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Anh Trung Nguyen,1,2 Hai Quang Pham,3,4 Thanh Xuan Nguyen,1,2,5 Thu Thi Hoai Nguyen,1,2 Huong Thi Thu Nguyen,1,2 Tam Ngoc Nguyen,1,2 Dung Thi Kim Dinh,1 Hai Thanh Phan,3,4 Son Hoang Nguyen,6 Bach Xuan Tran,7,8 Carl A Latkin,8 Roger CM Ho,9,10 Cyrus SH Ho,9 Thang Pham,1,2 Huyen Thi Thanh Vu1,2 1Hanoi Medical University, Hanoi, Vietnam; 2National Geriatric Hospital, Hanoi, Vietnam; 3Institute for Global Health Innovations, Duy Tan University, Da Nang, Vietnam; 4Faculty of Medicine, Duy Tan University, Da Nang 550000, Vietnam; 5Dinh Tien Hoang Institute of Medicine, Hanoi, Vietnam; 6Center of Excellence in Health Services and System Research, Nguyen Tat Thanh University, Ho Chi Minh, Vietnam; 7Institute for Preventive Medicine and Public Health, Hanoi Medical University, Hanoi 100000, Vietnam; 8Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; 9Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 10Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, SingaporeCorrespondence: Huyen Thi Thanh VuDepartment of Geriatrics, Hanoi Medical University, 01 Ton That Tung, Hanoi, VietnamTel +84 913531579Email vuthanhhuyen11@hmu.edu.vnBackground: Diabetes-related complications have become increasingly prevalent and complicated to manage, especially among frail older adults with co-morbidities, poor physical function, and impaired cognition. Thus, knowledge, attitude, and practice (KAP) of elderly diabetic patients play an essential role in controlling the disease and its complications.Patients and Methods: A cross-sectional study was conducted on 176 diabetic patients at the outpatient clinics, National Geriatric Hospital, Hanoi, Vietnam from August to November 2015. Patients’ knowledge, attitude, and practice regarding diabetes mellitus were assessed using a structured questionnaire. Exploratory factor analysis and multivariate Tobit regression model were used to identify factors associated with knowledge, attitude, practice about diabetes mellitus.Results: Of 176 diabetic patients, patients’ knowledge was divided into two main groups: “Diabetes definition and management” (mean score = 57.7 ± 25.6) and “Targets for diabetic control” (mean score = 66.1 ± 30.4). Patients scored high points of attitudes toward diabetes severity and its complications (mean score = 95.8 ± 13.0); however, knowledge and practice scores were only moderate (mean score = 68.1 ± 16.8). There were only 8.5% of people having daily self-blood glucose monitoring. Advanced age, low educational level, rural area, and duration of diabetes less than 5 years were negative associated with knowledge, attitude, and practice regarding diabetes mellitus. This study also shows that frailty and co-morbidities/diabetic complications could impair patients’ knowledge.Conclusion: Older patients with diabetes had high levels of perceived severity attitudes on diabetes mellitus. However, the knowledge and practice levels were still inadequate. Pragmatic diabetic health literacy, counseling and education programs, as well as home-based treatments are viable options to improve health outcomes.Keywords: attitude, diabetes, elderly, knowledge, practice

Collagen fiber architecture within the skeletal muscle extracellular matrix (ECM) is significant to passive muscle mechanics. While it is thought that collagen fibers re-orient themselves in response to changes in muscle length, this has not been dynamically visualized and quantified within a muscle. The goal of this study was to measure changes in collagen alignment across a range of muscle lengths and compare the corresponding alignment to muscle mechanics. We hypothesized that collagen fibers dynamically increase alignment in response to muscle stretching, and this change in alignment is related to passive muscle stiffness. Further, we hypothesized that digesting collagen fibers with collagenase would reduce the re-alignment response to muscle stretching. Using DBA/2J and D2.mdx mice, we isolated extensor digitorum longus (EDL), soleus, and diaphragm muscles for collagenase or sham treatment and decellularization to isolate intact or collagenase-digested decellularized muscles (DCMs). These DCMs were mechanically tested and imaged using second harmonic generation microscopy to measure collagen alignment across a range of strains. We found that collagen alignment increased in a strain-dependent fashion, but collagenase did not significantly affect the strain-dependent change in alignment. We also saw that the collagen fibers in the diaphragm epimysium (surface ECM) and perimysium (deep ECM) started at different angles, but still re-oriented in the same direction in response to stretching. These robust changes in collagen alignment were weakly related to passive DCM stiffness. Overall, we demonstrated that the architecture of muscle ECM is dynamic in response to strain and is related to passive muscle mechanics. STATEMENT OF SIGNIFICANCE: Our study presents a unique visualization and quantification of strain-induced changes in muscle collagen fiber alignment as they relate to passive mechanics. Using dynamic imaging of collagen in skeletal muscle we demonstrate that as skeletal