Summary Background On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor ...clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9. Methods We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome. Findings All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment. Interpretation Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning. Funding National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China.
Abstract Background This double-blind, randomized controlled trial aimed to investigate inhaled budesonide and oral dexamethasone compared with placebo for their prophylactic efficacy against acute ...mountain sickness after acute high-altitude exposure. Methods There were 138 healthy young male lowland residents recruited and randomly assigned to receive inhaled budesonide (200 μg, twice a day bid), oral dexamethasone (4 mg, bid), or placebo (46 in each group). They traveled to 3900 m altitude from 400 m by car. Medication started 1 day before high-altitude exposure and continued until the third day of exposure. Primary outcome measure was the incidence of acute mountain sickness after exposure. Results One hundred twenty-four subjects completed the study (42, 39, and 43 in the budesonide, dexamethasone, and placebo groups, respectively). Demographic characteristics were comparable among the 3 groups. After high-altitude exposure, significantly fewer participants in the budesonide (23.81%) and dexamethasone (30.77%) groups developed acute mountain sickness compared with participants receiving placebo (60.46%) ( P = .0006 and P = .0071, respectively). Both the budesonide and dexamethasone groups had lower heart rate and higher pulse oxygen saturation (SpO2 ) than the placebo group at altitude. Only the budesonide group demonstrated less deterioration in forced vital capacity and sleep quality than the placebo group. Four subjects in the dexamethasone group reported adverse reactions. Conclusions Both inhaled budesonide (200 μg, bid) and oral dexamethasone (4 mg, bid) were effective for the prevention of acute mountain sickness, especially its severe form, compared with placebo. Budesonide caused fewer adverse reactions than dexamethasone.
Summary PIK3CA gene mutations are found in numerous cancers but correlate differently with prognosis. Although the frequency of PIK3CA gene mutation in esophageal squamous cell carcinoma (ESCC) has ...been previously studied, a prognostic analysis has not been reported. Ninety-six surgically resected ESCC tissues were collected from Chinese patients and DNA was extracted. Gene mutations in PIK3CA (exons 9 and 20), EGFR (exons 18, 19, 20 and 21), KRAS (exons 2 and 3), and BRAF (exons 11 and 15) were screened using mutant-enriched liquid chip technology. PIK3CA gene mutations were identified in 12 of 96 ESCC cases (12.5%). No mutations were identified in EGFR , KRAS or BRAF genes in this study. Correlations between clinicopathological features and PIK3CA mutation status were analyzed and finally, patient survival information was used to determine the prognostic significance of PIK3CA mutation. Interestingly, the frequency of PIK3CA mutation was higher in female ESCC patients (31.3%, 5/16) than in males (8.8%, 7/80), and higher in patients with non–lymph node metastasis (19.6%, 10/51, P = .013) than in patients with lymph node metastasis (4.4%, 2/45, P = .025). Furthermore, patients with PIK3CA -mutated tumors showed a trend towards favorable overall survival ( P = .085) but not disease-free survival ( P = .238), suggesting that PIK3CA gene status may be a favorable predictive marker in ESCC patients.
Abstract Background: Despite substantial trial evidence that demonstrates the effectiveness of pharmacologic treatment for reducing blood pressure (BP) and cardiovascular events, many patients are ...nonadherent to their hypertension treatment. Objectives: The purpose of this study was to examine patient adherence to hypertension medications using pharmacy data (ie, outpatient, inpatient, and mail-order prescriptions) and the association between adherence measures and systolic BP (SBP) control. Methods: The study included Medicare+Choice beneficiaries (aged ⩾ 65 years) who were continuously enrolled in an integrated delivery system in 2003, and who had documented hypertension and received ⩾1 hypertension drug in 2002. This analysis used automated clinical data and the 2000 US Census. We estimated 2 measures of hypertension treatment adherence in 2003 using the supply of dispensed drugs in days (proportion of days covered ⩾80%): (1) adherence to ⩾1 hypertension drug; and (2) adherence to the full hypertension treatment regimen. We defined the regimen by the number of hypertension drugs used concurrently in 2002. We assessed adherence annually and during the 30, 60, and 90 days before an SBP measurement. Logistic regression was used to examine the association between adherence and the number of drugs in the hypertension regimen, as well as the association between adherence and elevated SBP (⩾140 mm Hg). We adjusted for patient sociodemographic and clinical characteristics. Results: The majority (52.8%) of patients had multidrug hypertension regimens. In 2003, 87.3% of subjects were adherent to ⩾ 1 hypertension drug; 72.1% were adherent to their full regimen. After adjustment, we found that subjects with multidrug regimens were significantly more likely to be adherent to ⩾ 1 drug and significantly less likely to be adherent to their full regimen, compared with patients on a 1-drug regimen. Over one-third of subjects had elevated SBP in 2003. Both adherence measures were associated with lower odds of having elevated SBP (eg, odds ratio = 0.87 95% CI, 0.84–0.89 for adherence to the full regimen). For subjects with multidrug regimens, partial adherence and nonadherence to the regimen were associated with higher odds of having elevated SBP. Conclusions: Adherence measures using automated pharmacy data can identify patients who are nonadherent to their drug treatment regimen and who are more likely to have inadequately controlled BP. Adherence measures that account for the number of drugs in a patients' drug regimen might help identify additional patients at risk for poor BP outcomes due to partial treatment adherence.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more ...than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus–host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.
