 21 months, 95%CI: 115.5-26.5 vs. 6 months, 95%CI: 5.3-6.7, P<0.001). Subgroup analysis found no significant differences in mOS and mCSS between liver resection and non-liver resection surgery cohorts (P=0.886 and P=0.813, respectively).[l陈3] Similar results were obtained in the PSM analysis. The mOS and mCSS in the surgery group were longer than in the non-surgery group (mOS: 20 months vs. 7 months, P<0.001; mCSS: 20 months vs. 6 months, P<0.001). The multivariate analysis documented that surgery was an independent predictor for OS and CSS before and after PSM.Conclusions HCC patients with invasion of regional lymph nodules may get more survival benefit from surgery than other types of treatment.
Frequency-dependent gating of feedforward inhibition in thalamofrontal synapses
Authors: Lee Jungmin , Choi Joonho , Rah Jong Cheol
Published: April 2020

Thalamic recruitment of feedforward inhibition is known to enhance the fidelity of the receptive field by limiting the temporal window during which cortical neurons integrate excitatory inputs. Feedforward inhibition driven by the mediodorsal nucleus of the thalamus (MD) has been previously observed, but its physiological function and regulation remain unknown. Accumulating evidence suggests that elevated neuronal activity in the prefrontal cortex is required for the short-term storage of information. Furthermore, the elevated neuronal activity is supported by the reciprocal connectivity between the MD and the medial prefrontal cortex (mPFC). Therefore, detailed knowledge about the synaptic connections during high-frequency activity is critical for understanding the mechanism of short-term memory. In this study, we examined how feedforward inhibition of thalamofrontal connectivity is modulated by activity frequency. We observed greater short-term synaptic depression during disynaptic inhibition than in thalamic excitatory synapses during high-frequency activities. The strength of feedforward inhibition became weaker as the stimulation continued, which, in turn, enhanced the range of firing jitter in a frequency-dependent manner. We postulated that this phenomenon was primarily due to the increased failure rate of evoking action potentials in parvalbumin-expressing inhibitory neurons. These findings suggest that the MD-mPFC pathway is dynamically regulated by an excitatory-inhibitory balance in an activity-dependent manner. During low-frequency activities, excessive excitations are inhibited, and firing is restricted to a limited temporal range by the strong feedforward inhibition. However, during high-frequency activities, such as during short-term memory, the activity can be transferred in a broader temporal range due to the decreased feedforward inhibition.
Rising trends and persisting inequalities in cesarean section rates in Nepal: evidence from demographic and health surveys 2006-2016
Authors: Acharya Kiran , Paudel Yuba Raj , Dhungana Chandra Mani
Published: April 2020

Background Sustainable development goals require member countries to reduce maternal mortality ratio below 70 per 100,000 live births by 2030. Addressing inequalities in accessing emergency obstetric care is crucial for reducing the maternal mortality ratio. This study was undertaken to examine the time trends and socio-demographic inequalities in the utilization of cesarean section (CS) in Nepal during the period of 2006 and 2016.Methods Data from the Nepal Demographic and Health Surveys (NDHS) 2006, 2011 and2016 were sourced for this study. Women who had a live birth in the last five years of the survey (most recent birth if there were two or more childbirths) were the unit of analysis for this study. Absolute and relative inequalities in CS rates were expressed in-terms of rate difference and rate ratios, respectively. We used binary logistic regression models to assess the rate of cesarean sections by background socio-demographic characteristics of women. Results Age and parity adjusted CS rates were found to have increased almost three-fold (from 3.2%,95% CI:2.1-4.3 in 2006 to 10.5%;95% CI:8.9-11.9 in 2016) over the decade. In 2016, women from Mountain region (3.0%;95% CI:1.1-4.9), those from poorest wealth quintile (2.4%,95% CI:(1.2-3.7) and those living in province 6(2.4%,95% CI:1.3-3.5) had CS rate below 5%. Whereas, women from the richest income quintile (25.1%,95% CI :20.2-30.1), with higher education (21.2%,95% CI:14.7-27.8) and those delivering in private facilities (37.1%,95% CI:30.5-43.7) had CS rate above 15%. Women from the richest income quintile (OR-3.3,95% CI: 1.6-7.0) and those delivered in private/NGO-run facilities (OR-3.6;95% CI:2.7-4.9) were more than three times more likely to deliver by CS compared to women from the poorest income quintile and those delivering in public facilities, respectively. Conclusion To improve maternal and newborn health, strategies need to be revised to address the underuse of C-section in poor, mountain region and province 2, province 5, province 6 and province 7 so that universal access to comprehensive sexual and reproductive health care services is ensured. Simultaneously, there is a pressing need for policies, guidelines and continuous monitoring of CS rates to reduce overuse in rich women, women with higher education and those delivered in private facilities.
Hop tests and psychological PROs provide a demanding and clinician-friendly RTS assessment of patients after ACL reconstruction, a registry study.
Authors: Piussi Ramana , Beischer Susanne , Thomeé Roland , Senorski Eric Hamrin
Published: April 2020