muscle is stretched, collagen fibers re-orient themselves along the axis of stretch and increase their alignment. The degree of alignment and the increase in alignment are each weakly related to passive muscle stiffness. Collagenase treatments further demonstrate that the basis for muscle Extracellular matrix stiffness is dependent on factors beyond collagen crosslinking and alignment. Together the study contributes to the knowledge of the structure-function relationships of muscle extracellular matrix to tissue stiffness relevant to conditions of fibrosis and aberrant stiffness., Competing Interests: Conflict of Interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced that work reported in this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: There is increasing awareness that patients without standard modifiable risk factors (SMuRFs; diabetes, hypercholesterolaemia, hypertension and smoking) may represent a unique subset of patients with acute coronary syndrome (ACS). We aimed to investigate the prevalence and outcomes of patients with SMuRF-less ACS undergoing percutaneous coronary intervention (PCI) compared with those with SMuRFs., Methods: We analysed data from the Melbourne Interventional Group PCI Registry. Patients with coronary artery disease were excluded. The primary outcome was 30-day mortality. Secondary outcomes included in-hospital and 30-day events. Long-term mortality was investigated using Cox-proportional hazards regression., Results: From 1 January 2005 to 31 December 2020, 2727/18 988 (14.4%) patients were SMuRF less, with the proportion increasing over time. Mean age was similar for patients with and without SMuRFs (63 years), and fewer females were SMuRF-less (19.8% vs 25.4%, p<0.001). SMuRF-less patients were more likely to present with cardiac arrest (6.6% vs 3.9%, p<0.001) and ST-elevation myocardial infarction (59.1% vs 50.8%, p<0.001) and were more likely to experience postprocedural cardiogenic shock (4.5% vs 3.6%, p=0.019) and arrhythmia (11.2% vs 9.9%, p=0.029). At 30 days, mortality, myocardial infarction, revascularisation and major adverse cardiac and cerebrovascular events did not differ between the groups. During median follow-up of 7 years, SMuRF-less patients had an adjusted 13% decreased rate of mortality (HR 0.87 (95% CI 0.78 to 0.97))., Conclusions: The proportion of SMuRF-less patients increased over time. Presentation was more often a devastating cardiac event compared with those with SMuRFs. No difference in 30-day outcomes was observed and SMuRF-less patients had lower hazard for long-term mortality., Competing Interests: Competing interests: The Melbourne Interventional Group acknowledges funding from Abbott Vascular, AstraZeneca, Bristol Myers Squibb, Medtronic, and Pfizer. These companies do not have access to data and do not have the right to review manuscripts or abstracts before publication., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose: This prospective study aimed to investigate estrogen-induced carcinogenesis by assessing the background levels of abasic sites (apurinic/apyrimidinic sites, AP sites) in Taiwanese breast cancer patients following 5 years of postoperative treatment without recurrence (5-year survivors) (n = 70). The study also sought to compare the extent of these DNA lesions with those found in healthy controls and in breast cancer patients prior to treatment., Methods: Abasic sites were measured using an aldehyde reactive probe and quantified as the total number of abasic sites per total nucleotides. Characterization of the abasic sites in subjects recruited for this study was conducted using the abasic site cleavage assay using putrescine or T7 exonuclease (T7 Exo) and/or exonuclease III (Exo III)., Results: The number of abasic sites detected in 5 year survivors (26.7 ± 10.2 per 10 6 total nucleotides, n = 70) was significantly reduced by 46.9% compared to those in breast cancer patients before treatment (50.3 ± 59.2 per 10 6 total nucleotides, P < 0.001), and was similar to the levels observed in healthy controls (23.3 ± 13.5 per 10 6 total nucleotides, P > 0.05). Further investigation into the specific types of abasic sites indicated that the number of abasic sites excisable by putrescine in controls, breast cancer patients, and 5-year survivors were 63.3%, 78.6%, and 67.7%, respectively. These findings suggest the involvement of oxidative stress rather than depurination/depyrimidination of DNA adducts in the formation of abasic sites. Further analyses were performed using exonuclease cleavage assay to characterize the specific types of abasic sites including 5'-cleaved, 3'-cleaved, intact, and residual abasic sites. Results demonstrated that the proportion of residual abasic sites detected in controls, breast cancer patients, and 5-year survivors were estimated to be 32.7%, 48.8%, and 34.0%, respectively., Conclusion: Overall, these findings suggest clear evidence of treatment-related effects on the reduction of levels of abasic sites as well as on the profile of abasic sites in 5 year survivors., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors alone are responsible for the content and writing of this article.

