Does gambling expenditure have any effect on crime?

BACKGROUND AND AIMS: Australians spend more per capita on gambling than any other country in the world. Electronic gaming machines (EGM) expenditure accounts for almost 90% of this expenditure. No study to date has conducted a rigorous longitudinal analysis of the relationship between gambling expenditure and crime. This study aimed to estimate the short- and long-run relationship between gambling expenditure and crime. DESIGN: Longitudinal analysis using panel autoregressive distributed lag (ARDL) modelling. SETTING AND CASES: Recorded property and violent crimes committed in New South Wales (NSW), Australia, between 28 December 2015 and 5 January 2020. MEASUREMENTS: Monthly gross EGM expenditure profit, broken down by Local Government Area (LGA). Monthly recorded rates of assault, break enter and steal (dwelling), break enter and steal (non-dwelling), break enter and steal (total), motor vehicle theft, stealing from a motor vehicle, stealing from a retail store, stealing from the person, stealing (total) and fraud. FINDINGS: Each 10% increase in gambling expenditure in NSW is associated with annual: 7.4% increase in assaults, 10.5% increase in break and enter (dwelling) offences; 10.3% increase in break and enter (non-dwelling) offences; 11% increase in motor vehicle theft offences; 8.2% increase in stealing from motor vehicle offences; and 7.4% increase in fraud offences. CONCLUSION: Electronic gaming expenditure appears to be positively associated with property and violent crime in New South Wales, Australia.

Enhancing nursing students' cultural awareness through Community of Inquiry-guided online 'Internationalization at Home' strategies-An intervention study.

AIM: Internationalization at Home (IaH) strategies play an important role in nursing curricula to enhance nursing students' cultural awareness in the globalized world. The Community of Inquiry (CoI) is a theoretical framework for the optimal design of online learning environments to support critical inquiry and discourse among students and teachers. To optimise nursing students' online cultural awareness learning experiences, it was timely to develop online IaH strategies based on a sound theoretical model. This study aimed to examine the effectiveness of CoI-guided online IaH strategies on enhancing the cultural awareness of nursing undergraduates who enrolled in a community nursing course. DESIGN: This was an interventional pre-test post-test study. METHOD: One hundred and six nursing undergraduates who enrolled in the course participated in the study. The online IaH strategies were developed focusing on the interactions of teaching presence, cognitive presence and social presence of CoI framework and they were integrated into the course. A previously validated Cultural Awareness Scale was adopted for pre-post evaluation. Higher scores indicate greater cultural awareness. RESULTS: The results showed that there was a significantly higher total score of cultural awareness of participating students at post-online IaH strategies. To be effective, aligning CoI-guided online IaH strategies with course content, pedagogy and assessment was shown to be significant. The inclusion of technological elements in related strategies was also critical to engage student learning. The positive change on the total score of cultural awareness suggested the effectiveness of the deployed strategies. In this ever-changing educational landscape, it may provide insights to educators regarding considering online IaH strategies with theoretical underpinning for curriculum planning and design.

Intraventricular 4D flow cardiovascular magnetic resonance for assessing patients with heart failure with preserved ejection fraction: a pilot study.

Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. Intraventricular four-dimensional flow (4D flow) phase-contrast cardiovascular magnetic resonance (CMR) can assess different components of left ventricular (LV) flow including direct flow, delayed ejection, retained inflow and residual volume. This could be utilised to identify HFpEF. This study investigated if intraventricular 4D flow CMR could differentiate HFpEF patients from non-HFpEF and asymptomatic controls. Suspected HFpEF patients and asymptomatic controls were recruited prospectively. HFpEF patients were confirmed using European Society of Cardiology (ESC) 2021 expert recommendations. Non-HFpEF patients were diagnosed if suspected HFpEF patients did not fulfil ESC 2021 criteria. LV direct flow, delayed ejection, retained inflow and residual volume were obtained from 4D flow CMR images. Receiver operating characteristic (ROC) curves were plotted. 63 subjects (25 HFpEF patients, 22 non-HFpEF patients and 16 asymptomatic controls) were included in this study. 46% were male, mean age 69.8 ± 9.1 years. CMR 4D flow derived LV direct flow and residual volume could differentiate HFpEF vs combined group of non-HFpEF and asymptomatic controls (p < 0.001 for both) as well as HFpEF vs non-HFpEF patients (p = 0.021 and p = 0.005, respectively). Among the 4 parameters, direct flow had the largest area under curve (AUC) of 0.781 when comparing HFpEF vs combined group of non-HFpEF and asymptomatic controls, while residual volume had the largest AUC of 0.740 when comparing HFpEF and non-HFpEF patients. CMR 4D flow derived LV direct flow and residual volume show promise in differentiating HFpEF patients from non-HFpEF patients.

Diagnostic accuracy of cardiovascular magnetic resonance strain analysis and atrial size to identify heart failure with preserved ejection fraction.

Aims: Heart failure with preserved ejection fraction (HFpEF) continues to be a diagnostic challenge. Cardiac magnetic resonance atrial measurement, feature tracking (CMR-FT), tagging has long been suggested to diagnose HFpEF and potentially complement echocardiography especially when echocardiography is indeterminate. Data supporting the use of CMR atrial measurements, CMR-FT or tagging, are absent. Our aim is to conduct a prospective case-control study assessing the diagnostic accuracy of CMR atrial volume/area, CMR-FT, and tagging to diagnose HFpEF amongst patients suspected of having HFpEF. Methods and results: One hundred and twenty-one suspected HFpEF patients were prospectively recruited from four centres. Patients underwent echocardiography, CMR, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements within 24 h to diagnose HFpEF. Patients without HFpEF diagnosis underwent catheter pressure measurements or stress echocardiography to confirm HFpEF or non-HFpEF. Area under the curve (AUC) was determined by comparing HFpEF with non-HFpEF patients. Fifty-three HFpEF (median age 78 years, interquartile range 74-82 years) and thirty-eight non-HFpEF (median age 70 years, interquartile range 64-76 years) were recruited. Cardiac magnetic resonance left atrial (LA) reservoir strain (ResS), LA area index (LAAi), and LA volume index (LAVi) had the highest diagnostic accuracy (AUCs 0.803, 0.815, and 0.776, respectively). Left atrial ResS, LAAi, and LAVi had significantly better diagnostic accuracy than CMR-FT left ventricle (LV)/right ventricle (RV) parameters and tagging (P < 0.01). Tagging circumferential and radial strain had poor diagnostic accuracy (AUC 0.644 and 0.541, respectively). Conclusion: Cardiac magnetic resonance LA ResS, LAAi, and LAVi have the highest diagnostic accuracy to identify HFpEF patients from non-HFpEF patients amongst clinically suspected HFpEF patients. Cardiac magnetic resonance feature tracking LV/RV parameters and tagging had low diagnostic accuracy to diagnose HFpEF.

Protein and peptide delivery to lungs by using advanced targeted drug delivery.

The challenges and difficulties associated with conventional drug delivery systems have led to the emergence of novel, advanced targeted drug delivery systems. Therapeutic drug delivery of proteins and peptides to the lungs is complicated owing to the large size and polar characteristics of the latter. Nevertheless, the pulmonary route has attracted great interest today among formulation scientists, as it has evolved into one of the important targeted drug delivery platforms for the delivery of peptides, and related compounds effectively to the lungs, primarily for the management and treatment of chronic lung diseases. In this review, we have discussed and summarized the current scenario and recent developments in targeted delivery of proteins and peptide-based drugs to the lungs. Moreover, we have also highlighted the advantages of pulmonary drug delivery over conventional drug delivery approaches for peptide-based drugs, in terms of efficacy, retention time and other important pharmacokinetic parameters. The review also highlights the future perspectives and the impact of targeted drug delivery on peptide-based drugs in the coming decade.

