Breast Cancer Diagnosis Method Based on Cross-Mammogram Four-View Interactive Learning.

Computer-aided diagnosis systems play a crucial role in the diagnosis and early detection of breast cancer. However, most current methods focus primarily on the dual-view analysis of a single breast, thereby neglecting the potentially valuable information between bilateral mammograms. In this paper, we propose a Four-View Correlation and Contrastive Joint Learning Network (FV-Net) for the classification of bilateral mammogram images. Specifically, FV-Net focuses on extracting and matching features across the four views of bilateral mammograms while maximizing both their similarities and dissimilarities. Through the Cross-Mammogram Dual-Pathway Attention Module, feature matching between bilateral mammogram views is achieved, capturing the consistency and complementary features across mammograms and effectively reducing feature misalignment. In the reconstituted feature maps derived from bilateral mammograms, the Bilateral-Mammogram Contrastive Joint Learning module performs associative contrastive learning on positive and negative sample pairs within each local region. This aims to maximize the correlation between similar local features and enhance the differentiation between dissimilar features across the bilateral mammogram representations. Our experimental results on a test set comprising 20% of the combined Mini-DDSM and Vindr-mamo datasets, as well as on the INbreast dataset, show that our model exhibits superior performance in breast cancer classification compared to competing methods.

NLRP3-inflammasome inhibition by MCC950 attenuates cardiac and pulmonary artery remodelling in heart failure with preserved ejection fraction.

AIMS: The purpose of this study was to evaluate the role of the NLRP3-inflammasome in heart failure with preserved ejection fraction (HFpEF). MAIN METHODS: Serum inflammatory cytokines were detected in patients with heart failure. Correlation analysis was performed to investigate the relationship between serum inflammatory cytokines and left ventricular diastolic function. A 'two-hit' (metabolic stress and mechanical stress) mouse model of HFpEF was established. Furthermore, MCC950 was used to determine the role of NLRP3-inflammasome inhibition in cardiac and pulmonary artery remodelling in HFpEF mice. KEY FINDINGS: Compared with heart failure patients with reduced ejection fraction, patients with HFpEF have significantly elevated serum inflammatory cytokine levels. Serum NLRP3 and interleukin-1ß levels were positively correlated with the diastolic function of HFpEF. In the HFpEF mouse model, the inhibition of the NLRP3-inflammasome by MCC950 improved exercise intolerance, glucose intolerance, and left ventricular diastolic function, but had no significant effect on systolic function. Meanwhile, MCC950 attenuated the release of inflammatory cytokines, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, the potential protective effects of MCC950 are achieved by inhibiting activation of the NLRP3-IL-1ß pathway and cascade expansion of downstream inflammatory cytokines. Additionally, the inhibition of NLRP3-inflammasome by MCC950 reduced pulmonary artery pressure and improved pulmonary artery remodelling in HFpEF. SIGNIFICANCE: The NLRP3-inflammasome plays a considerable role in inflammation and cardiac and pulmonary artery remodelling in HFpEF by activating the cascade reaction of inflammatory cytokines. This study is the first to comprehensively elucidate the role of the NLRP3-inflammasome in HFpEF, and will provide reference for future study.

Serum uric acid: A risk factor for right ventricular dysfunction and prognosis in heart failure with preserved ejection fraction.

Background: Hyperuricemia and right ventricular dysfunction (RVD) are both widespread in heart failure with preserved ejection fraction (HFpEF) patients. RVD is associated with a poor prognosis in HFpEF. The correlation between serum uric acid (UA) levels and right ventricular function is unclear. The prognostic performance of UA in patients with HFpEF needs further validation. Methods and results: A total of 210 patients with HFpEF were included in the study and divided into two groups according to UA level: the normal UA group (≤7 mg/dl) and the high UA group (>7 mg/dl). The variables examined included clinical characteristics, echocardiography, and serum biochemical parameters. Right ventricular function was assessed by tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (TAPSV). Baseline characteristics were compared between the two groups, and the correlation between baseline UA and RVD was assessed using multifactorial binary logistic regression. Kaplan-Meier curves were used to describe all-cause mortality and heart failure readmission. Results showed that right ventricular function parameters were worse in the high UA group. After adjusting for UA, left ventricular posterior wall thickness (LVPWT), N-terminal B-type natriuretic peptide (NT-proBNP), atrial fibrillation (AF), and low-density lipoprotein cholesterol (LDL-C), UA (odds ratio = 2.028; p < 0.001) was independently associated with RVD, and UA >7 mg/dl (HR = 2.98; p < 0.001) was associated with heart failure readmission in patients with HFpEF. Conclusion: Elevated serum UA is closely associated with RVD and significantly associated with the heart failure readmission rate in patients with HFpEF.

