Data driven analysis reveals prognostic genes and immunological targets in human sepsis-associated acute kidney injury.

BACKGROUND: The molecular mechanism of sepsis-associated acute kidney injury (SA-AKI) is unclear. We analyzed co-differentially expressed genes (co-DEGs) to elucidate the underlying mechanism and intervention targets of SA-AKI. METHODS: The microarray datasets GSE65682, GSE30718, and GSE174220 were downloaded from the Gene Expression Omnibus (GEO) database. We identified the co-DEGs and constructed a gene co-expression network to screen the hub genes. We analyzed immune correlations and disease correlations and performed functional annotation of the hub genes. We also performed single-cell and microenvironment analyses and investigated the enrichment pathways and the main transcription factors. Finally, we conducted a correlation analysis to evaluate the role of the hub genes. RESULTS: Interleukin 32 (IL32) was identified as the hub gene in SA-AKI, and the main enriched signaling pathways were associated with hemopoiesis, cellular response to cytokine stimulus, inflammatory response, and regulation of kidney development. Additionally, IL32 was significantly associated with mortality in SA-AKI patients. Monocytes, macrophages, T cells, and NK cells were closely related to IL32 and were involved in the immune microenvironment in SA-AKI patients. IL32 expression increased significantly in the kidney of septic mouse. Toll-like receptor 2 (TLR2) was significantly and negatively correlated with IL32. CONCLUSION: IL32 is the key gene involved in SA-AKI and is significantly associated with prognosis. TLR2 and relevant immune cells are closely related to key genes.

The nomogram to predict the occurrence of sepsis-associated encephalopathy in elderly patients in the intensive care units: A retrospective cohort study.

Background: Sepsis-associated encephalopathy (SAE) is a critical and common problem in elderly patients with sepsis, which is still short of efficient predictive tools. Therefore, this study aims to screen the risk factors and establish a useful predictive nomogram for SAE in elderly patients with sepsis in the intensive care unit (ICU). Patients and methods: Elderly patients (age ≥ 65 years) with sepsis were selected from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Data from demographics and laboratory examinations were collected on the first day of admission to the ICU. SAE was defined by two criteria in the presence of sepsis: ① a Glasgow Coma Scale (GCS) score of < 15 or ② delirium. Differences in demographics and laboratory tests were calculated between SAE and non-SAE groups. Participants were randomly divided into a training set and a validation set without replacement at a ratio of 6:4. A predictive nomogram was constructed in the training set by logistic regression analysis and then validated. The predictive capability of the nomogram was demonstrated by receiver operating characteristic (ROC) analysis and calibration curve analysis. Results: A total of 22,361 patients were selected, of which 2,809 patients (12.7%) died in the hospital and 8,290 patients (37.1%) had SAE. In-hospital mortality in the SAE group was higher than that in the non-SAE group (18.8 vs. 8.9%, p < 0.001). Based on the results of logistic regression analysis, a nomogram integrating age, Na+, Sequential Organ Failure Assessment (SOFA) score, heart rate, and body temperature were constructed. The area under the curve (AUC) of the nomogram was 80.2% in the training set and 80.9% in the validation set. Calibration curve analysis showed a good predictive capacity of the nomogram. Conclusion: SAE is an independent risk of in-hospital mortality in elderly patients in the intensive care unit. The nomogram has an excellent predictive capability of SAE and helps in clinical practice.

Hospitalization Costs of Respiratory Diseases Attributable to Temperature in Australia and Projections for Future Costs in the 2030s and 2050s under Climate Change.

This study aimed to estimate respiratory disease hospitalization costs attributable to ambient temperatures and to estimate the future hospitalization costs in Australia. The associations between daily hospitalization costs for respiratory diseases and temperatures in Sydney and Perth over the study period of 2010-2016 were analyzed using distributed non-linear lag models. Future hospitalization costs were estimated based on three predicted climate change scenarios-RCP2.6, RCP4.5 and RCP8.5. The estimated respiratory disease hospitalization costs attributable to ambient temperatures increased from 493.2 million Australian dollars (AUD) in the 2010s to more than AUD 700 million in 2050s in Sydney and from AUD 98.0 million to about AUD 150 million in Perth. The current cold attributable fraction in Sydney (23.7%) and Perth (11.2%) is estimated to decline by the middle of this century to (18.1-20.1%) and (5.1-6.6%), respectively, while the heat-attributable fraction for respiratory disease is expected to gradually increase from 2.6% up to 5.5% in Perth. Limitations of this study should be noted, such as lacking information on individual-level exposures, local air pollution levels, and other behavioral risks, which is common in such ecological studies. Nonetheless, this study found both cold and hot temperatures increased the overall hospitalization costs for respiratory diseases, although the attributable fractions varied. The largest contributor was cold temperatures. While respiratory disease hospitalization costs will increase in the future, climate change may result in a decrease in the cold attributable fraction and an increase in the heat attributable fraction, depending on the location.

