Predictive performance of multi-model ensemble forecasts of COVID-19 across European nations

BackgroundShort-term forecasts of infectious disease burden can contribute to situational awareness and aid capacity planning. Based on best practice in other fields and recent insights in infectious disease epidemiology, one can maximise the predictive performance of such forecasts if multiple models are combined into an ensemble. Here we report on the performance of ensembles in predicting COVID-19 cases and deaths across Europe between 08 March 2021 and 07 March 2022. MethodsWe used open-source tools to develop a public European COVID-19 Forecast Hub. We invited groups globally to contribute weekly forecasts for COVID-19 cases and deaths reported from a standardised source over the next one to four weeks. Teams submitted forecasts from March 2021 using standardised quantiles of the predictive distribution. Each week we created an ensemble forecast, where each predictive quantile was calculated as the equally-weighted average (initially the mean and then from 26th July the median) of all individual models predictive quantiles. We measured the performance of each model using the relative Weighted Interval Score (WIS), comparing models forecast accuracy relative to all other models. We retrospectively explored alternative methods for ensemble forecasts, including weighted averages based on models past predictive performance. ResultsOver 52 weeks we collected and combined up to 28 forecast models for 32 countries. We found a weekly ensemble had a consistently strong performance across countries over time. Across all horizons and locations, the ensemble performed better on relative WIS than 84% of participating models forecasts of incident cases (with a total N=862), and 92% of participating models forecasts of deaths (N=746). Across a one to four week time horizon, ensemble performance declined with longer forecast periods when forecasting cases, but remained stable over four weeks for incident death forecasts. In every forecast across 32 countries, the ensemble outperformed most contributing models when forecasting either cases or deaths, frequently outperforming all of its individual component models. Among several choices of ensemble methods we found that the most influential and best choice was to use a median average of models instead of using the mean, regardless of methods of weighting component forecast models. ConclusionsOur results support the use of combining forecasts from individual models into an ensemble in order to improve predictive performance across epidemiological targets and populations during infectious disease epidemics. Our findings further suggest that median ensemble methods yield better predictive performance more than ones based on means. Our findings also highlight that forecast consumers should place more weight on incident death forecasts than incident case forecasts at forecast horizons greater than two weeks. Code and data availabilityAll data and code are publicly available on Github: covid19-forecast-hub-europe/euro-hub-ensemble.

THEMIS: A Framework for Cost-Benefit Analysis of COVID-19 Non-Pharmaceutical Interventions

Since December 2019, the world has been ravaged by the COVID-19 pandemic, with over 150 million confirmed cases and 3 million confirmed deaths worldwide. To combat the spread of COVID-19, governments have issued unprecedented non-pharmaceutical interventions (NPIs), ranging from mass gathering restrictions to complete lockdowns. Despite their proven effectiveness in reducing virus transmission, the policies often carry significant economic and humanitarian cost, ranging from unemployment to depression, PTSD, and anxiety. In this paper, we create a data-driven system dynamics framework, THEMIS, that allows us to compare the costs and benefits of a large class of NPIs in any geographical region across different cost dimensions. As a demonstration, we analyzed thousands of alternative policies across 5 countries (United States, Germany, Brazil, Singapore, Spain) and compared with the actual implemented policy. Our results show that moderate NPIs (such as restrictions on mass gatherings) usually produce the worst results, incurring significant cost while unable to sufficiently slow down the pandemic to prevent the virus from becoming endemic. Short but severe restrictions (complete lockdown for 4-5 weeks) generally produced the best results for developed countries, but only if the speed of reopening is slow enough to prevent a resurgence. Developing countries exhibited very different trade-off profiles from developed countries, and suggests that severe NPIs such as lockdowns might not be as suitable for developing countries in general.

Short-term forecasting of COVID-19 in Germany and Poland during the second wave - a preregistered study

We report insights from ten weeks of collaborative COVID-19 forecasting for Germany and Poland (12 October - 19 December 2020). The study period covers the onset of the second wave in both countries, with tightening non-pharmaceutical interventions (NPIs) and subsequently a decay (Poland) or plateau and renewed increase (Germany) in reported cases. Thirteen independent teams provided probabilistic real-time forecasts of COVID-19 cases and deaths. These were reported for lead times of one to four weeks, with evaluation focused on one- and two-week horizons, which are less affected by changing NPIs. Heterogeneity between forecasts was considerable both in terms of point predictions and forecast spread. Ensemble forecasts showed good relative performance, in particular in terms of coverage, but did not clearly dominate single-model predictions. The study was preregistered and will be followed up in future phases of the pandemic.