Relationship between adipose tissue distribution and arterial stiffness in HFpEF.

OBJECTIVES: Heart failure and preserved ejection fraction (HFpEF) in patients is often complicated by abdominal obesity and arteriosclerosis. The aim of this study was to determine the relationship between adipose tissue distribution and arterial stiffness in patients with HFpEF. METHODS: This was a cross-sectional descriptive study involving 93 patients with HFpEF. Several anthropometric measurements were measured, including height, weight, waist circumference, body fat mass, percent body fat, body fat rate, and visceral fat area (VFA). We calculated body mass index. Arterial stiffness was assessed by measurement of brachial-ankle pulse wave velocity (baPWV). The association between VFA and baPWV was investigated by linear regression analysis. RESULTS: In univariate analysis, VFA showed strong relations with bilateral baPWV in Spearman correlation analysis (P = 0.003 and P = 0.002, respectively). After adjusting for VFA, age, systolic blood pressure, diastolic blood pressure, and heart rate, VFA and age were significantly and positively associated with bilateral baPWV (P = 0.024 and P = 0.032, respectively). After adjusting for VFA, age, left ventricular posterior wall, and interventricular septal thickness, VFA and age were still significantly correlated with bilateral baPWV (P = 0.028 and P = 0.008, respectively). CONCLUSIONS: In patients with HFpEF, adipose tissue distribution was correlated with arterial stiffness. VFA was independently associated with baPWV.

Short-term/long-term prognosis with or without beta-blockers in patients without heart failure and with preserved ejection fraction after acute myocardial infarction: a multicenter retrospective cohort study.

BACKGROUND: The role of beta-blockers in acute myocardial infarction patients without heart failure and with preserved left ventricular ejection fraction (LVEF ≥ 50%) is unknown. Our study aimed to retrospectively analyze the associations of beta-blockers on such patients. METHODS: This is a multicenter, retrospective study. After screening 5,332 acute myocardial infarction patients, a total of 2519 patients without heart failure and with LVEF ≥ 50% were included. The patients were divided into two groups: the prescribed (n = 2049) and unprescribed (n = 470) beta-blockers group. The propensity score inverse probability treatment weighting was used to control confounding factors. We analyzed the associations between beta-blockers and outcomes in the short-term (1-year) and long-term (median, 3.61 years). RESULTS: The primary outcome was all-cause mortality. The secondary outcomes were all-cause rehospitalization, cardiac death, recurrent myocardial infarction, new-onset heart failure rehospitalization. This study shows no statistically significant association between discharged with beta-blockers and all-cause mortality, either in the short-term [IPTW Adjusted, HR 1.02; 95%CI 0.43-2.40; P = 0.966] or long-term [IPTW Adjusted, HR 1.17; 95%CI 0.70-1.94; P = 0.547]. Discharged with beta-blockers was significantly associated with a reduced risk of short-term recurrent myocardial infarction [IPTW Adjusted, HR 0.44; 95%CI 0.20-0.97; P = 0.043], but there was no long-term relationship [IPTW Adjusted, HR 1.11; 95%CI 0.61-2.03; P = 0.735]. Other outcomes, such as new-onset heart failure rehospitalization and all-cause rehospitalization, were not observed with meaningful differences in either the short- or long-term. The results of sensitivity analysis were consistent with this. CONCLUSIONS: Beta-blockers might be associated with a reduced risk of recurrent myocardial infarction in patients without heart failure and with preserved left ventricular ejection fraction after acute myocardial infarction, in the short term. Beta-blockers might not be related to all-cause mortality in those patients, either in the short-term or long-term. Clinical trial registration Influence of Beta-blockers on Prognosis in Patients with Acute Myocardial Infarction Complicated with Normal Ejection Fraction, NCT04485988, Registered on 24/07/2020. Retrospectively registered.