Exposure to fine particulate matter (PM2.5) during landscape fire events and the risk of cardiorespiratory emergency department attendances: a time-series study in Perth, Western Australia.

BACKGROUND: Landscape fires (LFs) are the main source of elevated particulate matter (PM2.5) in Australian cities and towns. This study examined the associations between daily exposure to fine PM2.5 during LF events and daily emergency department attendances (EDA) for all causes, respiratory and cardiovascular outcomes. METHODS: Daily PM2.5 was estimated using a model that included PM2.5 measurements on the previous day, remotely sensed aerosols and fires, hand-drawn tracing of smoke plumes from satellite images, fire danger ratings and the atmosphere venting index. Daily PM2.5 was then categorised as high (≥99th percentile), medium (96th-98th percentile) and low (≤95th percentile). Daily EDA for all-cause and cardiorespiratory conditions were obtained from the Western Australian Emergency Department Data Collection. We used population-based cohort time-series multivariate regressions with 95% CIs to assess modelled daily PM2.5 and EDA associations from 2015 to 2017. We estimated the lag-specific associations and cumulative risk ratios (RR) at lags of 0-3 days, adjusted for sociodemographic factors, weather and time. RESULTS: All-cause EDA and overall cardiovascular presentations increased on all lagged days and up to 5% (RR 1.05, 95% CI 1.03 to 1.06) and 7% (RR 1.07, 95% CI 1.01 to 1.12), respectively, at the high level. High-level exposure was also associated with increased acute lower respiratory tract infections at 1 (RR 1.19, 95% CI 1.10 to 1.29) and 3 (RR 1.17, 95% CI 1.10 to 1.23) days lags and transient ischaemic attacks at 1 day (RR 1.25, 95% CI 1.02 to 1.53) and 2 (RR 1.20, 95% CI 1.01 to 1.42) days lag. CONCLUSIONS: Exposure to PM2.5 concentrations during LFs was associated with an increased risk of all-cause EDA, overall EDA cardiovascular diseases, acute respiratory tract infections and transient ischaemic attacks.

The procalcitonin-to-cortisol ratio is a potential prognostic predictor in sepsis with abdominal source: a retrospective observational study.

BACKGROUND: The aim of the study was to investigate the procalcitonin-to-cortisol ratio (P/C ratio) as a prognostic predictor among septic patients with abdominal source. METHODS: We retrospectively enrolled 132 post-surgery patients between 18 and 90 years old with sepsis of the abdominal source. On the second day of sepsis onset, cortisol, procalcitonin (PCT), Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, C-response protein (CRP), and other baseline characteristics were collected. In addition, the length of ICU stay, length of mechanical ventilation (MV) days, length of shock days, and 28-day mortality were also recorded. Univariate analysis was performed to screen potential risk factors. Stratified analysis was used to identify the interaction among the risk factors. Multivariate analysis was also utilized to demonstrate the relationship between the risk factors and mortality. The receiver operator characteristic (ROC) curve analysis was conducted to evaluate the risk factors. A restricted cubic spline (RCS) demonstrated the association between survival outcome and the P/C ratio variation. RESULTS: A total of twenty-nine patients died, and 103 patients survived within 28 d. There were significant differences in cortisol, PCT, P/C ratio, interleukin (IL)-6, SOFA, and APACHE II scores between the survival and non-survival groups. No significant interaction was observed in the stratified analysis. Logistic regression analysis revealed that P/C ratio (P=0.033) was significantly related to 28-day mortality. Based on ROC curves, P/C ratio (AUC=0.919) had a higher AUC value than cortisol or PCT. RCS analysis depicted a positive relationship between survival possibility and P/C ratio decrement. CONCLUSION: P/C ratio might be a potential prognostic predictor in septic patients with abdominal sources.

Comparison of Different Surgical Methods for Necrotizing Pancreatitis: A Meta-Analysis.