Background There is growing interest in assessing psychological well-being in patients after anterior cruciate ligament (ACL) reconstruction. It is unknown whether an assessment of psychological outcome in addition to tests of muscle function can facilitate decisions on return to sport (RTS). Therefore, the aim of this study was to evaluate passing rates in different physical RTS test batteries, with and without the inclusion of psychological outcome measures 1 year after ACL reconstruction. Method In this cross-sectional cohort study a total of 320 patients (51% men) aged 18-65 years were included 1 year after ACL reconstruction. Passing rates on different muscle function (MF) test batteries (with results presented as Limb Symmetry Index (LSI)), consisting of knee extension and flexion strength tests, 3 hop tests, and 2 psychological patient-reported outcomes (PROs); Quality of Life subscale from the Knee injury and Osteoarthritis Outcome Score (KOOS-QoL) and ACL Return to Sport after Injury (ACL-RSI), were evaluated 1 year after ACL reconstruction. Muscle function test batteries comprised: 2 MF tests (vertical hop and hop for distance; pass=90% LSI); 2 MF tests and 2 PRO (pass=90% LSI, 62.5 on KOOS-QoL and 76.6 on ACL-RSI), 5 MF tests (2 strength and 3 hop tests, pass=90% LSI), and 5 MF tests and 2 PRO (pass=90% LSI, 62.5 on KOOS-QoL and 76.6 on ACL-RSI). Results Passing rates in the different test batteries were 47% for 2 MF tests, 19% for 2 MF tests and 2 PROs, 29% for 5 MF tests and 13% for 5 MF tests and 2 PROs. The use of psychological PROs together with tests of muscle function gave the lowest passing rates (13%). There was a very strong correlation between passing 2 hop tests and 2 PROs and passing 5 MF tests (rφ=0.41) as well as passing 5 MF tests and 2 PROs (rφ=0.79). Conclusion The use of hop tests together with psychological PROs provides a clinician-friendly RTS test battery for assessment 1 year after ACL reconstruction as the passing rate was 19% when using 2 hop-tests combined with 2 PROs, compared with 29% when using 5 tests of MF requiring advanced testing equipment.
High fetal hemoglobin level is associated with increased risk of cerebral vasculopathy in children with sickle cell disease in Mayotte.
Authors: Elenga Narcisse , CHAMOUINE Abdourahim , SAANDI Thoueiba , MUSZLAK Mathias , LARMARAUD Juliette , LAMBRECHT Laurent , POISSON Jean , BALICCHI Julien , PISSARD Serge
Published: April 2020

Background: Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia, specific to each population, would be prognostically useful and could inform personalized therapeutics. The objective of this study was to describe the genetic modulators of sickle cell disease in a cohort of pediatric patients followed up in Mayotte. Methods: In this retrospective cohort study, clinical and biological data, collected between 1 January 2007 and 31 December 2017, in children younger than 18 years, were considered for the analysis. Results: We included 185 children with 72 % SS, 16 % Sβ0-thalassemia and 12 % Sβ+ thalassemia. The mean age was 9.5 years; 10 % of patients were lost to follow up. The Bantu haplotype was associated with an increase in hospitalizations and transfusions. The alpha-thalassemic mutation was associated with a decrease of hemolysis biological parameters (anemia, reticulocytes), and less cerebral vasculopathy. The Single Nucleotide Polymorphisms BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were associated with the group of children with HbF> 10%. The survival analysis without occurrence of cerebral vasculopathy showed that the group of patients with HbF> 10% presented a significant risk of early onset of cerebral vasculopathy. Conclusions: The most remarkable result of our study was the association of SNPs with the phenotypic groups that we aimed to determine. BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were correlated with the HbF group> 10%, which presents a higher risk of cerebral vasculopathy and would be oriented towards the hemolytic sub-phenotype.
Prevalence of human alveolar echinococcosis in China: a systematic review and meta-analysis
Authors: Wang Xuanzhuo , Dai Guodong , Li Min , Jia Wanzhong , Guo Zhongmin , Lu Jiahai
Published: April 2020