The duration of beta-blocker therapy and outcomes in patients without heart failure or left ventricular systolic dysfunction after acute myocardial infarction: A multicenter prospective cohort study.

BACKGROUND: The duration of beta-blocker therapy in patients without heart failure (HF) or left ventricular systolic dysfunction after acute myocardial infarction (AMI) is unclear. HYPOTHESIS: Continuous beta-blocker therapy is associated with an improved prognosis. METHODS: This is a prospective, multicenter, cohort study. One thousand four hundred and eighty-three patients eventually met the inclusion criteria. The study groups included the continuous beta-blocker therapy group (lasted ≥6 months) and the discontinuous beta-blocker therapy group (consisting of the no-beta-blocker therapy group and the beta-blocker therapy <6 months group). The inverse probability treatment weighting was used to control confounding factors. The study tried to learn the role of continuous beta-blocker therapy on outcomes. The median duration of follow-up was 13.0 months. The primary outcomes were cardiac death and major adverse cardiovascular events (MACE). The secondary outcomes were all-cause death, stroke, unstable angina, rehospitalization for HF, and recurrent myocardial infarction (MI). RESULTS: Compared with discontinuous beta-blocker therapy, continuous beta-blocker therapy was associated with a reduced risk of unstable angina, recurrent MI, and MACE (hazard ratio [HR]: 0.51; 95% CI: 0.32-0.82; p = 0.006); but this association was not available for cardiac death (HR: 0.57; 95% CI: 0.24-1.36; p = 0.206). When compared to the subgroups of no-beta-blocker therapy and beta-blocker therapy <6 months, respectively, continuous beta-blocker therapy was still observed to be associated with a reduced risk of unstable angina, recurrent MI, and MACE. CONCLUSIONS: Continuous beta-blocker therapy was associated with a reduced risk of unstable angina or recurrent MI or MACE in patients without HF or left ventricular systolic dysfunction after AMI.

ST-segment resolution as a marker for severe myocardial fibrosis in ST-segment elevation myocardial infarction.

OBJECTIVE: To investigate the relationship between ST-segment resolution (STR) and myocardial scar thickness after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Forty-two STEMI patients with single-branch coronary artery stenosis or occlusion were enrolled. ST-segment elevations were measured at emergency admission and at 24 h after PCI. Late gadolinium-enhanced cardiac magnetic resonance imaging (CMR-LGE) was performed 7 days after PCI to evaluate myocardial scars. Statistical analyses were performed to assess the utility of STR to predict the development of transmural (> 75%) or non-transmural (< 75%) myocardial scars, according to previous study. RESULTS: The sensitivity and specificity of STR for predicting transmural scars were 96% and 88%, respectively, at an STR cut-off value of 40.15%. The area under the curve was 0.925. Multivariate logistic proportional hazards regression analysis disclosed that patients with STR < 40.15% had a 170.90-fold higher probability of developing transmural scars compared with patients with STR ≥ 40.15%. Pearson correlation and linear regression analyses showed STR percentage was significantly associated with myocardial scar thickness and size. CONCLUSION: STR < 40.15% at 24 h after PCI may provide meaningful diagnostic information regarding the extent of myocardial scarification in STEMI patients.

TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-ß/Smads and ERK1/2 signaling pathways.