Purpose: To compare the effectiveness and safety of three methods of open necrosectomy, minimally invasive surgery and endoscopic step-up approach for necrotizing pancreatitis. Methods: We searched Pubmed, Embase, ScienceDirect, and CNKI full text database (CNKI) (to December 25, 2019). RCT, prospective cohort study (PCS), and retrospective cohort study (RCS) comparing the effectiveness and safety of any two of above-mentioned three methods were included. Results: There was no significant difference in major complications or death, and mortality between the minimally invasive surgery treatment group and the endoscopic step-up approach treatment group (RR = 1.66, 95%CI: 0.83-3.33, P = 0.15; RR = 1.05, 95%CI: 0.59-1.86, P = 0.87); the incidence rate of new-onset multiple organ failure, enterocutaneous fistula, pancreatic-cutaneous fistula, intra-abdominal bleeding, and endocrine pancreatic insufficiency in the endoscopic step-up approach treatment group was significantly lower than minimally invasive surgery group (RR = 2.65, 95%CI: 1.10-6.36, P = 0.03; RR = 6.63, 95%CI: 1.59-27.60, P = 0.009; RR = 7.73, 95%CI: 3.00-19.89, P < 0.0001; RR = 1.91, 95%CI: 1.13-3.24, P = 0.02; RR = 1.83, 95%CI: 1.9-3.16, P = 0.02); hospital stay in the endoscopic step-up approach group was significantly shorter than minimally invasive surgical treatment group (MD = 11.26, 95%CI: 5.46-17.05, P = 0.0001). The incidence of pancreatic-cutaneous fistula in the endoscopic escalation step therapy group was significantly lower than that in the open necrosectomy group (RR = 0.11, 95%CI: 0.02-0.58, P = 0.009). Conclusion: Compared with minimally invasive surgery and open necrosectomy, although endoscopic step-up approach cannot reduce the main complications or death and mortality of patients, it can significantly reduce the incidence of some serious complications, such as pancreatic-cutaneous fistula, enterocutaneous fistula, intra-abdominal bleeding, endocrine pancreatic insufficiency, and can significantly shorten the patient's hospital stay.

Endoscopic gastric fenestration of debriding pancreatic walled-off necrosis: A pilot study.

BACKGROUND: Endoscopic drainage of walled-off necrosis (WON) is still a challenge due to stent-associated problems. We explored endoscopic gastric fenestration (EGF) as an innovative alternative intervention. AIM: To assess the feasibility, efficacy and safety of EGF for WON. METHODS: Between March 2019 and March 2020, five patients with symptomatic WON in close contact with the stomach wall were treated by EGF. Endoscopic ultrasound (EUS) was used to select appropriate sites for gastric fenestration, which then proceeded layer by layer as in endoscopic submucosal dissection. Both the stomach muscularis propria and pseudocyst capsule were penetrated. Fenestrations were expanded up to 1.5-3 cm for drainage or subsequent necrosectomy. RESULTS: EGF failed in Case 1 due to nonadherence of WON to the gastric wall. EGF was successfully implemented in the other four cases by further refinement of fenestration site selection according to computed tomography, endoscopy and EUS features. The average procedure time for EGF was 124 min (EUS assessment, 32.3 min; initial fenestration, 28.8 min; expanded fenestration, 33 min), and tended to decrease as experience gradually increased. The diameter of the fenestration site was 1.5-3 cm, beyond the caliber of a lumen-apposing metal stent (LAMS), to ensure effective drainage or subsequent necrosectomy. Fenestration sites showed surprising capacity for postoperative self-healing within 1-3 wk. No EGF-related complications were seen. WON disappeared within 3 wk after EGF. In Case 3, another separate WON, treated by endoscopic LAMS drainage, recurred within 4 d after LAMS removal due to stent-related hemorrhage, and resolved slowly over almost 3 mo. No recurrences were observed in the five patients. CONCLUSION: EGF is an innovative and promising alternative intervention for WON adherent to the gastric wall. The challenge resides in the gauging of actual adherence and in selecting appropriate fenestration sites.

Auscultation-assisted bedside postpyloric placement of feeding tube in critically ill patients: a prospective, observational study.