Adverse effects of hydroxychloroquine and azithromycin on contractility and arrhythmogenicity revealed by human engineered cardiac tissues.

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic as declared by World Health Organization (WHO). In the absence of an effective treatment, different drugs with unknown effectiveness, including antimalarial hydroxychloroquine (HCQ), with or without concurrent administration with azithromycin (AZM), have been tested for treating COVID-19 patients with developed pneumonia. However, the efficacy and safety of HCQ and/or AZM have been questioned by recent clinical reports. Direct effects of these drugs on the human heart remain very poorly defined. To better understand the mechanisms of action of HCQ +/- AZM, we employed bioengineered human ventricular cardiac tissue strip (hvCTS) and anisotropic sheet (hvCAS) assays, made with human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCMs), which have been designed for measuring cardiac contractility and electrophysiology, respectively. Our hvCTS experiments showed that AZM induced a dose-dependent negative inotropic effect which could be aggravated by HCQ; electrophysiologically, as revealed by the hvCAS platform, AZM prolonged action potentials and induced spiral wave formations. Collectively, our data were consistent with reported clinical risks of HCQ and AZM on QTc prolongation/ventricular arrhythmias and development of heart failure. In conclusion, our study exposed the risks of HCQ/AZM administration while providing mechanistic insights for their toxicity. Our bioengineered human cardiac tissue constructs therefore provide a useful platform for screening cardiac safety and efficacy when developing therapeutics against COVID-19.

Correlation between frataxin expression and contractility revealed by in vitro Friedreich's ataxia cardiac tissue models engineered from human pluripotent stem cells.

BACKGROUND: Friedreich's ataxia (FRDA) is an autosomal recessive disease caused by a non-coding mutation in the first intron of the frataxin (FXN) gene that suppresses its expression. Compensatory hypertrophic cardiomyopathy, dilated cardiomyopathy, and conduction system abnormalities in FRDA lead to cardiomyocyte (CM) death and fibrosis, consequently resulting in heart failure and arrhythmias. Murine models have been developed to study disease pathology in the past two decades; however, differences between human and mouse physiology and metabolism have limited the relevance of animal studies in cardiac disease conditions. To bridge this gap, we aimed to generate species-specific, functional in vitro experimental models of FRDA using 2-dimensional (2D) and 3-dimensional (3D) engineered cardiac tissues from FXN-deficient human pluripotent stem cell-derived ventricular cardiomyocytes (hPSC-hvCMs) and to compare their contractile and electrophysiological properties with healthy tissue constructs. METHODS: Healthy control and FRDA patient-specific hPSC-hvCMs were derived by directed differentiation using a small molecule-based protocol reported previously. We engineered the hvCMs into our established human ventricular cardiac tissue strip (hvCTS) and human ventricular cardiac anisotropic sheet (hvCAS) models, and functional assays were performed on days 7-17 post-tissue fabrication to assess the electrophysiology and contractility of FRDA patient-derived and FXN-knockdown engineered tissues, in comparison with healthy controls. To further validate the disease model, forced expression of FXN was induced in FXN-deficient tissues to test if disease phenotypes could be rescued. RESULTS: Here, we report for the first time the generation of human engineered tissue models of FRDA cardiomyopathy from hPSCs: FXN-deficient hvCTS displayed attenuated developed forces (by 70-80%) compared to healthy controls. High-resolution optical mapping of hvCAS with reduced FXN expression also revealed electrophysiological defects consistent with clinical observations, including action potential duration prolongation and maximum capture frequency reduction. Interestingly, a clear positive correlation between FXN expression and contractility was observed (ρ > 0.9), and restoration of FXN protein levels by lentiviral transduction rescued contractility defects in FXN-deficient hvCTS. CONCLUSIONS: We conclude that human-based in vitro cardiac tissue models of FRDA provide a translational, disease-relevant biomimetic platform for the evaluation of novel therapeutics and to provide insight into FRDA disease progression.