BACKGROUND: Cardiac fibrosis is the most important pathogenesis leading to cardiac remodeling and heart failure after myocardial infarction (MI). Tissue nonspecific alkaline phosphatase (TNAP) has recently been recognized as a potential prognostic factor for MI. Nevertheless, the role of TNAP in cardiac fibrosis after MI has not been explicitly delineated. METHODS: A systematic review and meta-analysis was conducted to assess the effect of serum TNAP levels on mortality in patients with ischemic heart disease (IHD). A correlation analysis was performed to investigate the relationship between serum levels of TNAP and biomarkers of fibrosis. Heart biopsies from patients with MI and a mouse model of MI were used to detect the expression and distribution of TNAP. Furthermore, we established adenovirus-mediated knockdown and overexpression of TNAP, using a combination of in vivo and in vitro studies in mice, to determine the role and mechanism of TNAP in cardiac fibrosis after MI. In the in vitro studies, cardiac fibroblasts were cultured on soft plates. FINDINGS: After searching the main databases and performing a detailed assessment of the full-text articles, eight studies with 14,816 individuals were included in the quantitative analysis. We found that a high serum TNAP level was associated with an increased risk of mortality in patients with IHD and MI. The correlation analysis revealed a positive correlation between serum TNAP levels and the concentration of fibrosis biomarkers (PICP/PIIINP). The expression of TNAP was upregulated in the myocardium of patients with MI and in a mouse model of MI, accompanied by fibroblast activation and the deposition of collagen fibers. In the in vivo study, TNAP knockdown ameliorated cardiac fibrosis and improved cardiac function in mice. TNAP overexpression aggravated cardiac fibrosis and worsened cardiac function. In the in vitro study, TNAP promoted cardiac fibroblast differentiation, migration and proliferation. Mechanistically, the pro-fibrotic effect of TNAP on cardiac fibroblasts was at least partially achieved by activating the TGF-ß1/Smads and ERK1/2 signaling pathways. INTERPRETATION: Based on these findings, TNAP plays an important pro-fibrotic role in cardiac fibrosis after MI by activating TGF-ß/Smads and ERK1/2 signaling, indicating that it functions as a potential regulator of and therapeutic target in cardiac fibrosis. FUNDING: This work was supported by the National Natural Science Foundation of China.

Clinical characteristics and predictive value of lower CD4+T cell level in patients with moderate and severe COVID-19: a multicenter retrospective study.

BACKGROUND: In December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei, China. Moreover, it has become a global pandemic. This is of great value in describing the clinical symptoms of COVID-19 patients in detail and looking for markers which are significant to predict the prognosis of COVID-19 patients. METHODS: In this multicenter, retrospective study, 476 patients with COVID-19 were enrolled from a consecutive series. After screening, a total of 395 patients were included in this study. All-cause death was the primary endpoint. All patients were followed up from admission till discharge or death. RESULTS: The main symptoms observed in the study included fever on admission, cough, fatigue, and shortness of breath. The most common comorbidities were hypertension and diabetes mellitus. Patients with lower CD4+T cell level were older and more often male compared to those with higher CD4+T cell level. Reduced CD8+T cell level was an indicator of the severity of COVID-19. Both decreased CD4+T [HR:13.659; 95%CI: 3.235-57.671] and CD8+T [HR: 10.883; 95%CI: 3.277-36.145] cell levels were associated with in-hospital death in COVID-19 patients, but only the decrease of CD4+T cell level was an independent predictor of in-hospital death in COVID-19 patients. CONCLUSIONS: Reductions in lymphocytes and lymphocyte subsets were common in COVID-19 patients, especially in severe cases of COVID-19. It was the CD8+T cell level, not the CD4+T cell level, that reflected the severity of the patient's disease. Only reduced CD4+T cell level was independently associated with increased in-hospital death in COVID-19 patients. TRIAL REGISTRATION: Prognostic Factors of Patients With COVID-19, NCT04292964 . Registered 03 March 2020. Retrospectively registered.

Clinical characteristics and fatal outcomes of hypertension in patients with severe COVID-19.