The ovarian follicle is a complex structure that protects and helps in the maturation of the oocyte, and then releases it through the controlled molecular and structural remodeling process of ovulation. The progesterone receptor (PGR) has been shown to be essential in regulating ovulation-related gene expression changes. In this study, we found disrupted expression of the cellular adhesion receptor gene Sema7A in the granulosa cells of PGR -/- mice during ovulation. We subsequently found that expression of Sema7A in preovulatory follicles is promoted by gonadotropins and hypoxia, establishing an asymmetrical pattern with the SEMA7A protein enriched at the apex of large antral follicles. Sema7A expression was downregulated through a PGR-dependent mechanism in the periovulatory period, the abundance of SEMA7A protein was reduced, and the asymmetric pattern became more homogeneous after an ovulatory stimulus. Receptors for Sema7A can either repel or promote intercellular adhesion. During ovulation, striking inverse regulation of repulsive Plxnc1 and adhesive Itga5/Itgb1 receptors likely contributes to dramatic tissue remodeling. The adhesive receptor Itga5 was significantly increased in periovulatory granulosa cells and cumulus-oocyte complexes (COCs), and functional assays showed that periovulatory granulosa cells and COCs acquire increased adhesive phenotypes, while Sema7A repels granulosa cell contact. These findings suggest that the regulation of Sema7A and its associated receptors, along with the modulation of integrin α5, may be critical in establishing the multilaminar ovarian follicle structure and facilitating the remodeling and apical release of the cumulus-oocyte complex during ovulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Emery, Dunning, Dinh, Akison, Robker and Russell.)

Progesterone receptor (PGR) plays diverse roles in reproductive tissues and thus coordinates mammalian fertility. In the ovary, rapid acute induction of PGR is the key determinant of ovulation through transcriptional control of a unique set of genes that culminates in follicle rupture. However, the molecular mechanisms for this specialized PGR function in ovulation is poorly understood. We have assembled a detailed genomic profile of PGR action through combined ATAC-seq, RNA-seq and ChIP-seq analysis in wildtype and isoform-specific PGR null mice. We demonstrate that stimulating ovulation rapidly reprograms chromatin accessibility in two-thirds of sites, correlating with altered gene expression. An ovary-specific PGR action involving interaction with RUNX transcription factors was observed with 70% of PGR-bound regions also bound by RUNX1. These transcriptional complexes direct PGR binding to proximal promoter regions. Additionally, direct PGR binding to the canonical NR3C motif enable chromatin accessibility. Together these PGR actions mediate induction of essential ovulatory genes. Our findings highlight a novel PGR transcriptional mechanism specific to ovulation, providing new targets for infertility treatments or new contraceptives that block ovulation., (Published by Oxford University Press on behalf of Nucleic Acids Research 2023.)

Objectives: We sought to establish the minimum level of clinical benefit attributable to the Victorian Cardiac Outcomes Registry (VCOR) for the registry to be cost-effective., Design: A modelled cost-effectiveness study of VCOR was conducted from the Australian healthcare system and societal perspectives., Setting: Observed deaths and costs attributed to coronary heart disease (CHD) over a 5-year period (2014-2018) were compared with deaths and costs arising from a hypothetical situation which assumed that VCOR did not exist. Data from the Australian Bureau of Statistics and published sources were used to construct a decision analytic life table model to simulate the follow-up of Victorians aged ≥25 years for 5 years, or until death. The assumed contribution of VCOR to the proportional change in CHD mortality trend observed over the study period was varied to quantify the minimum level of clinical benefits required for the registry to be cost-effective. The marginal costs of VCOR operation and years of life saved (YoLS) were estimated., Primary Outcome Measures: The return on investment (ROI) ratio and the incremental cost-effectiveness ratio (ICER)., Results: The minimum proportional change in CHD mortality attributed to VCOR required for the registry to be considered cost-effective was 0.125%. Assuming this clinical benefit, a net return of $A4.30 for every dollar invested in VCOR was estimated (ROI ratio over 5 years: 4.3 (95% CI 3.6 to 5.0)). The ICER estimated for VCOR was $A49 616 (95% CI $A42 228 to $A59 608) per YoLS. Sensitivity analyses found that the model was sensitive to the time horizon assumed and the extent of registry contribution to CHD mortality trends., Conclusions: VCOR is likely cost-effective and represents a sound investment for the Victorian healthcare system. Our evaluation highlights the value of clinical