Background: Human alveolar echinococcosis (HAE), caused by the larvae of Echinococcus multilocularis，is a severe parasitic disease that is a major public health concern. New HAE cases in China account for 91% of the global HAE burden every year. Although there are a few studies and systematic reviews (SRs) on the prevalence of HAE in China, trends in the prevalence have not been estimated. This study aims to describe the overall variation in the trend of HAE prevalence in China, and provide evidence for preventive measures in the future. Methods: Thirty-five eligible studies were retrieved from PubMed, Web of Science, EMBASE, CNKI, Wanfang Data, and VIP, and included in the SR and meta-analysis. An adjusted Agency for Healthcare Research and Quality checklist was used to evaluate study quality. The arcsine transformation was used to adjust the individual reported prevalence, and the pooled HAE prevalence was calculated. Heterogeneity was evaluated using the chi-square test and I2 statistic. Forest plots were generated for the meta-analysis, and publication bias of the studies was assessed using the Egger’s test and funnel plots. We conducted subgroup analyses, sensitivity analyses, and meta-regression analyses to analyze the source of heterogeneity and factors potentially influencing the prevalence of HAE. Results: The meta-analysis indicated that the pooled HAE prevalence in China was 0.96% (95% CI: 0.71 to 1.25%). Factors potentially influencing HAE prevalence were female sex (OR=1.60, 95% CI: 1.35 to 1.91, P＜0.01), being ≥30 years old (OR=4.72, 95% CI: 2.29 to 9.75, P＜0.01), and being farmers and/or herdsmen (OR=2.54, 95% CI: 1.60 to 4.02, P＜0.01). The results of the meta-regression analysis (R2=38.11%, P < 0.01) indicated that HAE prevalence is on a downward trend.Conclusions: HAE prevalence has decreased over time and maintained low levels after 2005 in China. This decline was influenced by the utilization of One Health strategies as intervention measures. Therefore, these One Health strategies should be used as references to formulate future programs for HAE control. More high-quality epidemiological investigations and surveillance programs should be conducted in order to improve HAE control in the future.
A novel ultra-sensitive method for the detection of FGFR3 mutations in urine of bladder cancer patients – Design of the Urodiag® PCR Kit for surveillance of patients with non-muscle-invasive bladder cancer (NMIBC)
Authors: ROPERCH Jean-Pierre , HENNION Claude
Published: April 2020