The aim of this study is to investigate clinical characteristics and fatal outcomes of hypertension as well as the role of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) use in patients with severe coronavirus disease 2019 (COVID-19). A total of 220 (female: 51.8%) patients with severe COVID-19 were included. The mean age of included patients was 59.5 years and 70 (31.8%) patients had a history of hypertension. There were 23 patients (32.9%) receiving ACEI/ARB therapy. Patients with hypertension were older and had more comorbidities, and were more likely to suffer from severe inflammatory response and acute cardiac injury. Moreover, patients with hypertension were associated with significantly higher risk of in-hospital mortality than patients without hypertension. After adjustment of potential confounders, the independent correlation was still observed. In addition, ACEI/ARB users were associated with lower level of high-sensitivity cardiac troponin I and creatinine kinase-myocardial band, and lower risk of acute cardiac injury than ACEI/ARB non-users. In conclusion, patients with hypertension were more likely to suffer from severe inflammatory response, acute cardiac injury and had high risk of in-hospital mortality in severe COVID-19. The use of ACEI/ARB may protect patients with COVID-19 from acute cardiac injury.

Combination of eosinophil percentage and high-sensitivity C-reactive protein predicts in-hospital major adverse cardiac events in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

BACKGROUND: Eosinophil levels predict prognosis in ST-segment elevation myocardial infarction (STEMI) patients. Both eosinophils and high-sensitivity C-reactive protein (hs-CRP) play a major role in the acute inflammatory response of myocardial infarction. The purpose of this study was to evaluate eosinophil percentage (EOS%) and hs-CRP as prognostic markers for in-hospital adverse events in STEMI patients undergoing primary percutaneous coronary intervention. METHODS: We retrospectively analyzed the clinical data of 518 patients. Major adverse cardiac events (MACEs) were defined as cardiac rupture, cardiac arrest, malignant arrhythmia, and cardiac death. Based on the receiver operating characteristic (ROC) analysis, all patients were regrouped into 3 groups (None, One, and Two) according to cutoff EOS% value (≤0.3%) and hs-CRP value (>11.8 mg/L). Both Cox regression analyses and the KM (Kaplan-Meier) survival curve were used to examine the prognostic role of combined hs-CRP and EOS% in cardiovascular events. RESULTS: Of the 518 STEMI patients, 50 of them developed MACEs. Patients who developed MACEs had a significantly lower EOS% and higher hs-CRP than patients who remained MACE-free. In the multivariable Cox regression analysis, the highest risk of in-hospital MACEs was constantly observed in patients with a combined low EOS% and elevated hs-CRP. Patients with reduced EOS% and high hs-CRP had significantly higher incidence rates of cardiac rupture (P = .001), cardiac arrest (P = .001), and malignant arrhythmia (P < .001); furthermore, they had the worst cumulative survival compared with the other two groups. CONCLUSION: Combined reduced EOS% and elevated hs-CRP were valuable tools for identifying patients at risk of in-hospital MACEs.

Prognostic value of NT-proBNP in patients with severe COVID-19.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China has been declared a public health emergency of international concern. The cardiac injury is a common condition among the hospitalized patients with COVID-19. However, whether N terminal pro B type natriuretic peptide (NT-proBNP) predicted outcome of severe COVID-19 patients was unknown. METHODS: The study initially enrolled 102 patients with severe COVID-19 from a continuous sample. After screening out the ineligible cases, 54 patients were analyzed in this study. The primary outcome was in-hospital death defined as the case fatality rate. Research information and following-up data were obtained from their medical records. RESULTS: The best cut-off value of NT-proBNP for predicting in-hospital death was 88.64 pg/mL with the sensitivity for 100% and the specificity for 66.67%. Patients with high NT-proBNP values (> 88.64 pg/mL) had a significantly increased risk of death during the days of following-up compared with those with low values (≤88.64 pg/mL). After adjustment for potential risk factors, NT-proBNP was independently correlated with in-hospital death. CONCLUSION: NT-proBNP might be an independent risk factor for in-hospital death in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials, NCT04292964. Registered 03 March 2020.

Mathematical modeling of the 'inoculum effect': six applicable models and the MIC advancement point concept.