quality registries in Australia., Competing Interests: Competing interests: PL is supported by an Australian Government Research Training Program (RTP) scholarship. EZ has received grants from Amgen, AstraZeneca, Pfizer, Shire and Zoll Medical, outside the submitted work. DL has received honoraria or study grants from AbbVie, Amgen, Astellas, AstraZeneca, Bohringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Sanofi, Shire and Zoll Medical, outside the submitted work. DS is supported by the National Heart Foundation Fellowship and Viertel Foundation Award. CMR is supported by a National Health and Medical Research Council Principal Research Fellowship (GNT1136372). All other authors have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The healthy skeletal muscle extracellular matrix (ECM) has several functions including providing structural integrity to myofibers, enabling lateral force transmission, and contributing to overall passive mechanical properties. In diseases such as Duchenne Muscular dystrophy, there is accumulation of ECM materials, primarily collagen, which results in fibrosis. Previous studies have shown that fibrotic muscle is often stiffer than healthy muscle, in part due to the increased number and altered architecture of collagen fibers within the ECM. This would imply that the fibrotic matrix is stiffer than the healthy matrix. However, while previous studies have attempted to quantify the extracellular contribution to passive stiffness in muscle, the outcomes are dependent on the type of method used. Thus, the goals of this study were to compare the stiffness of healthy and fibrotic muscle ECM and to demonstrate the efficacy of two methods for quantifying extracellular-based stiffness in muscle, namely decellularization and collagenase digestion. These methods have been demonstrated to remove the muscle fibers or ablate collagen fiber integrity, respectively, while maintaining the contents of the extracellular matrix. Using these methods in conjunction with mechanical testing on wildtype and D2. mdx mice, we found that a majority of passive stiffness in the diaphragm is dependent on the ECM, and the D2. mdx diaphragm ECM is resistant to digestion by bacterial collagenase. We propose that this resistance is due to the increased collagen cross-links and collagen packing density in the ECM of the D2. mdx diaphragm. Taken altogether, while we did not find increased stiffness of the fibrotic ECM, we did observe that the D2. mdx diaphragm conveyed resistance against collagenase digestion. These findings demonstrate how different methods for measuring ECM-based stiffness each have their own limitations and can produce different results., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lucas Smith reports financial support was provided by National Institute of Arthritis and Musculoskeletal and Skin Diseases., (© 2023 The Author(s).)

Although curcumin in the form of nanoparticles has been demonstrated as a potential anti-tumor compound, the impact of curcumin and nanocurcumin in vitro on normal cells and in vivo in animal models is largely unknown. This study evaluated the toxicity of curcumin-loaded micelles in vitro and in vivo on several tumor cell lines, primary stromal cells, and zebrafish embryos. Breast tumor cell line (MCF7) and stromal cells (human umbilical cord vein endothelial cells, human fibroblasts, and human umbilical cord-derived mesenchymal stem cells) were used in this study. A zebrafish embryotoxicity (FET) assay was conducted following the Organisation for Economic Co-operation and Development (OECD) Test 236. Compared to free curcumin, curcumin PM showed higher cytotoxicity to MCF7 cells in both monolayer culture and multicellular tumor spheroids. The curcumin-loaded micelles efficiently penetrated the MCF7 spheroids and induced apoptosis. The nanocurcumin reduced the viability and disturbed the function of stromal cells by suppressing cell migration and tube formation. The micelles demonstrated toxicity to the development of zebrafish embryos. Curcumin-loaded micelles demonstrated toxicity to both tumor and normal primary stromal cells and zebrafish embryos, indicating that the use of nanocurcumin in cancer treatment should be carefully investigated and controlled.

Background: Renal impairment post-percutaneous coronary intervention (post-PCI) is a well-described adverse effect following the administration of contrast media. Within a large cohort of registry patients, we aimed to explore the incidence, predictors and clinical outcomes of renal impairment post-PCI., Methods: The Victorian Cardiac Outcomes Registry is an Australian state-based clinical quality registry focusing on collecting data from all PCI capable centres. Data from 36 970 consecutive PCI cases performed between 2014 and 2018 were analysed. Patients were separated into three groups based on post-procedure creatinine levels (new renal impairment (NRI), defined as an absolute rise in serum creatinine>44.2 µmol/L or>25% of baseline creatinine; new renal impairment requiring dialysis (NDR), defined as worsening renal failure that necessitated a new requirement for renal dialysis; no NRI). Multivariate logistic regression analysis was performed to investigate the impact of NRI and NDR on clinical outcomes., Results: 3.1% (n=1134) of patients developed NRI, with an additional 0.6% (n=225) requiring dialysis. 