Optimizing Vaccine Allocation to Combat the COVID-19 Pandemic

The outbreak of COVID-19 has spurred extensive research worldwide to develop a vaccine. However, when a vaccine becomes available, limited production and distribution capabilities will likely lead to another challenge: who to prioritize for vaccination to mitigate the near-end impact of the pandemic? To tackle that question, this paper first expands a state-of-the-art epidemiological model, called DELPHI, to capture the effects of vaccinations and the variability in mortality rates across subpopulations. It then integrates this predictive model into a prescriptive model to optimize vaccine allocation, formulated as a bilinear, non-convex optimization model. To solve it, this paper proposes a coordinate descent algorithm that iterates between optimizing vaccine allocations and simulating the dynamics of the pandemic. We implement the model and algorithm using real-world data in the United States. All else equal, the optimized vaccine allocation prioritizes states with a large number of projected cases and sub-populations facing higher risks (e.g., older ones). Ultimately, the optimized vaccine allocation can reduce the death toll of the pandemic by an estimated 10-25%, or 10,000-20,000 deaths over a three-month period in the United States alone. Highlights- This paper formulates an optimization model for vaccine allocation in response to the COVID-19 pandemic. This model, referred to as DELPHI-V-OPT, integrates a predictive epidemiological model into a prescriptive model to support the allocation of vaccines across geographic regions (e.g., US states) and across risk classes (e.g., age groups). - This paper develops a scalable coordinate descent algorithm to solve the DELPHI-V-OPT model. The proposed algorithm converges effectively and in short computational times. Therefore, the proposed approach can be implemented efficiently, and allows extensive sensitivity analyses for scenario planning and policy analysis. - Computational results demonstrate that optimized vaccine allocation strategies can curb the death toll of the COVID-19 pandemic by an estimated at 10-25%, or 10,000-20,000 deaths over a three-month period in the United States alone. These results highlight the critical role of vaccine allocation to combat the COVID-19 pandemic, in addition to vaccine design and vaccine production.

Ensemble Forecasts of Coronavirus Disease 2019 (COVID-19) in the U.S.

BackgroundThe COVID-19 pandemic has driven demand for forecasts to guide policy and planning. Previous research has suggested that combining forecasts from multiple models into a single "ensemble" forecast can increase the robustness of forecasts. Here we evaluate the real-time application of an open, collaborative ensemble to forecast deaths attributable to COVID-19 in the U.S. MethodsBeginning on April 13, 2020, we collected and combined one- to four-week ahead forecasts of cumulative deaths for U.S. jurisdictions in standardized, probabilistic formats to generate real-time, publicly available ensemble forecasts. We evaluated the point prediction accuracy and calibration of these forecasts compared to reported deaths. ResultsAnalysis of 2,512 ensemble forecasts made April 27 to July 20 with outcomes observed in the weeks ending May 23 through July 25, 2020 revealed precise short-term forecasts, with accuracy deteriorating at longer prediction horizons of up to four weeks. At all prediction horizons, the prediction intervals were well calibrated with 92-96% of observations falling within the rounded 95% prediction intervals. ConclusionsThis analysis demonstrates that real-time, publicly available ensemble forecasts issued in April-July 2020 provided robust short-term predictions of reported COVID-19 deaths in the United States. With the ongoing need for forecasts of impacts and resource needs for the COVID-19 response, the results underscore the importance of combining multiple probabilistic models and assessing forecast skill at different prediction horizons. Careful development, assessment, and communication of ensemble forecasts can provide reliable insight to public health decision makers.

Evolved avian influenza virus (H7N9) isolated from human cases in a middle Yangtze River city in China, from February to April 2017.