Background We have recently developed a highly accurate urine-based test, named Urodiag ® , associating FGFR3 mutation and DNA methylation assays for recurrence surveillance in patients with low-, intermediate-, and high-risk NMIBC. Previously, the detection of four FGFR3 mutations (G372C, R248C, S249C and Y375C) required amplification steps and PCR products were analyzed by capillary electrophoresis (Allele Specific-PCR, AS-PCR), which was expensive and time-consuming. Here, we present the development a novel ultra-sensitive multiplex PCR assay as called “Mutated Allele Specific Oligonucleotide-PCR (MASO-PCR)”, generating cost-effective, simple, fast and clinically applicable assay for the detection of FGFR3 mutations in voided urine. Methods Comparative clinical performances of MASO-PCR and AS-PCR technologies were performed from 263 urine DNA samples (87 FGFR3 mutated and 176 FGFR3 wild-type). In the development of Urodiag ® PCR Kit, we studied the stability and reproducibility of each all-in-one PCR master mix (single reaction mixture including all the necessary PCR components) for MASO-PCR and QM-MSPCR (Quantitative Multiplex Methylation-Specific PCR to co-amplify SEPTIN9 , HS3ST2 and SLIT2 methylated genes) assays. Results Complete concordance (100%) was observed between the MASO-PCR and AS-PCR results. Each PCR master mix displayed excellent reproducibility and stability after 12 months of storage at -20°C, with intra-assay standard deviations lower than 0.3 Ct and coefficient of variations (CV) lower than 1%. The limit of detection (LoD) of MASO-PCR was 5% mutant detection in a 95% of wild-type background. The limit of quantification (LoQ) of QM-MSPCR was 10 pg of bisulfite-converted DNA. Conclusions We developed and clinically validated the MASO-PCR assay, generating cost-effective, simple, fast and clinically applicable assay for the detection of FGFR3 mutations in urine. We also designed the Urodiag ® PCR Kit, which includes the MASO-PCR and QM-MSPCR assays. Adapted to routine clinical laboratory (simplicity, accuracy), the kit will be a great help to urologists for recurrence surveillance in patients at low-, intermediate- and high-risk NMIBC. Reducing the number of unnecessary cystoscopies, it will have extremely beneficial effects for patients (painless) and for the healthcare systems (low cost).
Computerized Adaptive Testing for Sleep Disorders: Development of An Item Bank and Validation in A Simulated Study
Authors: She Menghua , Li Yaling , Tu Dongbo , Cai Yan
Published: April 2020

Background: As more and more people suffer from sleep disorders, developing an efficient, cheap and accurate assessment tool for screening sleep disorders is becoming more urgent. This study developed a computerized adaptive testing for sleep disorders (CAT-SD). Methods: A large sample of 1,304 participants was recruited to construct the item pool of CAT-SD and to investigate the psychometric characteristics of CAT-SD. More specifically, firstly the analyses of unidimensionality, model fit, item fit, item discrimination parameter and differential item functioning (DIF) were conducted to construct a final item pool which meets the requirements of item response theory (IRT) measurement. In addition, a simulated CAT study with real response data of participants was performed to investigate the psychometric characteristics of CAT-SD, including reliability, validity and predictive utility (sensitivity and specificity). Results: The final unidimensional item bank of the CAT-SD not only had good item fit, high discrimination and no DIF; Moreover, it had acceptable reliability, validity and predictive utility. Conclusions: The CAT-SD could be used as an effective and accurate assessment tool for measuring individuals' severity of the sleep disorders and offers a bran-new perspective for screening of sleep disorders with psychological scales.
Increased expression of activating receptors and up-regulated function of natural killer cells in peripheral blood of patients with HBV-related hepatocellular carcinoma
Authors: Pei Yan-tao , Yuan Wen-fang , Zhang Qian , Yue Xin-yan , Chen Xiu-li , Jia Lin
Published: April 2020

Background

This study aimed to investigate and identify the characteristics of peripheral natural killer (NK) cells of hepatocellular carcinoma (HCC) patients who infected with hepatitis B virus.
Methods

Flow cytometry was utilized to identify the frequency and receptors of NK cells, in the meantime, to analyze the killing ability and cytotoxicity of NK cells of patients of which embraced 36 cases of HBV-associated HCC, 34 individuals who suffered in HBV-associated cirrhosis (LC) and 30 non-liver dysfunction healthy individuals as control (HC).
Results

Cell counts for NK and CD56dimNK were reduced in patients with HCC, however, there was no statistically significant. The count of CD56brightNK cells in the HCC subpopulation was remarkably higher than the subset of the HC (P < 0.05). The counts of activated receptors of NKG2D/p30 were elevated in patients with HCC, as well as the NKp44 and the NKp46. There was no statistically meaningful difference of inhibitory receptor expressions such as CD158a/b on peripheral NK cells of patients with HCC and LC and those with HC (P > 0.05). Following an IL-12 stimulation, the production of INF-γ/-α of patients with HCC was less than those produced by HC (P < 0.05). However, killing activity and cytotoxicity, as the primary responsibilities of the natural killer cells, were upregulated in HCC individuals. HBV associated individuals were found lower counts and capability to produce cytokines of natural killer cells. Nevertheless, the killing capacity and cytotoxicity of NK cells were stronger than those of the HC group. This may be associated with the increased activating receptors expression of NK cells.
Conclusions