We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA.
SARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004).
As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.
May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.
Transforming growth factor-beta (TGF-β) plays a significant role in the pathogenesis of the intimal hyperplasia of transplant arteriosclerosis (TA). The aim of this study was to evaluate the efficacy ...of an oral inhibitor of TGF-β receptor I kinase (SD-208) on the development of TA.
BALB/c (H-2(d)) donor aortas were transplanted into C57BL/6 (H-2(b)) recipients, and the mice then received different doses (40 or 60 mg/kg) of SD-208 or control vehicle by daily gavage for 8 weeks. The grafts were analyzed by histology and morphometry at 1, 2, 4, 6 and 8 weeks after transplantation. The effects of TGF-β and SD-208 on neointimal smooth muscle-like cell (SMLC) and vascular smooth muscle cell (VSMC) proliferation and migration were evaluated, and the expression levels of Smad3, P-Smad3, connective tissue growth factor (CTGF) and collagen I were determined by in vitro experiments.
The intimal hyperplasia of the SD-208-treated group was significantly reduced compared with the vehicle-treated control group (32% and 48% reduction for 40 mg/kg and 60 mg/kg SD-208 compared with the controls, respectively n = 5, p < 0.05). SD-208 reduced SMLC proliferation and the production of intimal collagen by 21% and 75%, respectively, in the grafts. SD-208 also abolished the promoting effect of TGF-β on SMLC proliferation and migration but did not affect TGF-β inhibition of VSMCs in vitro. CTGF, a protein downstream of TGF-β, was downregulated with the inhibition of Smad3 phosphorylation by SD-208, both in vitro and in vivo. Moreover, we found that the endogenous Smad3 in SMLCs was upregulated from 2 weeks after transplantation and was 64% higher than in VSMCs at 8 weeks.
These results demonstrate that SD-208 can effectively reduce the formation of intimal hyperplasia of TA in the murine aortic allograft model.
To develop a physical, adaptive motion perturbation model to predict tumor motion using feedback from dynamic measurement of breathing conditions to compensate for breathing irregularities.
A novel ...respiratory motion perturbation (RMP) model was developed to predict tumor motion variations caused by breathing irregularities. This model contained 2 terms: the initial tumor motion trajectory, measured from 4-dimensional computed tomography (4DCT) images, and motion perturbation, calculated from breathing variations in tidal volume (TV) and breathing pattern (BP). The motion perturbation was derived from the patient-specific anatomy, tumor-specific location, and time-dependent breathing variations. Ten patients were studied, and 2 amplitude-binned 4DCT images for each patient were acquired within 2 weeks. The motion trajectories of 40 corresponding bifurcation points in both 4DCT images of each patient were obtained using deformable image registration. An in-house 4D data processing toolbox was developed to calculate the TV and BP as functions of the breathing phase. The motion was predicted from the simulation 4DCT scan to the treatment 4DCT scan, and vice versa, resulting in 800 predictions. For comparison, noncorrected motion differences and the predictions from a published 5-dimensional model were used.
The average motion range in the superoinferior direction was 9.4 ± 4.4 mm, the average ΔTV ranged from 10 to 248 mm
(-26% to 61%), and the ΔBP ranged from 0 to 0.2 (-71% to 333%) between the 2 4DCT scans. The mean noncorrected motion difference was 2.0 ± 2.8 mm between 2 4DCT motion trajectories. After applying the RMP model, the mean motion difference was reduced significantly to 1.2 ± 1.8 mm (P=.0018), a 40% improvement, similar to the 1.2 ± 1.8 mm (P=.72) predicted with the 5-dimensional model.
A novel physical RMP model was developed with an average accuracy of 1.2 ± 1.8 mm for interfraction motion prediction, similar to that of a published lung motion model. This physical RMP was analytically derived and is able to adapt to breathing irregularities. Further improvement of this RMP model is under investigation.