BACKGROUND AND OBJECTIVES: To assess the efficacy and safety of auscultation-assisted bedside postpyloric feeding tube (ABPFT) placement in early enteral nutritional support for critically ill patients. METHODS AND STUDY DESIGN: A prospective observational study was conducted and 92 critically ill patients who met the inclusion criteria undergoing ABPFT placement after the intravenous injection of 10 mg of metoclopramide were included. Abdominal X-ray was performed to confirm the location of the catheter tip. End points investigated were the success rate of tube placement, rate of jejunal tube placement, duration of the procedure, length of insertion, and number of attempts. Operational-related adverse events or complications were also documented and evaluated. RESULTS: The total success rate of postpyloric feeding tube implantation was 97.8% (90/92), among which, 89.1% (82/92) of the tubes were placed proximal to the jejunum. The first-attempt success rate was 91.3% (84/92) and the mean attempt per individual patient was 1.11±0.38 times. The mean operation time was 28.6±17.7 minutes, and the mean insertion length of tube was 106±9.6 cm. A total of 27 adverse events occurred in 19.6% (18/92) patients and there was no serious adverse events or complications during the study period. CONCLUSIONS: Assistance by auscultation can significantly improve the success rate of nasal feeding tube placement. This simple, safe and fast approach is feasible for the application among health practitioners in the intensive care unit.

Joint effects of heatwaves and air quality on ambulance services for vulnerable populations in Perth, western Australia.

As the frequency, intensity, and duration of heatwaves increases, emergency health serviceutilization, including ambulance service, has correspondingly increased across the world. The negative effects of air pollution on health complicate these adverse health effects. This research work is the first known study to analyze the joint effects of heatwaves and air quality on the ambulance service in Western Australia (WA). The main objective is to investigate the potential joint effects of heatwaves and air quality on the ambulance service for vulnerable populations in the Perth metropolitan area. A time series design was used. Daily data on ambulance callouts, temperature and air pollutants (CO, SO2, NO2, O3, PM10 and PM2.5) were collected for the Perth metropolitan area, WA from 2006 to 2015. Poisson regression modeling was used to assess the association between heatwaves, air quality, and ambulance callouts. Risk assessments on age, gender, socio-economic status (SES), and joint effects between heatwaves and air quality on ambulance callouts were conducted. The ambulance callout rate was higher during heatwave days (14.20/100,000/day) compared to non-heatwave days (13.95/100,000/day) with a rate ratio of 1.017 (95% confidence interval 1.012, 1.023). The ambulance callout rate was higher in males, people over 60 years old, people with low SES, and those living in coastal areas during period of heatwaves. Exposure to CO, SO2, O3 and PM2.5 increased risk on ambulance callouts and exposure to NO2 showed joint effect with heatwave and increased risk of ambulance callouts by 3% after adjustment of all other risk factors. Ambulance callouts are an important indicator for evaluating heatwave-related emergency morbidity in WA. As the median concentrations of air pollutants in WA were lower than the Australian National Standards, the interactive effects of heatwaves and air quality on ambulance service need to be further examined, especially when air pollutants exceed the standards.

Joint effect of heatwaves and air quality on emergency department attendances for vulnerable population in Perth, Western Australia, 2006 to 2015.

BACKGROUND: As global warming and the frequency and intensity of heatwaves increases, health service utilization, including emergency department attendances (EDA) have correspondingly increased across the world. The impact of air quality on health adds to the complexity of the effects. Potential joint effects between heatwaves and air quality on EDA have been rarely reported in the literature, prompting this study. OBJECTIVES: To investigate the potential joint effect of heatwaves and air quality on the EDA for vulnerable populations in the Perth metropolitan area, Western Australia. METHODS: A time series design was used. Daily data on EDA, heatwaves (excess heat factor>0) and air pollutants (CO, SO2, NO2, O3, PM10 and PM2.5) were collected for Perth, Western Australia from 2006 to 2015. Poisson regression modelling was used to assess the associations between heatwaves, air quality, and EDA. Risk assessments on age, gender, Aboriginality, socio-economic status (SES), and joint effect between heatwaves and air quality on EDA were conducted. RESULTS: The EDA rate was higher in heatwave days (77.86/100,000/day) compared with non-heatwave days (73.90/100,000/day) with rate ratio of 1.053 (95% confidence interval 1.048, 1.058). The EDA rate was higher in males, people older than 60 years or younger than 15 years, Aboriginal people, and people with low SES. Exposure to CO, SO2, O3 and PM2.5 increased risk on EDA and exposure to PM2.5 showed joint effect with heatwave and increased risk of EDA by 6.6% after adjustment of all other risk factors. CONCLUSIONS: EDA is an important indicator to evaluate heatwave related morbidity for emergency medical service as EDA rate increased during heatwaves with relative high concentrations of air pollutants. As all air pollutants measured in the study were lower than the Australian National Standards, the joint effect of heatwaves and air quality needs to be further examined when it exceeds the standards.