Polycystin-2 Plays an Essential Role in Glucose Starvation-Induced Autophagy in Human Embryonic Stem Cell-Derived Cardiomyocytes.

Autophagy is a process essential for cell survival under stress condition. The patients with autosomal dominant polycystic kidney disease, which is caused by polycystin-1 or polycystin-2 (PKD2) mutation, display cardiovascular abnormalities and dysregulation in autophagy. However, it is unclear whether PKD2 plays a role in autophagy. In the present study, we explored the functional role of PKD2 in autophagy and apoptosis in human embryonic stem cell-derived cardiomyocytes. HES2 hESC line-derived cardiomyocytes (HES2-CMs) were transduced with adenoviral-based PKD2-shRNAs (Ad-PKD2-shRNAs), and then cultured with normal or glucose-free medium for 3 hours. Autophagy was upregulated in HES2-CMs under glucose starvation, as indicated by increased microtubule-associated protein 1 light chain 3-II level in immunoblots and increased autophagosome and autolysosome formation. Knockdown of PKD2 reduced the autophagic flux and increased apoptosis under glucose starvation. In Ca2+ measurement, Ad-PKD2-shRNAs reduced caffeine-induced cytosolic Ca2+ rise. Co-immunoprecipitation and in situ proximity ligation assay demonstrated an increased physical interaction of PKD2 with ryanodine receptor 2 (RyR2) under glucose starvation condition. Furthermore, Ad-PKD2-shRNAs substantially attenuated the starvation-induced activation of AMP-activated protein kinase (AMPK) and inactivation of mammalian target of rapamycin (mTOR). The present study for the first time demonstrates that PKD2 functions to promote autophagy under glucose starvation, thereby protects cardiomyocytes from apoptotic cell death. The mechanism may involve PKD2 interaction with RyR2 to alter Ca2+ release from sarcoplasmic reticulum, consequently modulating the activity of AMPK and mTOR, resulting in alteration of autophagy and apoptosis. Stem Cells 2018;36:501-513.

A Regularizer Approach for RBF Networks Under the Concurrent Weight Failure Situation.

Many existing results on fault-tolerant algorithms focus on the single fault source situation, where a trained network is affected by one kind of weight failure. In fact, a trained network may be affected by multiple kinds of weight failure. This paper first studies how the open weight fault and the multiplicative weight noise degrade the performance of radial basis function (RBF) networks. Afterward, we define the objective function for training fault-tolerant RBF networks. Based on the objective function, we then develop two learning algorithms, one batch mode and one online mode. Besides, the convergent conditions of our online algorithm are investigated. Finally, we develop a formula to estimate the test set error of faulty networks trained from our approach. This formula helps us to optimize some tuning parameters, such as RBF width.

Do drug seizures predict drug-related emergency department presentations or arrests for drug use and possession?

BACKGROUND: Direct evidence of the effect of drug seizures on drug use and drug-related harm is fairly sparse. The aim of this study was to see whether seizures of heroin, cocaine and ATS predict the number of people arrested for use and possession of these drugs and the number overdosing on them. METHOD: We examined the effect of seizure frequency and seizure weight on arrests for drug use and possession and on the frequency of drug overdose with autoregressive distributed lag (ARDL) models. Granger causality tests were used to test for simultaneity. RESULTS: Over the short term (i.e. up to 4 months), increases in the intensity of high-level drug law enforcement (as measured by seizure weight and frequency) directed at ATS, cocaine and heroin did not appear to have any suppression effect on emergency department (ED) presentations relating to ATS, cocaine and heroin, or on arrests for use and/or possession of these drugs. A significant negative contemporaneous relationship was found between the heroin seizure weight and arrests for use and/or possession of heroin. However no evidence emerged of a contemporaneous or lagged relationship between heroin seizures and heroin ED presentations. CONCLUSION: The balance of evidence suggests that, in the Australian context, increases in the monthly seizure frequency and quantity of ATS, cocaine and heroin are signals of increased rather than reduced supply.