Seven cases of avian influenza A H7N9 virus infection were reported from February to April 2017 in Changsha City. Viral genome was acquired by RT-PCR, aligned with other H7N9 viruses using Clustal W, and phylogenetic trees were constructed using the neighbor-joining method. Our results showed the representativeness of H7N9 virus infections in Middle Yangtze River City. The hemagglutinin segment contained Thr160Ala, Gly186Val and Gln226Leu substitutions, which are associated with increased binding affinity in humans. Phylogenetic analysis indicated that H7N9 viruses had an avian origin, and belonged to the Yangtze River Delta lineage. The proportion of PB2 Ala588Val substitutions in viruses revealed a significantly increasing in recent years, from 0.8 % (1 of 128 cases) to 84.9 % (275 of 324 cases). The data indicate that H7N9 viruses may be more capable of infecting mammals, even though they are still considered low pathogenic avian influenza virus. Hence, the prevalence and genetic evolution of this virus should be closely monitored to prevent more severe human pandemics.

The role of two-component regulatory system in ß-lactam antibiotics resistance.

The irrational use of antibiotics in agriculture and in the medical field has led to a variety of pathogenic microorganisms that produce drug resistance and even multidrug resistance. B-lactam is one of the most widely used antibiotics to treat infectious diseases. Resistance to ß-lactam resistance can be primarily due to the presence ß-lactamase, mutation of ß-lactam targets and overexpression of efflux pumps. Two-component regulatory systems are composed of histidine kinase and response regulator that regulate gene expression under different environmental conditions. In this review, we summarized the mechanisms by which ß-lactam resistance is developed and the role of the two-component regulatory system in ß-lactam resistance.

Side chain carbon losssalidroside analogues (N04) protects EAhy926 human endothelial cells against hypoxia injury by regulating the expressions of HIF-1α-related factors / 医学研究生学报

Objective Salidroside is a major active component of integripetal rhodiola herbal medicine, which has a significant activity against hypoxia and ischemia.This study was to investigate the effects of side chain carbon losssalidroside analogues (N04) on the expressions of HIF-1α-related factors in the hypoxia-injured EAhy926 human vascular endothelial cells.Methods EAhy926 human umbilical vein endothelial cells in the logarithmic growth phase were randomly divided into a normal control, a hypoxia model control, a salidroside, a high-dose N04, a medium-dose N04, and a low-dose N04 group.The hypoxia model was established by depriving the culture medium of sugar and serum and culturing the EAhy926 cells in an environment of 95%N2+5%CO2 for 2 hours, followed by intervention with salidroside at 1×10-6 mol/L and N04 at 1×10-6, 1×10-7, and 1×10-8 mol/L, respectively.Then, the activity of the cells was detected by MTT assay, their LDH activity examined by spectrophotometry, the mRNA expressions of HIF-1α and VEGF measured by RT-PCR, the protein expressions of HIF-1α, VEGF and pVHL determined by Western blot, and the activity of eNOS measured by ELISA.Results Compared with the normal control group, the hypoxia model cells showed significantly reduced activity (0.51±0.05 vs 0.27±0.02, P<0.01), an elevated LDH level ([6.65±1.43] vs [78.82±2.33] U/L, P<0.01), and decreased eNOS activity ([1.56±0.23] vs [1.16±0.20] U/100 mL, P<0.01).In comparison with the hypoxia model group, the cells treated with high-, medium-, and low-dose N04 exhibited remarkably increased activity (0.27±0.02 vs 0.0.42±0.05, 0.40±0.03 and 0.37±0.04, P<0.01), a reduced LDH level ([78.82±2.33] vs [53.05±3.90], [58.42±4.45] and [62.73±3.63] U/L, P<0.01), and increased eNOS activity ([1.16±0.20] vs [3.01±0.47], [2.60±0.26] and [2.32±0.29] U/100 mL, P<0.01).The activity of eNOS was also increased in the salidroside group ([2.32±0.29] U/100 mL, P<0.01).The cell activity in the high-and medium-dose N04 groups was markedly higher than that in the salidroside group (P<0.05), and so was the eNOS activity in the high-dose N04 group and the LDH level in the medium-and low-dose N04 groups (P<0.05).In comparison with the normal control group, the expressions of HIF-1α mRNA, HIF-1α protein and VEGF protein were significantly up-regulated in the hypoxia model group (P<0.01) while that of the pVHL protein markedly down-regulated (P<0.01).Compared with the hypoxia model group, the expressions of HIF-1α mRNA, HIF-1α protein and VEGF protein were remarkably reduced (P<0.05), while that of the pVHL protein markedly elevated (P<0.05).Both the expressions of VEGF mRNA and HIF-1α protein were significantly lower in the medium-and low-dose N04 groups than in the salidroside group (P<0.05).Conclusion N04 can protect vascular endothelial cells against hypoxia-induced injury by regulating the expression of HIF-1α-related factors and eNOS.