This study demonstrated that the activating receptors expression and the cytotoxicity of NK cells in the blood were independent predictors of development in HCC patients, and the recovery of NKG2D+CD56dim NK cells could increase the prognostic value.
Clinical manifestations, CT features and outcome of 39 patients with COVID-19: retrospective case analysis
Authors: Lu Haohao , Zheng Chuansheng , Tong Qiaoxia , Tian Jin
Published: April 2020

1. BackgroundTo explore the manifestations and evolution of the pulmonary CT in COVID-19, and to analyze the causes and countermeasures of “Recurrent positive” in discharged patients.2. MethodsData of 39 patients with COVID-19 were collected. RT-PCR was positive at admission.From onset to discharge, pulmonary CT was performed regularly.During the treatment,Blood-RT,CRP and D-dimer were detected.3.ResultFrom the onset to 14 days, the lesions in pulmonary CT increased significantly.After treatment, pulmonary CT before discharge showed that some patients' lesions were completely absorbed, and some residual strip like lesions or ground glass opacity with reduced density.Two weeks after discharge, there were 2 patients with new ground glass opacity.There were 20 patients with D-dimer increased.4.ConclusionIn the early stage of COVID-19, the pulmonary CT has the characteristic manifestations, which is helpful for early diagnosis.In the middle stage, pulmonary lesions changed rapidly.In the recovery stage, some of the patients remained strip like lesions.It is necessary to pay attention to the possibility of pulmonary fibrosis after recovery.The discharge standard of COVID-19 needs to be more strict to avoid “Recurrent positive”,the discharged patients should continue to be observed.D-dimer was increased in some patients, it is safe to use heparin in anticoagulation without contraindications.
Implementation of Highly Challenging Balance Training for Parkinson’s disease in Clinical Practice: A Process Evaluation
Authors: Leavy Breiffni , Joseph Conran , Kwak Lydia , Franzén Erika
Published: April 2020

Background
Process evaluations provide contextual insight into the way in which interventions are delivered. This information is essential when designing strategies to implement programs into wider clinical practice. We performed a process evaluation of the HiBalance effectiveness trial investigating the effects of a 10-week of highly challenging and progressive balance training for mild-moderate Parkinson’s disease (PD). Study aims were to investigate i) the quality and quantity of intervention delivery and ii) barriers and facilitators for implementation.
Methods
Process outcomes included; Fidelity; Dose (delivered and received) Recruitment and Reach. Investigation of barriers and facilitators was guided by the Consolidated Framework for Implementation Research. Program delivery was assessed across four neurological rehabilitation sites during a two-year period. Data collection was mixed-methods in nature and quantitative and qualitative data were merged during the analysis phase.
Results
Thirteen program trainers delivered the intervention to 12 separate groups during 119 training sessions. Trainer fidelity to program core components was very high in 104/110 (94%) of the sessions. Participant responsiveness to the core components was generally high, although adherence to the home exercise program was low (50%). No significant context-specific differences were observed across sites in terms of fidelity, dose delivered/ received or participant characteristics, despite varying recruitment methods. Facilitators to program delivery were; PD-specificity, high training frequency and professional autonomy. Perceived barriers included; cognitive impairment, absent reactional balance among participants, as well a heterogeneous group in relation to balance capacity.
Conclusion
These findings provide corroborating evidence for outcome evaluation results and valuable information for the further adaptation and implementation of this program. Important lessons can also be learned for researchers and clinicians planning to implement challenging exercise training programs for people with mild-moderate PD.
Trial registration:
ClinicalTrials.gov, NCT02727478, registered 30 march − Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02727478
Social Determinants of Mental Health Care Systems: Intensive Community Based Care in The Veterans Health Administration
Authors: Bhalla Ish P , Stefanovics Elina A , Rosenheck Robert A
Published: April 2020