The Impact of Alcohol Restriction on Hospital and Emergency Department Service Utilizations in Two Remote Towns in the Kimberley Region of Western Australia.

Background: In a remote region of Western Australia, Kimberley, residents have nearly twice the State average per capita consumption of alcohol, four and a half times the level of alcohol-related hospitalizations and nearly three times the level of alcohol-related deaths. This study aimed to evaluate the long term effects of alcohol sale restrictions on health service utilization in two remote towns in Kimberley. Methods: Sale of high strength packaged alcohol was restricted in Fitzroy Crossing and Halls Creek since October 2007 and May 2009, respectively. Alcohol-related Emergency Department (ED) attendances and hospitalizations utilized by local residents before and after the intervention between 2003 and 2013 was compared by using yearly rates (/1,000 person-years) and interrupted time series analysis with Autoregressive Integrated Moving Average (ARIMA) modeling. The Western Australia specific aetiological fractions (AAFs) were applied to hospital inpatient data for estimation of the proportion of hospital separations attributable to alcohol. Results: In Fitzroy Crossing, there was a significant reduction of over 40% on rates (/1,000 person-years) of alcohol-related acute hospitalizations (54.2 [95% CI: 53.8-54.7] vs. 31.7 [31.4-32.1]) and ED attendances (534.1[532.8-535.5] vs. 294.5 [293.5-295.4]). In Halls Creek, there was a significant reduction of over 50% on rates (/1,000 person-years) of alcohol- related acute hospitalizations (17.7 [17.6-17.8] vs. 8.0 [7.9-8.1]) and ED attendance (248.4 [247.9-248.9] vs. 111.1[110.8-111.5]). Domestic violence and injury related hospitalization rates were also reduced by over 20% in both towns. Conclusions: The total restriction of selling high strength alcohol through a community driven process has shown to be effective in reducing alcohol-related health service utilization in post-intervention period. Continue monitoring is required to address new emerging issues. Future research on health service utilization related to alcohol by using interrupted time series analysis incorporating ARIMA modeling and applying AAFs are recommended for evaluating alcohol-related interventions.

Cultural and linguistic diversity increases the likelihood of compulsory community treatment.

BACKGROUND: People from culturally and linguistically diverse (CALD) backgrounds are over-represented in compulsory admissions to hospital but little is known about whether this also applies to community treatment orders (CTOs). AIMS: We investigated any differences between Australian- and foreign-born patients in the likelihood of CTO placement using state-wide databases from Western Australia. METHODS: Cases and controls from administrative health data were matched on age, sex, diagnosis and time of hospital discharge (the index date). Logistic regression was then used to identify potential predictors of a CTO. We also assessed if any differences in CTO placement between Australian- and foreign-born patients had effects on bed-days or community contacts in the subsequent year. RESULTS: We identified 2958 CTO cases and controls from November 1997 to December 2008 (total n=5916). Of these, 74% had schizophrenia or other non-affective psychoses. Patients who were born in New Zealand, the United Kingdom or Ireland had very similar rates of CTO placement compared to those who were Australian-born. By contrast, there was a gradient of increasing risk of CTO placement for people born in Continental Europe (ORadj=1.36; 95% CI=1.07-1.71, p=0.01) and then the Rest of the World (ORadj=1.61; 95% CI=1.31-1.97, p<0.001). However, there was no evidence of additional benefit in terms of health service use in the following year. CONCLUSIONS: In common with other coercive treatments, people from culturally and linguistically diverse (CALD) backgrounds are more likely to be placed on CTOs. Further research is needed to establish if this is for similar reasons.

Outcome and risk factors associated with extent of central nervous system injury due to exertional heat stroke.