Antimicrobial treatment regimens against bacterial pathogens are designed using the drug's minimum inhibitory concentration (MIC) measured at a bacterial density of 5.7 log10(colony-forming units (CFU)/mL) in vitro. However, MIC changes with pathogen density, which varies among infectious diseases and during treatment. Incorporating this into treatment design requires realistic mathematical models of the relationships. We compared the MIC-density relationships for Gram-negative Escherichia coli and non-typhoidal Salmonella enterica subsp. enterica and Gram-positive Staphylococcus aureus and Streptococcus pneumonia (for n = 4 drug-susceptible strains per (sub)species and 1-8 log10(CFU/mL) densities), for antimicrobial classes with bactericidal activity against the (sub)species: ß-lactams (ceftriaxone and oxacillin), fluoroquinolones (ciprofloxacin), aminoglycosides (gentamicin), glycopeptides (vancomycin) and oxazolidinones (linezolid). Fitting six candidate mathematical models to the log2(MIC) vs. log10(CFU/mL) curves did not identify one model best capturing the relationships across the pathogen-antimicrobial combinations. Gompertz and logistic models (rather than a previously proposed Michaelis-Menten model) fitted best most often. Importantly, the bacterial density after which the MIC sharply increases (an MIC advancement-point density) and that density's intra-(sub)species range evidently depended on the antimicrobial mechanism of action. Capturing these dependencies for the disease-pathogen-antimicrobial combination could help determine the MICs for which bacterial densities are most informative for treatment regimen design.

Optimisation of Folate-Mediated Liposomal Encapsulated Arsenic Trioxide for Treating HPV-Positive Cervical Cancer Cells In Vitro.

High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO's therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.

[Clinical effect of checklist for early recognition and treatment of acute illness in department of intensive care unit: a prospective observational study].

OBJECTIVE: To evaluate the clinical performance of checklist for early recognition and treatment of acute illness (CERTAIN) on patients in the intensive care unit (ICU). METHODS: A prospective observational study was performed. 100 patients (age > 18 years old, the length of ICU stay > 72 hours) admitted to ICU of the Second People's Hospital of Lu'an from January to July in 2018 were enrolled. By convenience sampling methods, 50 patients admitted to the hospital from January to April in 2018 were selected as the control group. Standard ward inspection was given to the control group by three senior-level and intermediate-level doctors blinded from the research plan; at the end of March 2018, these three doctors were trained with the CERTAIN checklist and certified by the Mayo Clinic distance learning training. Fifty patients enrolled from March to July 2018 received medical rounds using CERTAIN (observation group). The CERTAIN checklist contained 20 items that cover the range of daily critical ward rounds, which need clinicians to quantify each item. The data included the length of ICU stay, central venous catheter (CVC) indwelling time, catheter indwelling time, duration of mechanical ventilation, drug use rate, ICU mortality, and incidence of adverse events were collected and compared between the two groups. The independent factors affecting ICU death were analyzed by log-rank univariate analysis and Cox regression multivariate analysis. RESULTS: Compared with control group, the length of ICU stay (days: 8.68±4.84 vs. 13.64±9.37), catheter indwelling time (days: 8.16±5.29 vs. 13.32±9.31), duration of mechanical ventilation (days: 3.46±4.14 vs. 6.62±9.57) in observation group were significantly decreased, insulin use rate (34.0% vs. 56.0%) and ICU mortality (2.0% vs. 14.0%) were significantly decreased, with statistically significant differences (all P < 0.05). Besides, the use of CERTAIN can significantly improve the efficiency of the ward inspection. The ward inspection time was shortened from (8.00±0.45) minutes to (5.00±0.33) minutes by using the CERTAIN checklist (t = 9.312, P < 0.01). Survival analysis showed that CERTAIN application could reduce ICU mortality (χ2 = 3.898, P = 0.048), but the use of CERTAIN was not an independent factor for reducing ICU mortality [odds ratios (OR) = 1.001, P = 0.922]. CONCLUSIONS: CERTAIN application has a significant effect on critical patients. It is suggested to spread in ICU of China.