Gene regulatory network during the osteogenic differentiation process of dental follicle stem cells:A bioin-formatic analysis / 实用口腔医学杂志

Objective:To study the gene regulatory network during the osteogenic differentiation process of dental follicle stem cells (DFSCs)with bioinformatic analysis.Methods:The differentially expressed genes during the osteogenic diffrentiation process of DF-SCs were selected from the GEO Datasets.Then the relationship among the genes were analysed using DAVID and GeneMANIA data-base.Results:Numerous differentially expressed genes during the osteogenic differentiation process of DFSCs were obtained,289 genes with significance of different expression(P <0.05)were enriched into “cell differentiation”,“cell proliferation”,“skeletal sys-tem development”and “calcium signaling pathway”subgroups.ALPL,CTSK,TUFT1 ,TGFBR2,FHL2,ROR2,STC1 ,POSTN, ZBTB1 6,FRZB,PRELP and IGFBP5 were enriched into the “skeletal system development”subgroup.The 1 2 genes exhibited interac-tions,including co-expression,co-localization,genetic interaction and signal pathways.Conclusion:There is a complex molecular regulatory network among the differentially expressed genes during the osteogenic differentiation process of DFSCs.It is necessary to an-alyse the osteogenic differentiation process of DFSCs as a whole from WNT,TGFbeta,MAPK siganal pathyways,Homeobox transcrip-tion factors and osteogenic differentiation marker genes.

Pathogenesis of severe hand-food-mouth disease complicated with neurogenic pulmonary edema / 国际儿科学杂志

Severe hand-food-mouth disease can be accompanied by neurogenic pulmonary edema,whicn can rapidly lead to death.The pathogenesis of neurogenic pulmonary edema may be related to the comprehensive influences on neural factors,humoral factors and multiple bioactive substances after the central nervous system is damaged.It is of great impotance to investingate the pathogenesis of neurogenic pulmonary edema,which facilitates timely treatment and prevention of the complications.

Efficacy and safety of a combined oral contraceptive containing drospirenone 3 mg and ethinylestradiol 20 μg in the treatment of premenstrual dysphoric disorder：a randomized, double blind placebo-controlled study / 中华妇产科杂志

Objective To compare the efficacy and safety of a new low-dose oral contraceptive pill (YAZ) containing drospirenone 3 mg and ethinylestradiol 20 μg with placebo in reducing symptoms of premenstrual dysphoric disorder (PMDD). Methods This multicenter, double-blind, randomized clinical trial consisted of 2 run-in and 3 treatment cycles (84 days) with daily symptom charting; 187 women with symptoms of PMDD were randomized to either placebo group (n=94) or YAZ group (n=93), and assessed with daily record of severity of problems scale (DRSP) and clinical global impressions scale (CGI) before, during and after the treatments. Hormones were administered for 24 days, followed by 4 days of inactive pills. Results Compared with baseline level of DRSP, both groups got improvement after treatment; the YAZ group (median-28.7, range:-82.5 to 2.3) had greater improvement than that in the placebo group (median-23.7, range:-86.0 to 11.8), while there was not significant difference (P>0.05). The main adverse effects of YAZ included intermenstrual bleeding [13% (12/93) versus 3% (3/94)], menorrhagia [9% (8/93) versus 1%(1/94)], nausea [5%(5/93) versus 4%(4/94)] and skin rash [4%(4/93) versus 2%(2/94)]. Conclusions YAZ could improve symptoms of PMDD better than placebo, while without statistic significance in this study. The most common adverse effects are intermenstrual bleeding, menorrhagia, nausea and rash.