Abstract Background Comprehensive health economic evaluation, a key component of the Cancer Screening Program in Urban China (CanSPUC), was expected to support government policy-making on screening ...initiatives for common cancers (lung, breast, colorectal, oesophageal, liver, and stomach cancer) in urban China. Estimation of expenditure for cancer diagnosis and treatment from a societal perspective was an essential component. The aim of this study was to estimate direct medical and non-medical expenditure and to discern the resultant financial burden. Methods A multicentre cross-sectional survey of patients with target cancers or precancerous lesions was conducted in 37 tertiary hospitals in 13 provinces across China, from 2012 to 2014. Each patient was interviewed with a structured questionnaire for sociodemographic, clinical, and expenditure information. Expenditure data was converted to 2014 values and presented as US$. Expenditure and financial burden were quantified as a whole and by subgroups. Findings Of the included 14 594 patients with cancer (mean age 56·7 years, 58% male), annual household income was $8607. Mean expenditure per patient was $9739 (95% CI 9612–9866), and non-medical expenditure accounted for 9·3%. Expenditure per patient with colorectal, oesophageal, lung, stomach, liver or breast cancer was $10 978 (10 636–11 321), $10 506 (10 199–10 813), $9970 (9664–10 276), $9891 (9606–10 176), $8668 (8358–8977) and $8532 (8234–8831), respectively. Expenditure increased from stage I to stage IV for colorectal, stomach, and breast cancer (p<0·0001). Out-of-pocket expenditure of newly diagnosed cancer (2 months before and 10 months after diagnosis) per cancer patient was $4947 (4875–5020), accounting for 57·5% of annual household income, presenting 77·6% of families with an unmanageable financial burden. Apart from cancer site and stage, hospital type, education, occupation, insurance type, and previous years' household income were also significant predictors of expenditure (F=247·9, 56·3, 29·7, 12·8, and 28·7, respectively; all p<0·0001) as well as self-reported financial burden (χ2 =130·4, 495·1, 1112·2, 1009·4, and 1848·2, respectively; all p<0·0001). In addition, for the included 1532 precancerous patients, mean expenditure was $3221 (3055–3387), a third of expenditure for patients with cancer. Interpretation Expenditure for diagnosis and treatment seemed catastrophic for patients with cancer in China, and non-medical expenditure was substantial. Expenditure and financial burden varied within subgroups, especially between patients with different degrees of lesions, suggesting that cancer screening might be cost-effective in China. Funding National Health and Family Plan Committee of China.
Abstract Background Oral glucocorticoids can prevent acute mountain sickness (AMS). Whether inhaled budesonide (BUD) can prevent AMS remains unknown. Objective Our aim was to investigate the ...effectiveness of BUD in AMS prevention. Methods Eighty subjects were randomly assigned to receive budesonide (BUD, inhaled), procaterol tablet (PT), budesonide/formoterol (BUD/FM, inhaled), or placebo tablet (n = 20 in each group). Subjects were treated for 3 days before ascending from 500 m to 3700 m within 2.5 h by air. Lake Louis AMS questionnaire, blood pressure, heart rate, and oxygen saturation (SpO2 ) were examined at 20, 72, and 120 h after high-altitude exposure. Pulmonary function was measured at 20 h after exposure. Results Compared with placebo, BUD significantly reduced the incidence of AMS (70% vs. 25% at 20 h, p < 0.05; both 10% vs. 5% at 72 and 120 h, both p > 0.05) without side effects. The relative risk was 0.357, and the risk difference was 0.45. Mean SpO2 was higher in BUD, BUD/FM, and PT groups than in the placebo group at 20 h ( p < 0.05). SpO2 in all 80 subjects dropped after ascent (98.1% to 88.12%, p < 0.01) and increased gradually, but it was still lower at 120 h than at baseline (92.04% vs. 98.1%, p < 0.01). Pulmonary function did not differ among the four groups at 20 h. Conclusion BUD can prevent AMS without side effects. The alleviation of AMS may be related to increased blood oxygen levels rather than pulmonary function.
Background
Breast cancer (BC), especially metastatic BC, is one of the most lethal diseases in women. CA 125 and CA 15-3 are commonly used indicators for diagnosis and prognosis of BC. Some ...serological indicators, such as lactate dehydrogenase (LDH) and C-reactive protein (CRP), can also be used to assess the prognosis and progression in BC.
Methods
Univariate Cox regression analysis and LASSO regression analysis were performed to identify prognostic factors and build prognostic models. We distributed the patients into 2 groups based on the median risk score, analyzed prognosis by Kaplan–Meier curve, and screened independent prognostic factors by multivariate Cox regression analysis.
Result
We identified 4 indicators-LDH, CRP, CA 15-3, and CA 125—related to the prognosis in BC and established a prognostic model. The high LDH group showed worse overall survival (OS) than low LDH group (P = .017; hazard ratio (HR), 1.528; 95% confidence interval (CI), 1.055-2.215). The high CRP group showed worse OS than low CRP group (P = .004; HR, 1.666; 95% CI, 1.143-2.429). The high CA153 group showed worse OS than low CA 15-3 group (P=.011; HR, 1.563; 95% CI, 1.075-2.274). The high CA 125 group showed worse OS than low CA 125 group (P = .021; HR, 1.499; 95% CI, 1.031-2.181). The area under the curve for risk score was .824, Ki-67 was .628, age was .511, and grade was .545. Risk score was found to be an independent prognostic factor using multivariate Cox regression analysis.
Conclusion
We successfully established an optimization model by combining 4 prognosis-related indicators to assess the prognosis in patients with metastatic BC.
PDF