Variation in fluoroquinolone pharmacodynamic parameter values among isolates of two bacterial pathogens of bovine respiratory disease.

To design an antimicrobial treatment regimen for a bacterial disease, data on the drug pharmacodynamics (PD) against selected drug-susceptible strains of the pathogen are used. The regimen is applied across such strains in the field, assuming the PD parameter values remain the same. We used time-kill experiments and PD modeling to investigate the fluoroquinolone enrofloxacin PD against different isolates of two bovine respiratory disease pathogens: four Mannheimia haemolytica and three Pasteurella multocida isolates. The models were fitted as mixed-effects non-linear regression; the fixed-effects PD parameter values were estimated after accounting for random variation among experimental replicates. There was both inter- and intra- bacterial species variability in the PD parameters Hill-coefficient and Emax (maximal decline of bacterial growth rate), with more variable PD responses among M. haemolytica than among P. multocida isolates. Moreover, the Hill-coefficient was correlated to the isolate's maximal population growth rate in the absence of antimicrobial exposure (a.k.a. specific growth rate; Spearman's ρ = 0.98, p-value = 0.003, n = 6 isolates excluding one outlier). Thus, the strain's properties such as growth potential may impact its PD responses. This variability can have clinical implications. Modifying the treatment regimen depending on phenotypic properties of the pathogen strain causing disease may be a precision medicine approach.

Effective Delivery of Arsenic Trioxide to HPV-Positive Cervical Cancer Cells Using Optimised Liposomes: A Size and Charge Study.

Despite the success of arsenic trioxide (ATO) in treating haematological malignancies, its potential to treat solid tumours has not been fully exploited, owing to its dose-limiting toxicity and poor pharmacokinetics. In order to overcome this hurdle, liposomal encapsulation of the drug with different surface charges (neutral, negative, and positive) and sizes (100, 200 and 400 nm) were synthesised and tested on human papilloma virus (HPV)-positive HeLa and HPV-negative HT-3 cervical cancer cell lines. Two epithelial cell lines-human keratinocytes (HK) and human colon cells (CRL-1790)-were used as controls. The synthesised liposomes were tested for their physico-chemical characteristics, drug loading efficiency, and toxicity on the studied cell lines. Neutral liposomes of 100 nm in size were the chosen formulation for delivering ATO into the studied cells, as they showed the least intrinsic cytotoxicity and the highest loading efficiency. The findings demonstrated that the optimised formulation of liposomes was an effective drug delivery method for HPV-infected cervical cancer cells. Furthermore, the toxicity vs. uptake ratio was highest for HeLa cells, while a reduced or minimal toxic effect was observed for non-HPV-infected cervical cancer cells and control cells. These findings may provide a promising therapeutic strategy for effectively managing cervical cancers.

Establishing Statistical Equivalence of Data from Different Sampling Approaches for Assessment of Bacterial Phenotypic Antimicrobial Resistance.