Rapid 2D-3D medical image registration based on CUDA / 生物医学工程学杂志

The medical image registration between preoperative three-dimensional (3D) scan data and intraoperative two-dimensional (2D) image is a key technology in the surgical navigation. Most previous methods need to generate 2D digitally reconstructed radiographs (DRR) images from the 3D scan volume data, then use conventional image similarity function for comparison. This procedure includes a large amount of calculation and is difficult to archive real-time processing. In this paper, with using geometric feature and image density mixed characteristics, we proposed a new similarity measure function for fast 2D-3D registration of preoperative CT and intraoperative X-ray images. This algorithm is easy to implement, and the calculation process is very short, while the resulting registration accuracy can meet the clinical use. In addition, the entire calculation process is very suitable for highly parallel numerical calculation by using the algorithm based on CUDA hardware acceleration to satisfy the requirement of real-time application in surgery.

An experimental study on inhibitory effects and mechanisms of N-butanol extract of Potentilla anserine L. against hypoxia-induced nitric oxide on hippocampus neurons of rats / 中国中西医结合急救杂志

Objective To study in vitro the inhibitory effects and mechanisms of N-butanol extract of Potentilla anserine L.(NP)against hypoxia-induced nitric oxide(NO)in hippocampus neuron of rats. Methods The models of hippocampus neurons hypoxia injury of Sprague-Dawley(SD)neonatal rats were cultured in vitro. The cultured hippocampus neurons were divided randomly into blank control group, hypoxia injury model group, nimodipine group(2 μmol/L)and NP high(250.0 mg/L),middle(62.5 mg/L),low(15.6 mg/L)dose groups. The activities of hippocampus neurons were examined by methyl thiazolyl tetrazolium(MTT)assay,and meanwhile their contents of nitrogen monoxidum(NO)were detected. Half quantity reverse transcription-polymerase chain reaction(RT-PCR)and Western blotting were used to detect neuronal nitric oxide synthetase(nNOS)mRNA and protein expression levels respectively in each group,immunocytochemistry stain was used to detect protein positive rate. Results Compared with blank control group,the activity of neuron〔absorbance(A)value〕was significantly decreased(0.0826±0.0095 vs. 0.3315±0.0105),content of NO(μmol/g:0.0509±0.0027 vs. 0.0291±0.0032), the expression levels of nNOS mRNA (0.1463±0.0081 vs. 0.0801±0.0058), the positive rate of nNOS〔(74.4238±3.9423)%vs.(28.3714±4.1361)%〕,the expression levels of nNOS protein(A value:1.9130±0.0471 vs. 0.5068±0.0368)were all significantly increased in the hypoxia injury model group(all P0.05). Conclusions NP can ameliorate the injury of rat hippocampus neurons induced by hypoxia in vitro. The possible mechanisms might be related to the effective inhibition of the synthesis of nNOS and NO excessive generation.

Neuroprotection of n-Butanol Extract from Roots of Potentilla anserina on Hypoxic Injury in Primary Hippocampal Neurons / 中草药·英文版

Objective To investigate the protective effect of n-butanol extract from the roots of Potentilla anserina (NP) on hypoxic hippocampal neurons in neonatal rats.Methods Primary cultured hippocampal neurons were pretreated with different concentration of NP (0.25,0.0625,and 0.0156 mg/mL) before incubation in a low oxygen (0.1％) environment for 4 h.Cell viability was evaluated by Trypan blue staining assay.Lactate dehydrogenase (LDH) released by neurons into the medium was measured.The activity of superoxide dismutase (SOD) in cell cytosol was determined using nitroblue tetrazolium.Morphological changes and mitochondrial function were observed by transmission electron microscopy.Results Hypoxic injury could decrease the cells viability of neuron,enhance LDH release (P ＜ 0.05),decrease SOD activity,and increase mitochondrial injury.Pretreatment with NP significantly increased cell viability,decreased LDH release (P ＜ 0.05),promoted SOD activity (P ＜ 0.05),and remarkably improved cellular ultra-microstructure compared with the model group.Conclusion NP could protect the primary hippocampal neurons from hypoxic injury by attenuating mitochondrial cell death.