96.3% (n=35 611) of patients did not develop NRI. Those who developed renal impairment were more comorbid, with higher rates of diabetes (22% vs 38% vs 38%, p<0.001), peripheral vascular disease (3.4% vs 8.2% vs 11%, p<0.001), chronic kidney disease (19% vs 49.7% vs 54.2%) and severe left ventricular dysfunction (5% vs 22% vs 40%, p<0.001). Multivariable analysis found that when compared with the no NRI group, those in the combined NRI/NDR group were at a greater risk of 30-day mortality (OR 4.77; 95% CI 3.89 to 5.86, p<0.001) and 30-day major adverse cardiac events (OR 3.72; 95% CI 3.15 to 4.39, p<0.001)., Conclusions: NRI post-PCI remains a common occurrence, especially among comorbid patients, and is associated with a significantly increased morbidity and mortality risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patient factors, such as sex and body mass index (BMI), are known to influence patient radiation exposure. Body surface area (BSA) and its association with patient radiation exposure has not been well studied., Methods and Results: We analysed height, weight, BMI and BSA in consecutive patients undergoing cardiac catheterisation and percutaneous coronary intervention (PCI) at a high-volume Australian centre between September 2016 and April 2020 to assess their association with dose-area product (DAP, Gycm 2 ). The mean age of the cohort was 64.5 ± 12.3 years with males comprising 68.8% ( n = 8100, 5124 diagnostic cardiac catheterisation cases and 2976 PCI cases). Median male BMI was 28.4 kg/m 2 [IQR 25.2-32.1] versus 28.8 kg/m 2 [24.7-33.7] for females, p = 0.01. Males had higher BSA (2.0 ± 0.2 m 2 ) than females (1.78 ± 0.2 m 2 ), p = 0.001. Each 0.4 m 2 increase in BSA conferred a 1.32x fold change in DAP (95% CI 1.29-1.36, p ≤ 0.001). Each 5 kg/m 2 increase in BMI was linked to a 1.13x DAP fold change (1.12-1.14, p ≤ 0.001). Male sex conferred a 1.23x DAP fold change (1.20-1.26, p ≤ 0.001). Multivariable modelling with BMI or BSA explained 14% of DAP variance (R 2 0.67 vs. 0.53 for both, p ≤ 0.001)., Conclusions: BSA is an important anthropometric measure between the sexes and a key predictor of radiation dose and radiation exposure beyond sex, BMI, and weight.

We investigated changes in some laboratory indices and the liver histology of chronic hepatitis patients who were exposed to dioxin. In 2014, we collected liver biopsy samples for histopathological examination from 33 chronic hepatitis patients living around the Da Nang Airbase, which is a dioxin-contaminated area due to the herbicide spraying in Vietnam. Dioxin exposure was measured by its levels in the blood. METAVIR classification was used to clarify the liver fibrosis stage. Laboratory tests included ten biochemical and six hematological indices that were measured in the blood. A regression linear model and binary logistic regression were used for data analysis. The observed alterations in the liver at the histological level mainly comprised hydropic degenerative hepatocytes, lymphocytes and polynuclear leukocytes surrounding the liver cells and granular and lipoic degeneration. In addition, increased TCDD levels were associated with increasing aminotransferase (AST), alanine aminotransferase, protein and total bilirubin levels and liver fibrosis stage. Similarly, increased TEQ-PCDD/Fs levels were associated with higher levels of AST and protein and liver fibrosis stage. In conclusion, dioxin exposure altered the liver histology and increased some biochemical marker indices and the liver fibrosis stage of chronic hepatitis patients living in dioxin-contaminated areas in Da Nang, Vietnam.

Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. Cumulus-oocyte complexes of PRKO mice exhibited normal morphology but showed some altered gene expression. The examination of mitochondrial activity showed subtle differences in PRKO oocytes but no differences in granulosa cell respiration, glycolysis or β-oxidation. Concurrently, RNA-seq identified novel functional pathways through which the PGR may regulate ovulation. PGR-A was the predominant transcriptionally active isoform in granulosa cells and 154 key PGR-dependent genes were identified, including a secondary network of transcription factors. In addition, the PGR regulated unique gene networks in the ovarian stroma. Collectively, we establish the effector pathways activated by the PGR across the ovarian cell types and conclude that PGR coordinates gene expression in the cumulus, granulosa and stromal cells at ovulation. Identifying these networks linking the PGR to ovulation provides novel targets for fertility therapeutics and nonhormonal contraceptive development.