Does prostate-specific antigen nadir predict longer-term outcomes of prostate cancer after neoadjuvant and adjuvant androgen deprivation therapy in conjunction with brachytherapy?

PURPOSE: To evaluate whether nadir prostate-specific antigen (nPSA), time to nPSA (TnPSA), and nPSA 3-years post-treatment are prognostic for prostate cancer (PC) in patients treated with temporary brachytherapy plus external beam radiation therapy (EBRT) and hormonal manipulation. METHODS AND MATERIALS: We retrospectively analyzed our database of 253 patients with Stage T1-T3 N0M0 PC who underwent brachytherapy with temporary brachytherapy plus EBRT. All patients received neoadjuvant androgen deprivation for a median of 6 months. Treatment consisted of three pulses of pseudo pulsed-dose-rate brachytherapy to a median dose of 18Gy with 50.4Gy in 28 fractions of EBRT. Treatment took place between December 1999 and March 2006. RESULTS: At a median of 6-years followup, nPSA value was a predictor of biochemical control. Rising nPSA categories of <0.01, 0.01-<0.05, 0.05-≤0.1, 0.1-≤ 1.0, or >1.0 ng/mL correlated with a deteriorating 5-year biochemical control (nBED) by the Phoenix definition of 100%, 90.0%, 82.5%, 64.3%, and 10%, respectively. A highly statistically significant relationship between nPSA value and subsequent clinical failure is also demonstrated. The relationship between TnPSA and nBED was strongly significant (p<0.0001), with a significantly longer nPSA for patients who had Phoenix nBED. A PSA of <1.5 ng/mL achieved 3-year post radiation therapy was prognostic for biochemical and clinical disease control (p<0.0001). CONCLUSION: The nPSA, TnPSA, and reaching a PSA cutoff level of <1.5 ng/mL at 3 years post-treatment can provide useful prognostic information on long-term biochemical and clinical control of PC in patients treated with pseudo PDR, EBRT, and hormone manipulation.

Long-term outcome for prostate cancer using pseudo pulse-dosed rate brachytherapy, external beam radiotherapy, and hormones.

PURPOSE: We report the long-term outcomes of pulse-dose rate (PDR) brachytherapy used in a nonstandard style (pseudo-PDR) with an high-dose rate brachytherapy technique in conjunction with external beam radiotherapy (EBRT) and hormonal manipulation on prostate cancer (PC). METHODS AND MATERIALS: We treated 253 patients with Stage T1-T3 N0M0 PC, between December 1999 and March 2006. All patients received neoadjuvant androgen deprivation for a median 6 months. Treatment consisted of three pulses of pseudo-PDR brachytherapy to a median dose of 18Gy with 50.4Gy in 28 fractions of EBRT. RESULTS: At a median 6 years followup, (range, 1-11 years), 5-year overall survival was 92%, and PC-specific survival was 96%. The 5-year biochemical control (biochemical no evidence of disease) by the Phoenix definition for low-, intermediate-, and high-risk groups was 95%, 90%, and 71%, respectively (p<0.00001). At 6 years, the incidence of Radiotherapy Oncology Group Grade 2 and 3 genitourinary toxicity was 1% and 6%; Radiotherapy Oncology Group Grade 2 and 3 gastrointestinal toxicity was 4% and 0%. Erectile preservation at 3 years was 58%. The Phoenix definition best predicted clinical failure with a high specificity (94%). CONCLUSIONS: Pseudo-PDR brachytherapy plus EBRT with limited neoadjuvant hormonal manipulation is an effective treatment option in localized PC, with minimal and tolerable morbidity and provides excellent control. This technique of a modified PDR-delivery technique appears as effective as high-dose rate therapy.

Multiple atherosclerosis-related biomarkers associated with short- and long-term mortality after stroke.