Effect of n-butanol Extract from Potentilla anserina on Hypoxiainduced Calcium Overload and SERCA2 Expression of Rat Cardiomyocytes / 中草药·英文版

ObjectiveTo investigate the effect of n-butanol extract from Potentilla anserina (NP) intervention on hypoxia-induced Ca2+ overload and SERCA2 expression of rat cardiomyocytes.MethodsPrimary cultured myocardial cell from SD neonatal rat (1-3 d) was used in the establishment of hypoxia model.After hypoxia for 3 h,the Ca2+ concentration of myocardial cells was measured with fura-2/AM fluorescent probe,and the biochemical indicator intracellular Ca2+-ATPase was examined and the mRNA and its protective protein levels of the sarcoplasmic reticulum (SR) Ca2+-ATPases (SERCA2) were assayed with RT-PCR,Western-blotting,and immune-cytochemical staining in each group.ResultsThe results showed that NP decreased Ca2+ concentration,increased the activity of Ca2+-ATPase,and improved the mRNA and protein expression of SERCA2 in hypoxia-injured myocardial cells as compared with the model group.ConclusionThese results indicate that NP could attenuate the Ca2+ overload.The mechanism might be explained as that NP could elevate the SERCA2 level,increase the activity of myocardium in rats,and further enhance the capacity of SR Ca2+ re-uptake.

Study on protective effect of alcohol extract of Potentilla Anserinea against acute myocardial ischemia/reperfusion-induced myocardial apoptosis in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the protective effect of alcohol extract of Potentilla anserina against myocardial apoptosis induced by acute myocardial ischemia/reperfusion by arteria coronaria ligation and the effect on the expressions of Caspase-3 and Caspase-9 in myocardial apoptosis signal pathway.</p><p><b>METHOD</b>Male SD rats were randomly divided into the sham-operated group, the model group, the diltiazem group (30 mg x kg(-1)) and P. anserine alcohol extract intervention groups (0.9, 1.8, 3.6 g x kg(-1)). Rat acute myocardial ischemia/reperfusion model was established by ligating left anterior descending. Apoptosis of myocardial cells were detected by TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay). The expressions of Caspase-3 and Caspase-9 mRNA were assayed by reverse transcription-polymerase chain reaction (RT-PCR). Semi-quantitative analysis was made for the expressions of Caspase-3 and Caspase-9 by immunohistochemistry.</p><p><b>RESULT</b>According to TUNEL results, after I/R injury-induced myocardial apoptosis, the apoptotic index (AI) of model group was (31.5 +/- 3.6)%. All P. anserine alcohol extract intervention groups showed obvious inhibition of ischemia/reperfusion-induced myocardial apoptosis. In the model group, myocardial apoptosis caused increased expression of Caspase-3, Caspase-9 mRNA and proteins. After the administration of P. anserine alcohol extract, 1.8, 3.6 g x kg(-1) dose groups showed notable decrease in Caspase-9 mRNA (P < 0.05), while the 0.9 g x kg(-1) dose group showed no significant difference with the model group. Alcohol extract of P. anserina in all dosages showed inhibitory effect on the expression of Caspase-3 mRNA in myocardial cells compared with model group (P < 0.05). Immunohistochemistry showed that administration of all dosages of alcohol extract of P. anserina could significantly reduce Caspase-3 and Caspase-9 protein expressions after I/R injury (P < 0.05).</p><p><b>CONCLUSION</b>The administration with alcohol extract of P. anserina can protect the myocardial tissue from apoptosis after acute myocardial ischemia and reperfusion injury in rats and inhibit the expressions of Caspase-9 and Caspase-3 mRNA and proteins.</p>

Scutellarin benzyl ester partially secured the ischemic injury by its anti-apoptosis mechanism in cardiomyocytes of neonatal rats / 中西医结合学报

To investigate the protective effects of scutellarin benzyl ester on neonatal rats' cardiomyocytes injured by ischemia and its anti-apoptosis mechanism.