To explore the relationship between the extent of central nervous system (CNS) injury and patient outcomes meanwhile research the potential risk factors associated with neurologic sequelae. In this retrospective cohort study, we analyzed data from 117 consecutive patients (86 survivors, 31 nonsurvivors) with exertional heat stroke (EHS) who had been admitted to intensive care unit (ICU) at 48 Chinese hospitals between April 2003 and July 2015. Extent of CNS injury was dichotomized according to Glasgow coma scale (GCS) score (severe 3-8, not severe 9-15). We then assessed differences in hospital mortality based on the extent of CNS injury by comparing 90-day survival time between the patient groups. Exploring the risk factors of neurologic sequelae. The primary outcomewas the 90-day survival ratewhich differed between the 2 groups (P = .023). The incidence of neurologic sequelae was 24.4%. For its risk factors, duration of recurrent hyperthermia (OR = 1.73, 95% CI: 1.20-2.49, P = .003), duration of CNS injury (OR = 1.39, 95% CI: 1.04-1.85, P = .025), and low GCS in the first 24 hours after admission (OR = 2.39, 95% CI: 1.11-5.15, P = .025) were selected by multivariable logistic regression. Cooling effect was eliminated as a factor (OR = 2641.27, 95% CI 0.40-1.73_107, P = .079). Significant differences in 90-day survival ratewere observed based on the extent of CNS injury in patients with EHS, and incidence was 24.4% for neurologic sequelae. Duration of recurrent hyperthermia, duration of CNS injury, and low GCS score in the first 24 hours following admission may be independent risk factors of neurologic sequelae. Cooling effect should be validated in the further studies.

Vulvar Cancer in China: Epidemiological Features and Risk Analysis.

Objective: Describe for the first time the clinical, epidemiological features of vulvar cancer in southwest China. Identify risk factors and provide reference for the prevention of vulvar cancer. Method: We retrospectively analyzed 885 patients admitted to the West China Second University Hospital for vulvar diseases between 2006 and 2016. Vulvar cancer patients with previously diagnosed vulvar nonneoplastic epithelial disorders (n=132) were analyzed and compared to those without prior history of vulvar nonneoplastic epithelial disorders (n=219). Comparisons were also made among cancer patients and non-cancer patients with vulvar nonneoplastic epithelial disorders (n=288) and vulvar squamous intraepithelial lesions (n=246). The risk factors leading to vulvar cancer for the patients with vulvar nonneoplastic epithelial disorder were analyzed by univariate analysis. Furthermore, differences of the epidemiological features of vulvar nonneoplastic epithelial disorders, vulvar squamous intraepithelial lesion and vulvar cancer were identified. Results: According to the univariate analysis, age, first coital age, educational level, smoking, history of vaginal atrophy, HPV infection, lesion sites of the upper vulva and histo-pathological changes are strongly positively correlated with vulvar cancer. By comparing the features of vulvar cancer with those of the vulvar nonneoplastic epithelial disorder and vulvar squamous intraepithelial lesion, we found that on average patients with vulvar cancer had the highest age (ranged from 50 to 59), the lowest first coital age and the highest number of pregnancies and births. The incidences of vulvar nonneoplastic epithelial disorder and vulvar cancer were 1/1000 and 2.5/100,000 respectively with an increasing trend during last 10 years. Conclusion: Age, first coital age, educational level, smoking, atrophic vagina history, HPV infection, lesion sites of the upper vulva and histo-pathological changes are the risk factors that lead to vulvar cancer. Vulvar nonneoplastic epithelial disorder, vulvar squamous intraepithelial lesion and vulvar cancer each has distinct epidemiological features. Prompt surgical intervention and subsequent treatments are the key to a better outcome of vulvar cancer.

[Bacterial endotoxin-induced endothelial cell injury and calcium overload associated with Toll-like receptor and calcium signal].