Background
Since deinstitutionalization in the 1950s-1970s, public mental health care has changed its focus from asylums to general hospitals, outpatient clinics and specialized community-based programs addressing both clinical and social determinants of mental health. Analysis of the place of community-based programs within a comprehensive health system such as the Veterans Health Administration (VHA) may illuminate the role of social forces in shaping contemporary public mental health systems.
Methods
National VHA administrative data were used to compare veterans who exclusively received outpatient clinic care to those receiving four types of specialized community-based services, addressing: 1) functional disabilities from severe mental illness (SMI), 2) justice system involvement, 3) homelessness, and 4) vocational rehabilitation. Bivariate comparisons and multinomial logistic regression analyses compared groups on demographics, diagnoses, service use, and psychiatric prescription fills.
Results
An hierarchical classification of 1,386,487 Veterans who received specialty mental health services from VHA in Fiscal Year 2012, showed 1,134,977 (81.8%) were seen exclusively in outpatient clinics; 27,931 (2.0%) received intensive SMI-related services; 42,985 (3.1%) criminal justice services; 160,273 (11.6%) specialized homelessness services; and 20,921 (1.5%) vocational services. Compared to those seen only in clinics, veterans in the four community treatment groups were more likely to be black, diagnosed with HIV and hepatitis, had more numerous substance use diagnoses and made more extensive use of mental health outpatient and inpatient care.
Conclusions
Almost one-fifth of VHA mental health patients receive specialized community-based services addressing, most prominently, major social determinants of health and multimorbid substance use disorders.
Triple therapy combined with ventriculoperitoneal shunts can improve neurological function and shorten hospitalization time in non-HIV cryptococcal meningitis patients with increased intracranial pressure
Authors: Li Min , Liu Jia , Deng Xuhui , Gan Qingzhou , Wang Yijie , Xu Xiaofeng , Jiang Ying , Peng Fuhua
Published: April 2020

Background: Raised intracranial pressure (ICP) and insufficient antifungal regimens, are the two main factors result to unsatisfactory outcomes in non-HIV cryptococcal meningitis (CM) patients. In this study, we try to discuss that whether triple therapy of amphotericin B (AmB), fluconazole (Flu), 5-flucytosine (5-FC) plus ventriculoperitoneal shunts (VPS) is superior to AmB, 5-FC, Flu plus intermittent lumbar puncture in induction therapy in non-HIV CM patients with increased ICP. Methods: We reviewed 66 clinical records from non-HIV CM patients with increased ICP. The demographic and clinical characteristics, BMRC staging, cerebrospinal ﬂuid proﬁles (CSF), brain magnetic resonance imaging, treatment, and outcomes of these individuals were retrospectively analyzed. All non-HIV CM patients with increased ICP (≥ 25 cmH2O) were divided into two groups, including 27 patients treated with triple antifungal agents and 39 patients treated with the same triple therapy plus VPS. Results: Triple therapy plus VPS group had a significantly higher frequency of satisfactory outcomes. More patients in triple therapy plus VPS group have CSF sterilization at 10 weeks follow-up. And patients in triple therapy plus VPS group present with lower CSF opening pressure, less CSF cryptococci count and CSF culture positive, and lower BMRC staging scores one week after VPS. Patients in triple therapy plus VPS group got the improvement in neurological function circumstances evaluated by comparing the BMRC staging before and after VPS. Triple therapy plus VPS group patients had shorter hospital stay. Conclusion: Triple antifungal agents combined with VPS can effectively reduce ICP, have faster rate of clearance of Cryptococcus, improve nerve function, shorten hospitalization time and get better outcomes in non-HIV CM patients with increased ICP. Our study indicated that triple therapy plus early VPS is maybe the optimal treatment for non-HIV CM patients with increased ICP.
OTX1 Exerts an Oncogenic Role and is Negatively Regulated by miR129-5p in Laryngeal Squamous Cell Carcinoma
Authors: Tu Xiu-Ping , Li Hao , Chen Liang-Si , Luo Xiao-Ning , Lu Zhong-Ming , Zhang Si-Yi , Chen Shao-Hua
Published: April 2020