Investigation of pain during risperidone microsphere injection and at injection sites: A 12-week multi-center evaluation / 中国组织工程研究

BACKGROUND: As the first long-acting atypical antipsychotics, the therapeutic effect and safety of risperidone microsphere have been proved. However, it may lead to serious pain due to the deep intramuscular injection.OBJECTIVE: To evaluate the pain levels by 12-week injection of rispeddone microsphere and to explore the relationship among dose and times of injection of risperidone microsphere and pain levels.METHODS: A total of 57 patients diagnosed as schizoprenia by DSM-Ⅳ, aged 18-65 years, were selected and injected risperidone microsphere once every 2 weeks with doses of 25, 37.5 and 50 mg. The pain levels were evaluated using 100 mm visual analogue scale during injection and at the injected sites. The effects of injected dose, injected frequency and injected sites on the pain were analyzed by the nurse questionnaire.RESULTS AND CONCLUSION: The pain levels among the different doses groups had no notable differences (F=1.35,P> 0.05), which demonstrated that the pain had no relationship with injected dose. However, the pain level of injected sites had correlation to injected doses. The pain level of the 50 mg group was greater than that of the 37.5 and 25 mg groups. Accordingly,patients who treated by high dose of risperidone microsphere should be intervened by nurses.

Chemotherapy resistance induced by interleukin-6 in ovarian cancer cells and its signal transduction pathways / 中华妇产科杂志

Objective To study the mechanism of chemotherapy resistance caused by interleukin-6 (IL-6) in ovarian cancer cells and its related signal pathways. Methods Ovarian cancer cell lines A2780(IL-6 receptor positive, while non-IL-6-expressing and cisplatin/paclitaxel-responsive) and SKOV3 cell lines( overexpressing of IL-6 receptor and IL-6 and cisplatin/paclitaxel-resistant) were suitable models for this study. The effect of exogenous (a short period of treatment with recombination IL-6) and endogenous IL-6(by transfecting with plasmid encoding for sense IL-6 ) in A2780 cells or deleting of endogenous IL-6expression in SKOV3 cells (by transfecting with plasmid encoding for antisense IL-6) on the sensitivity to cisplatin and paclitaxel was investigated. Meanwhile, the mechanism of chemotherapy resistance caused by IL-6 in ovarian cancer cells and its related signal pathways were also analyzed. Results We found that both exogenous and endogenous IL-6 induce cisplatin and paclitaxel resistance in non-IL-6-expressing A2780 cells (the resistance multiple to cisplatin and paclitaxel was: exogenous, 6. 25 and 7.31; endogenous, 7. 13 -8. 34 and 7. 61 - 10. 70), while deleting of endogenous IL-6 expression in IL-6-overexpressing SKOV3 cells promotes its sensitivity to anticancer drugs ( the resistance multiple to cisplatin and paclitaxel was 0. 15 and 0. 10, 0. 10 and 0. 08). IL-6 significantly up-regulated the expression levels of mRNA and protein of drug resistance-associated genes, MDR1 and GST-π, and apoptosis-inhibiting genes, bcl-2, bcl-xL and XIAP in a dose-dependent manner in A2780 cells. In accordance with this finding, the mRNA and protein levels of MDR1 and GST-π enhanced in sense IL-6-transfected A2780 cells, and reduced in antisense IL-6-transfected SKOV3 cells compared with the corresponding parental and control vector-transfected cells, which had no difference. It was found that PD98059 [ mitogen-activated protein kinase-extracellular signalregulated kinase (MEK) inhibitor ] and wortmannin [ phosphatidylinositol 3-kinase (PI3K) inhibitor ]significantly antagonized IL-6-induced phosphorylation of extracellular signal-regulated kinase ( ERK ) and protein kinase B (Akt), respectively, and both of them blocked IL-6-induced cisplatin and paclitaxel resistance and the inhibitory effects of PD98059 and wortmannin were dependent on its concentration.Conclusions These data suggest that IL-6-induced chemoresistance may be associated with increase of both drug resistance-associated genes ( MDR1 and GST-π) and apoptosis-inhibiting genes ( bcl-2, bcl-xL and XIAP), and activation of MEK/ERK and PL3K/Akt. Therefore, modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer.

Protective effects of n-butanol extract of Potentilla anserina on acute myocardial ischemic injury in mice / 中西医结合学报

To investigate the protective effects of the n-butanol extract of Potentilla anserina L. (NP) on pituitrin-induced acute myocardial ischemic injury in mice.