To assess phenotypic bacterial antimicrobial resistance (AMR) in different strata (e.g., host populations, environmental areas, manure, or sewage effluents) for epidemiological purposes, isolates of target bacteria can be obtained from a stratum using various sample types. Also, different sample processing methods can be applied. The MIC of each target antimicrobial drug for each isolate is measured. Statistical equivalence testing of the MIC data for the isolates allows evaluation of whether different sample types or sample processing methods yield equivalent estimates of the bacterial antimicrobial susceptibility in the stratum. We demonstrate this approach on the antimicrobial susceptibility estimates for (i) nontyphoidal Salmonella spp. from ground or trimmed meat versus cecal content samples of cattle in processing plants in 2013-2014 and (ii) nontyphoidal Salmonella spp. from urine, fecal, and blood human samples in 2015 (U.S. National Antimicrobial Resistance Monitoring System data). We found that the sample types for cattle yielded nonequivalent susceptibility estimates for several antimicrobial drug classes and thus may gauge distinct subpopulations of salmonellae. The quinolone and fluoroquinolone susceptibility estimates for nontyphoidal salmonellae from human blood are nonequivalent to those from urine or feces, conjecturally due to the fluoroquinolone (ciprofloxacin) use to treat infections caused by nontyphoidal salmonellae. We also demonstrate statistical equivalence testing for comparing sample processing methods for fecal samples (culturing one versus multiple aliquots per sample) to assess AMR in fecal Escherichia coli These methods yield equivalent results, except for tetracyclines. Importantly, statistical equivalence testing provides the MIC difference at which the data from two sample types or sample processing methods differ statistically. Data users (e.g., microbiologists and epidemiologists) may then interpret practical relevance of the difference.IMPORTANCE Bacterial antimicrobial resistance (AMR) needs to be assessed in different populations or strata for the purposes of surveillance and determination of the efficacy of interventions to halt AMR dissemination. To assess phenotypic antimicrobial susceptibility, isolates of target bacteria can be obtained from a stratum using different sample types or employing different sample processing methods in the laboratory. The MIC of each target antimicrobial drug for each of the isolates is measured, yielding the MIC distribution across the isolates from each sample type or sample processing method. We describe statistical equivalence testing for the MIC data for evaluating whether two sample types or sample processing methods yield equivalent estimates of the bacterial phenotypic antimicrobial susceptibility in the stratum. This includes estimating the MIC difference at which the data from the two approaches differ statistically. Data users (e.g., microbiologists, epidemiologists, and public health professionals) can then interpret whether that present difference is practically relevant.

Liposome­delivered baicalein induction of myeloid leukemia K562 cell death via reactive oxygen species generation.

Baicalein (BL), a potential cancer chemopreventative flavone, has been reported to inhibit cancer cell growth by inducing apoptosis and causing cell cycle arrest in various human cancer cell models. Delivery of BL via nanoliposomes has been shown to improve its oral bioavailability and long­circulating property in vivo. However, the role of BL in the inhibition of human chronic myeloid leukemia (CML) K562 cell growth and its underlying mechanisms has yet to be elucidated. In the present study, BL was formulated into liposomes with different sizes to improve its solubility and stability. The cytotoxic and pro­apoptotic effects of free BL and liposomal BL were also evaluated. The results demonstrated that 100 nm liposomes were the most stable formulation when compared with 200 and 400 nm liposomes. Liposomal BL inhibited K562 cell growth as efficiently as free BL (prepared in DMSO), indicating that the liposome may be a potential vehicle to deliver BL for the treatment of CML. Flow cytometry analysis showed that there was significant (P<0.005) cell cycle arrest in the sub­G1 phase (compared with vehicle control), indicating cell apoptosis following 20 µM liposomal BL or free BL treatment of K562 cells for 48 h. The induction of cell apoptosis by all BL preparations was further confirmed through the staining of treated cells with Annexin V­fluorescein isothiocyanate/propidium iodide. A significant increase in reactive oxygen species (ROS) gene-ration was observed in free BL and liposomal BL treated cells, with a higher level of ROS produced from those treated with free BL. This indicated that cell apoptosis induced by BL may be via ROS generation and liposome delivery may further extend the effect through its long­circulating property.

Recent advances in arsenic trioxide encapsulated nanoparticles as drug delivery agents to solid cancers.

Since arsenic trioxide was first approved as the front line therapy for acute promyelocytic leukemia 25 years ago, its anti-cancer properties for various malignancies have been under intense investigation. However, the clinical successes of arsenic trioxide in treating hematological cancers have not been translated to solid cancers. This is due to arsenic's rapid clearance by the body's immune system before reaching the tumor site. Several attempts have henceforth been made to increase its bioavailability toward solid cancers without increasing its dosage albeit without much success. This review summarizes the past and current utilization of arsenic trioxide in the medical field with primary focus on the implementation of nanotechnology for arsenic trioxide delivery to solid cancer cells. Different approaches that have been employed to increase arsenic's efficacy, specificity and bioavailability to solid cancer cells were evaluated and compared. The potential of combining different approaches or tailoring delivery vehicles to target specific types of solid cancers according to individual cancer characteristics and arsenic chemistry is proposed and discussed.