OBJECTIVES: We investigated the relationships of biomarkers of various pathophysiologic pathways including high-sensitivity C-reactive protein (hs-CRP), lipocalin-2 (LCN2), myeloperoxidase (MPO) and matrix metalloproteinases 9 (MMP9) with mortality in stroke patients. DESIGN AND METHODS: hs-CRP, LCN2 and MPO concentrations in 92 patients were determined using enzyme-linked immunosorbent assays. MMP9 mRNA concentrations were determined using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Twelve patients (13.0%) died at 6 months and 34 patients (37.0%) died at 5 years. The independent predictors for 6-month mortality were hs-CRP (adjusted OR=16.0) and LCN2 (adjusted OR=16.9), while for 5-year mortality was hs-CRP (adjusted OR=5.56). For patients with hs-CRP >3.4 mg/L, an increase in LCN2 was associated with 2.5-fold higher 6-month mortality, while an increase in normalized MMP9 mRNA was associated with 5.8-fold higher 6-month and 1.5-fold higher 5-year mortality. CONCLUSION: hs-CRP was the most significant independent predictor of both short- and long-term mortality after stroke, with LCN2 and MMP9 mRNA each adding further to the risk stratification.

Diagnostic utility of an anti-CCP point-of-care immunotest in Chinese patients with rheumatoid arthritis.

BACKGROUND: Early and accurate diagnosis of rheumatoid arthritis (RA) has become increasingly important. The clinical significance of anti-cyclic citrullinated peptide (CCP) antibody in Chinese RA adults was studied using an anti-CCP2 rapid test. METHODS: Anti-CCP antibody and rheumatoid factor (RF) were determined in 95 RA patients and 140 patients with rheumatic diseases other than RA. RESULTS: Two hundred and thirty five subjects were enrolled in this study. Both sensitivity and specificity of anti-CCP2 ELISA (78.9% & 95.7%) were higher than those of RF (67.4% & 84.3%). The area under the receiver operating characteristic curve for anti-CCP2 ELISA was 0.852 (95% CI: 0.792-0.913) which was larger than that for RF 0.775 (95% CI: 0.710-0.840). Both sensitivity and specificity (75.8% and 92.9%) of the anti-CCP2 rapid test were comparable to the ELISA. However, the sensitivity (62.1%) of a combined strategy by measuring anti-CCP antibody and RF was even lower than either marker alone although the specificity (98.6%) was slightly improved. CONCLUSIONS: Anti-CCP antibody is a valuable tool for diagnosis of RA in Chinese patients. With the use of the reliable and user-friendly anti-CCP rapid test, it may have an important role in the design of therapeutic strategies in RA patients.

Bayesian analysis of robust Poisson geometric process model using heavy-tailed distributions.

We propose a robust Poisson geometric process model with heavy-tailed distributions to cope with the problem of outliers as it may lead to an overestimation of mean and variance resulting in inaccurate interpretations of the situations. Two heavy-tailed distributions namely Student's t and exponential power distributions with different tailednesses and kurtoses are used and they are represented in scale mixture of normal and scale mixture of uniform respectively. The proposed model is capable of describing the trend and meanwhile the mixing parameters in the scale mixture representations can detect the outlying observations. Simulations and real data analysis are performed to investigate the properties of the models.

Genetic alterations in a telomerase-immortalized human esophageal epithelial cell line: implications for carcinogenesis.

Ectopic expression of viral oncoproteins disrupts cellular functions and limits the value of many existing immortalization models as models for carcinogenesis, especially for cancers without definitive viral etiology. Our newly established telomerase-immortalized human esophageal epithelial cell line, NE2-hTERT, retained nearly-diploid and non-tumorigenic characteristics, but exhibited genetic and genomic alterations commonly found in esophageal cancer, including progressive loss of the p16(INK4a) alleles, upregulation of anti-apoptotic proteins, epithelial-mesenchymal transition, whole-chromosome 7 gain and duplicated 5q arm. Our data also revealed a novel positive regulation of p16(INK4a) on cyclin D1. These findings probably represent early crucial events and mechanisms in esophageal carcinogenesis.