OBJECTIVE: To explore the effect of toll-like receptor 4 (TLR4), myeloid differentiation protein-2 (MD2), and stromal interaction molecular 1 (STIM1) for regulating human vascular endothelial calcium overload injury and inflammatory reaction induced by bacterial endotoxin (LPS). METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in Dulbecco's modification of Eagle's medium (DMEM). (1) The levels of TLR4, MD2 and nuclear factor-κB (NF-κB) were detected by reverse transcriotion-polymerase chain reaction (RT-PCR) before and 0.5, 1, 6, 12, 24 hours after LPS stimulation. (2) Intracellular calcium peak level was detected by confocal following probe fluo-3 AM loading in HUVEC cells induced with LPS and transfected by psiSTIM or psiTLR. (3) MD2, STIM1 or NF-κB protein level was detected by immunoprecipitation (IP) and immuno-blotting in HUVEC cells which were transfected by TLR4 inhibited expression (psiTLR) for 12 hours and followed by LPS stimulation for 6 hours. (4) HUVEC cells were randomly divided into 6 groups: control group, LPS group, PDTC 0.1 mg/L group, PDTC 1 mg/L group, psiTLR 1 h group and psiTLR 12 h group. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA) in supernatant. The mRNA levels of STIM1 and NF-κB were detected by RT-PCR. RESULTS: (1) The mRNA levels of TLR4, MD2, and NF-κB gradually increased after LPS induction and peaked at 6 hours (2-ΔΔCt: 23.52±2.88, 17.43±3.43, 18.13±2.99, respectively), which were statistically significant before the stimulation with LPS (2-ΔΔCt: 7.02±2.81, 5.19±3.22, 8.11±1.42, all P < 0.05). (2) Extracellular calcium influx in LPS group was increased significantly higher than control group (nmol/L: 108.13±22.33 vs. 41.57±13.19, P < 0.01). Extracellular calcium influx in psiSTIM+LPS group (nmol/L: 62.61±14.12 vs. 108.13±22.33, P < 0.05) and psiTLR+LPS group (nmol/L: 50.78±8.05 vs. 109.43±20.21, P < 0.01) were both suppressed as compared with LPS group. While extracellular calcium peak level in psiTLR+psiSTIM+LPS group further decreased (nmol/L: 39.31±6.42 vs. 109.43±20.21, P < 0.01). (3) MD2 protein but not STIM1 or NF-κB can be detected in anti-TLR4 precipitates in control (ctrl-) by immunoprecipitation. MD2 protein level increased in anti-TLR4 precipitates in LPS group (ctrl+) and was suppressed in TLR4 inhibiting group (psiTLR). (4) The levels of TNF-α in PDTC 1 mg/L group were significantly lower than those of LPS group (ng/L: 0.60±0.24 vs. 1.77±0.66, P < 0.01). The levels of IL-6 in PDTC 0.1 mg/L, 1 mg/L group and psiTLR 12 h group decreased significantly lower than that of LPS group (ng/L: 232.10±63.54, 134.32±37.23, 284.23±56.14 vs. 510.22±89.23, all P < 0.05). Compared to LPS group, the mRNA levels of NF-κB and STIM1 were obviously inhibited in PDTC 1 mg/L group and psiTLR 12 h group [NF-κB mRNA (2-ΔΔCt): 17.22±2.35, 13.24±3.54 vs. 30.16±2.06; STIM1 mRNA (2-ΔΔCt): 12.57±2.43, 12.21±2.46 vs. 25.12±2.02, all P < 0.05]. CONCLUSIONS: TLR4, MD2, NF-κB signal and SOC calcium channel STIM1 mediate LPS induced-calcium influx and inflammatory mediators level in HUVEC cells. Extracellular calcium overload and inflammatory response by endotoxin induction can be effectively inhibited by down-regulation of TLR4, NF-κB and/or STIM1.

Variation in Population Vulnerability to Heat Wave in Western Australia.

Heat waves (HWs) have killed more people in Australia than all other natural hazards combined. Climate change is expected to increase the frequency, duration, and intensity of HWs and leads to a doubling of heat-related deaths over the next 40 years. Despite being a significant public health issue, HWs do not attract the same level of attention from researchers, policy makers, and emergency management agencies compared to other natural hazards. The purpose of the study was to identify risk factors that might lead to population vulnerability to HW in Western Australia (WA). HW vulnerability and resilience among the population of the state of WA were investigated by using time series analysis. The health impacts of HWs were assessed by comparing the associations between hospital emergency department (ED) presentations, hospital admissions and mortality data, and intensities of HW. Risk factors including age, gender, socioeconomic status (SES), remoteness, and geographical locations were examined to determine whether certain population groups were more at risk of adverse health impacts due to extreme heat. We found that hospital admissions due to heat-related conditions and kidney diseases, and overall ED attendances, were sensitive indicators of HW. Children aged 14 years or less and those aged 60 years or over were identified as the most vulnerable populations to HWs as shown in ED attendance data. Females had more ED attendances and hospital admissions due to kidney diseases; while males had more heat-related hospital admissions than females. There were significant dose-response relationships between HW intensity and SES, remoteness, and health service usage. The more disadvantaged and remotely located the population, the higher the health service usage during HWs. Our study also found that some population groups and locations were resilient to extreme heat. We produced a mapping tool, which indicated geographic areas throughout WA with various vulnerability and resilience levels to HW. The findings from this study will allow local government, community service organizations, and agencies in health, housing, and education to better identify and understand the degree of vulnerability to HW throughout the state, better target preparatory strategies, and allocate limited resources to those most in need.