Background Atmospheric changes in pollen concentration may affect human health by triggering various allergic processes. We sought to assess if changes in pollen concentrations were associated with different acute coronary syndrome (ACS) subtype presentations and short-term clinical outcomes. Methods and Results We analyzed data in consecutive patients presenting with ACS (unstable angina, non-ST-segment-elevation myocardial infarction, and ST-segment-elevation myocardial infarction) treated with percutaneous coronary intervention between January 2014 and December 2017 and enrolled in the VCOR (Victorian Cardiac Outcomes Registry). Baseline characteristics were compared among patients exposed to different grass and total pollen concentrations. The primary outcome was occurrence of ACS subtypes and 30-day major adverse cardiac and cerebrovascular events (composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularization, or stroke). Of 15 379 patients, 7122 (46.3%) presented with ST-segment-elevation myocardial infarction, 6781 (44.1%) with non-ST-segment-elevation myocardial infarction, and 1476 (9.6%) with unstable angina. The mean age was 62.5 years, with men comprising 76% of patients. No association was observed between daily or seasonal grass and total pollen concentrations with the frequency of ACS subtype presentation. However, grass and total pollen concentrations in the preceding days (2-day average for grass pollen and 7-day average for total pollen) correlated with in-hospital mortality (odds ratio [OR], 2.17 [95% CI, 1.12-4.21]; P =0.021 and OR, 2.78 [95% CI, 1.00-7.74]; P =0.05), respectively, with a trend of 2-day grass pollen for 30-day major adverse cardiac and cerebrovascular events (OR, 1.50 [95% CI, 0.97-2.32]; P =0.066). Conclusions Increased pollen concentrations were not associated with differential ACS subtype presentation but were significantly related to in-hospital mortality following percutaneous coronary intervention, underscoring a potential biologic link between pollen exposure and clinical outcomes.

Objectives: Patients with ST-elevation myocardial infarction (STEMI) that occur while already in hospital ('in-hospital STEMI') face high mortality. However, data about this patient population are scarce. We sought to investigate differences in reperfusion and outcomes of in-hospital versus out-of-hospital STEMI., Design, Setting and Participants: Consecutive patients with STEMI all treated with percutaneous coronary intervention (PCI) across 30 centres were prospectively recruited into the Victorian Cardiac Outcomes Registry (2013-2018)., Primary and Secondary Outcomes: Patients with in-hospital STEMI were compared with patients with out-of-hospital STEMI with a primary endpoint of 30-day major adverse cardiovascular events (MACE). Secondary endpoints included ischaemic times, all-cause mortality and major bleeding., Results: Of 7493 patients with PCI-treated STEMI, 494 (6.6%) occurred in-hospital. Patients with in-hospital STEMI were older (67.1 vs 62.4 years, p<0.001), more often women (32% vs 19.9%, p<0.001), with more comorbidities. Patients with in-hospital STEMI had higher 30-day MACE (20.4% vs 9.8%, p<0.001), mortality (12.1% vs 6.9%, p<0.001) and major bleeding (4.9% vs 2.3%, p<0.001), than patients with out-of-hospital STEMI. According to guideline criteria, patients with in-hospital STEMI achieved symptom-to-device times of ≤70 min and ≤90 min in 29% and 47%, respectively. Patients with out-of-hospital STEMI achieved door-to-device times of ≤90 min in 71%. Occurrence of STEMI while in hospital independently predicted higher MACE (adjusted OR 1.77, 95% CI 1.33 to 2.36, p<0.001) and 12-month mortality (adjusted OR 1.49, 95% CI 1.08 to 2.07, p<0.001)., Conclusions: Patients with in-hospital STEMI experience delays to reperfusion with significantly higher MACE and mortality, compared with patients with out-of-hospital STEMI, after adjustment for confounders. Focused strategies are needed to improve recognition and outcomes in this high-risk and understudied population., Competing Interests: Competing interests: JS is supported by a Monash University scholarship. RD receives teaching and travel grants from Abbott, Medtronic and Boehringer. He serves on the advisory board of Astra Zeneca. SJD is proctor for Medtronic and his work is supported by a grant (1111170) from the National Health and Medical Research Council of Australia. SZ has obtained research funding from Abbott Vascular, Biotronik Australia and Medtronic Australia and speaking honoraria from AstraZeneca. All other authors have no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: In this study, we sought to evaluate the costs of percutaneous coronary intervention (PCI) across a variety of indications in Victoria, Australia, using a direct per-person approach, as well as to identify key cost drivers., Design: A cost-burden study of PCI in Victoria was conducted from the Australian healthcare system perspective., Setting: A linked dataset of patients admitted to public hospitals for PCI in Victoria was drawn from the Victorian Cardiac Outcomes Registry (VCOR) and the Victorian Admitted Episodes Dataset. Generalised linear regression modelling was used to evaluate key cost drivers. From 2014 to 2017, 20 345 consecutive PCIs undertaken in Victorian public hospitals were captured in VCOR., Primary Outcome Measures: Direct healthcare costs attributed to PCI, estimated using a casemix funding method., Results: Key cost drivers identified in the cost model included procedural complexity, patient length of stay and vascular access site. Although the total procedural cost increased from $A55 569 740 in 