Background Orthodenticle homeobox 1 (OTX1) is a transcription factor that plays important roles in various human cancers. However, the function of OTX1 in laryngeal squamous cell carcinoma (LSCC) is largely unknown. We aim to explore the roles of OTX1 in LSCC and possible molecular mechanism.Methods The expression levels of OTX1 were assessed in LSCC cell lines and tissue samples. We further examined the effect of OTX1 on LSCC progression. The upstream regulator of OTX1 was identified using computer algorithm and confirmed experimentally.Results OTX1 was highly expressed in 70.7% (70/99) of LSCC patient tissues. The OTX1 expression in LSCC was significantly correlated with lymph node metastasis. High OTX1 expression in LSCC patients was correlated with poor prognosis. Knockdown of OTX1 inhibits proliferation, colony formation, migration and invasion in LSCC cells. Knockdown of OTX1 inhibits tumor growth in a xenograft mouse model. Mechanistically, OTX1 might act as a direct target of miR-129-5p. OTX1 enhances tumorigenicity and tumor growth both in vitro and in vivo.Conclusions Our findings support that OTX1 is an oncogene in LSCC tumorigenesis and progression. Furthermore, OTX1as a direct target of miR-129-5p in LSCC cells.Taken together, OTX1 is a promising diagnostic and therapeutic marker for LSCC.
Developing a model of best practice for teams managing crisis in people with dementia: A consensus approach
Authors: Yates Jen , Stanyon Miriam , Challis David , Coleston-Shields Donna Maria , Dening Tom , Hoe Juanita , Jawahar Kaanthan , Lloyd-Evans Bryn , Moniz-Cook Esme , Poland Fiona , Streater Amy , Trigg Emma , Orrell Martin
Published: April 2020

Background: Teams delivering crisis resolution services for people with dementia and their carers provide short-term interventions to prevent admission to acute care settings. There is great variation in these services across the UK. This article reports on a consensus process undertaken to devise a Best Practice Model and evaluation Tool for use with teams managing crisis in dementia. Methods: The Best Practice Model and Tool were developed over a three stage process: (i) Evidence gathering and generation of candidate standards (systematic review and scoping survey, interviews and focus groups); (ii) Prioritisation and selection of standards (consultation groups, a consensus conference and modified Delphi process); (iii) Refining and operationalising standards (consultation group and field-testing). Results: 165 candidate standards arose from the evidence gathering stage; were refined and reduced to 90 through a consultation group exercise; and then reduced to 50 during the consensus conference and weighted using a modified Delphi process. Standards were then operationalised through a clinical consultation group and field-tested with 11 crisis teams and 5 non-crisis teams. Scores ranged from 48-92/100. The median score for the crisis teams was 74.5 (range 67-92), and the median score for non-crisis teams was 60 (range 48-72).Conclusions: With further psychometric testing, this Best Practice Model and Tool will be ideal for the planning, improvement and national benchmarking of teams managing dementia crises in the future.
Neuromonitoring with Intermittent Transcranial Doppler Sonography and Continuous Near Infrared Spectroscopy in Aortic Arch Surgery: An Observational Study
Authors: Thudium Marcus , Kornilov Evgeniya , Hilbert Tobias , Duerr Georg Daniel , Gestrich Christopher
Published: April 2020

Background

Aortic Arch repair for aortic dissection is still associated with a high mortality rate. Adequate means of neuromonitoring to guide cerebral hemodynamics, especially during selective anterior cerebral perfusion (SACP) are desirable. It is possible that this cannot be achieved by one monitoring modality alone. It was the objective of this study to investigate an easy multimodal monitoring setup consisting of EEG, near infrared spectroscopy (NIRS) and transcranial doppler sonography.
Methods

Patients with surgery for aortic dissection were included. In addition to standard hemodynamic monitoring, patients received continuous bilateral NIRS, processed EEG with bispectral index (BIS) and intermittent transcranial doppler sonography of the medial cerebral artery (MCA) with a standard B-mode ultrasound device. Doppler measurements were taken bilaterally before cardiopulmonary bypass (CPB), during CPB and during the selective brain perfusion phase in regular intervals
Results

Six patients with aortic dissection could be included. Two patients died, one in the operating room and one on ICU. Four patients survived without neurological deficit. Two, however, suffered from transient postoperative delirium. Multimodal monitoring led to change in CPB flow or cannula repositioning in 3 patients (50%). Left sided mean flow velocities of the MCA significantly decreased during selective brain perfusion (p = 0.028), as did BIS values (p = 0.028)
Conclusions

Multimodal monitoring consisting of BIS, NIRS and B-Mode transcranial sonography can have an impact on hemodynamic management in aortic arch operations. More research is needed to establish target parameters of cerebral perfusion.