Discrete element modeling of a mining-induced rock slide.

Slopes are subjected to stress redistributions during underground mining activities, and this may eventually cause deformation or landslide. This paper takes Madaling landslide in Guizhou Province, China as a case study to investigate the failure mechanism and its run-out behaviours by using discrete element method. Previous qualitative analysis indicated that the slope experienced four stages of failure mechanisms: (1) development of tension cracks, (2) development of stepped-like creep cracks, (3) development of potential rupture surfaces, and (4) occurrence of the landslide. PFC2D program was employed to model the pre-failure deformation characteristics in order to verify the failure mechanisms quantitatively. Subsequently, the run-out behaviours of the landslide were analyzed by PFC3D program. The results indicated that the movement could be summarized into four stages: acceleration stage, constant movement stage, rapid movement stage, and deceleration and deposition stage.

Inhibition of nuclear factor-kappa B enhances the tumor growth of ovarian cancer cell line derived from a low-grade papillary serous carcinoma in p53-independent pathway.

BACKGROUND: NF-kB can function as an oncogene or tumor suppressor depending on cancer types. The role of NF-kB in low-grade serous ovarian cancer, however, has never been tested. We sought to elucidate the function of NF-kB in the low-grade serous ovarian cancer. METHODS: The ovarian cancer cell line, HOC-7, derived from a low-grade papillary serous carcinoma. Introduction of a dominant negative mutant, IkBαM, which resulted in decrease of NF-kB function in ovarian cancer cell lines. The transcription ability, tumorigenesis, cell proliferation and apoptosis were observed in derivative cell lines in comparison with parental cells. RESULTS: Western blot analysis indicated increased expression of the anti-apoptotic proteins Bcl-xL and reduced expression of the pro-apoptotic proteins Bax, Bad, and Bid in HOC-7/IĸBαM cell. Further investigations validate this conclusion in KRAS wildtype cell line SKOV3. Interesting, NF-kB can exert its pro-apoptotic effect by activating mitogen-activated protein kinase (MAPK) phosphorylation in SKOV3 ovarian cancer cell, whereas opposite changes detected in p-MEK in HOC-7 ovarian cancer cell, the same as some chemoresistant ovarian cancer cell lines. In vivo animal assay performed on BALB/athymic mice showed that injection of HOC-7 induced subcutaneous tumor growth, which was completely regressed within 7 weeks. In comparison, HOC-7/IĸBαM cells caused sustained tumor growth and abrogated tumor regression, suggesting that knock-down of NF-kB by IĸBαM promoted sustained tumor growth and delayed tumor regression in HOC-7 cells. CONCLUSION: Our results demonstrated that NF-kB may function as a tumor suppressor by facilitating regression of low grade ovarian serous carcinoma through activating pro-apoptotic pathways.

Medium-term outcomes after pulmonary valve replacement with the Freestyle valve for congenital heart disease: a case series.

OBJECTIVES: The Freestyle valve may be used for pulmonary valve replacement (PVR). Whether its stentless design and anticalcification treatment improve durability relative to alternative bioprostheses, however, is unknown and long-term data are lacking. METHODS: We performed a retrospective review of all Freestyle PVRs performed by a single surgeon in two institutions. All patients were contacted for follow-up to establish survival, New York Heart Association class and reintervention. Up to date, echocardiography was obtained to assess valve function. Perioperative factors associated with structural valve dysfunction (SVD) were assessed using Cox regression. RESULTS: Between 2000 and 2014, PVR with a Freestyle valve was performed in 114 patients with congenital heart disease. There were 70 males and 44 females. The median age was 21 years (interquartile range 11-35 years). The median clinical and echocardiographic follow-up was 62 months (interquartile range 35-115 months, n = 110) and 58 months (interquartile range 30-93 months, n = 107), respectively. Follow-up was complete for 107 of 114 patients (94%). The survival rate was 95% at 5 years and 91% at 10 years. The rate of freedom from SVD at 5 years was 82%, and at 10 years was 61%. The reintervention-free survival rate was 85% at 5 years, and 71% at 10 years. CONCLUSION: The Freestyle valve in the pulmonary position in a congenital population is associated with low medium-term incidences of SVD and reintervention. It performs equally well to the homograft when a conduit is required and can be considered a valid alternative to stented bioprostheses when PVR alone is required.