2014 to $A72 179 656 in 2017, mean procedural costs remained stable over time ($A12 521 in 2014 to $A12 185 in 2017) after adjustment for confounding factors. Mean procedural costs were also stable across patient indications for PCI ($A9872 for unstable angina to $A15 930 for ST-elevation myocardial infarction) after adjustment for confounding factors., Conclusions: The overall cost burden attributed to PCIs in Victoria is rising over time. However, despite increasing procedural complexity, mean procedural costs remained stable over time which may be, in part, attributed to changes in clinical practice., Competing Interests: Competing interests: PL is supported by an Australian Government Research Training Program (RTP) scholarship (Award/Grant number is not applicable). EZ has received grants from Amgen, Astra Zeneca, Pfizer, Shire and Zoll Medical Corporation outside of the submitted work. DL has received honoraria or study grants from Abbvie, Amgen, Astellas, AstraZeneca, Bohringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Sanofi, Shire and Zoll Medical Corporation, outside the submitted work. DS is supported by the National Heart Foundation Fellowship and Viertel Foundation Award. CMR is supported by a National Health and Medical Research Council Principal Research Fellowship (GNT1136372). All other authors have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To explore the relationship between emergency medical service (EMS) delay time, overall time to reperfusion and clinical outcome in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI)., Methods: This was a retrospective observational study of 2976 patients with STEMI who presented to EMS and underwent PPCI between January 2014 and December 2017. We performed multivariable logistic models to assess the relationship between EMS delay time and 30-day mortality and to identify factors associated with system delay time., Results: EMS delay time accounted for the first half of total system delay (median=59 min (IQR=48-77)). Compared with those who survived, those who died had longer median EMS delay times (59 (IQR=11-74) vs 74 (IQR=57-98), p<0.001). EMS delay time was independently associated with a higher risk of mortality (adjusted OR 1.20; 95% CI 1.02 to 1.40, for every 30 min increase), largely driven by complicated patients with cardiogenic shock or cardiac arrest. Independent predictors of longer EMS delay times were older age, women, cardiogenic shock, cardiac arrest, prehospital notification and intensive care management. Although longer EMS delay times were associated with shorter door-to-balloon times, total system delay times increased with increasing EMS delay times., Conclusion: Increasing EMS delay times, particularly those result from haemodynamic complications, increase total time to reperfusion and are associated with 30-day mortality after STEMI. All efforts should be made to monitor and reduce EMS delay times for timely reperfusion and better outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite in-depth knowledge of the molecular mechanisms controlling embryonic heart development, little is known about the signals governing postnatal maturation of the human heart., Methods: Single-nucleus RNA sequencing of 54 140 nuclei from 9 human donors was used to profile transcriptional changes in diverse cardiac cell types during maturation from fetal stages to adulthood. Bulk RNA sequencing and the Assay for Transposase-Accessible Chromatin using sequencing were used to further validate transcriptional changes and to profile alterations in the chromatin accessibility landscape in purified cardiomyocyte nuclei from 21 human donors. Functional validation studies of sex steroids implicated in cardiac maturation were performed in human pluripotent stem cell-derived cardiac organoids and mice., Results: Our data identify the progesterone receptor as a key mediator of sex-dependent transcriptional programs during cardiomyocyte maturation. Functional validation studies in human cardiac organoids and mice demonstrate that the progesterone receptor drives sex-specific metabolic programs and maturation of cardiac contractile properties., Conclusions: These data provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.

Bleeding severity in patients undergoing percutaneous coronary intervention (PCI), defined by the Bleeding Academic Research Consortium (BARC), portends adverse prognosis. We analysed data from 37,866 Australian patients undergoing PCI enrolled in the Victorian Cardiac Outcomes Registry (VCOR), and investigated the association between increasing BARC severity and in-hospital and 30-day major adverse cardiac and cerebrovascular events (MACCE) (a composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularisation, or stroke). Independent predictors associated with major bleeding (BARC groups 3&5), and MACCE were also assessed. There was a stepwise increase in in-hospital and 30-day MACCE with greater severity of bleeding. Independent predictors of bleeding included female sex (Odds Ratio (OR) 1.34), age (OR 1.02), fibrinolytic therapy (OR 1.77), femoral access (OR 1.51), and ticagrelor (OR 1.42), all significant at the p < 0.001 level. Following adjustment of clinically important variables, BARC 3&5 bleeds (OR 4.37) were still predictive of cumulative in-hospital and 30-day MACCE. In conclusion, major bleeding is an uncommon but potentially fatal PCI complication and was independently associated with greater MACCE rates. Efforts to mitigate the occurrence of bleeding, including radial access and judicious use of potent antiplatelet therapies, may ameliorate the risk of short-term adverse clinical outcomes.

Objective: Women have reported higher mortality and major adverse cardiovascular events (MACE) following acute coronary syndromes (ACSs) compared with men. With this in mind, we aimed to identify predictors of poor quality of life (QoL) post-ACS as our primary outcome. We examined predictors of MACE, major cerebrovascular events and major bleeding as our secondary outcome., Design: Prospective cohort study., Setting: 30 metropolitan centres across the Victorian Cardiac Outcomes Registry network., Participants: 16 517 patients treated with percutaneous coronary intervention (PCI) for ACS (22.9% females). Selection/inclusion criteria: consecutive patients with successful or attempted PCI for ACS from 2013 to 2016, alive at 30 days post-PCI., Exclusion Criteria: patients not fulfilling ACS criteria. At 30 days, 2497 (64.7% females) completed the QoL EQ-5D-3L instrument., Primary and Secondary Outcome Measures: QoL, assessed using the EuroQo-5Dimensions (EQ-5D-3L) instrument by telephone at 30 days. Independent predictors of QoL were identified by univariate and multivariate logistic regression analyses., Results: Women were significantly older with more diabetes, cerebrovascular disease and renal failure. Regarding the primary outcome, female sex was independently associated with moderate/severe impairment in all EQ-5D-3L domains including mobility (OR 2.38, 95% CI 2.06 to 2.75, p<0.001), personal care (OR 2.14, 95% CI 1.73 to 2.66, p<0.001), activities of daily living (OR 1.84, 95% CI 1.63 to 2.08, p<0.001), pain/discomfort (OR 1.44, 95% CI 1.24 to 1.67, p<0.001) and anxiety/depression (OR 1.49, 95% CI 1.30 to 1.70, p<0.001). Women had significantly lower self-rated Visual Analogue Scale scores (80.0 for both groups, IQR 60-85 vs 70-90, p<0.001). There was no significant difference between the sexes in secondary outcomes., Conclusions: Female sex was a predictor of poorer QoL following PCI for ACS including significantly higher pain, anxiety and depression. This was independent of age, comorbidities and ACS presentation. There is a clinical need for a tailored approach in female ACS management, for example, emphasis on management of depressive and anxiety symptoms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study sought to determine the most risk-adjustment model for 30-day all-cause mortality in order to report risk-adjusted outcomes. The study also explored whether the exclusion of extreme high-risk conditions of cardiogenic shock, intubated out-of-hospital cardiac arrest (OHCA), or the need for mechanical ventricular support affected the model's predictive accuracy., Background: Robust risk-adjustment models are a critical component of clinical quality registries, allowing outcomes to be reported in a fair and meaningful way. The Victorian Cardiac Outcomes Registry encompasses all 30 hospitals in the state of Victoria, Australia, that undertake percutaneous coronary intervention., Methods: Data were collected on 27,544 consecutive percutaneous coronary intervention procedures from 2014 to 2016. Twenty-eight patient risk factors and procedural variables were considered in the modeling process. The multivariable logistic regression analysis considered derivation and validation datasets, along with a temporal validation period., Results: The model included risk-adjustment for cardiogenic shock, intubated OHCA, estimated glomerular filtration rate, left ventricular ejection fraction, angina type, mechanical ventricular support, ≥80 years of age, lesion complexity, percutaneous access site, and peripheral vascular disease. The C-statistic for the derivation dataset was 0.921 (95% confidence interval: 0.905 to 0.936), with C-statistics of 0.931 and 0.934 for 2 validation datasets reflecting the 2014 to 2016 and 2017 periods. Subgroup modeling excluding cardiogenic shock and intubated OHCA provided similar risk-adjusted outcomes (p = 0.32)., Conclusions: Our study has developed a highly predictive risk-adjustment model for 30-day mortality that included high-risk presentations. Therefore, we do not need to exclude high-risk cases in our model when determining risk-adjusted outcomes., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Progesterone receptor (PGR) co-ordinately regulates ovulation, fertilisation and embryo implantation through tissue-specific actions, but the mechanisms for divergent PGR action are poorly understood. Here we characterised PGR activity in mouse granulosa cells using combined ChIP-seq for PGR and H3K27ac and gene expression microarray. Comparison of granulosa, uterus and oviduct PGR-dependent genes showed almost complete tissue specificity in PGR target gene profiles. In granulosa cells 82% of identified PGR-regulated genes bound PGR within 3 kb of the gene and PGR binding sites were highly enriched in proximal promoter regions in close proximity to H3K27ac-modified active chromatin. Motif analysis showed highly enriched PGR binding to the PGR response element (GnACAnnnTGTnC), but PGR also interacted significantly with other transcription factor binding motifs. In uterus PGR showed far more tendency to bind intergenic chromatin regions and low evidence of interaction with other transcription factors. This is the first genome-wide description of PGR action in granulosa cells and systematic comparison of diverse PGR action in different reproductive tissues. It clarifies finely-tuned contextual PGR-chromatin interactions with implications for more targeted reproductive medicine.

Background Timely revascularization with percutaneous coronary intervention ( PCI ) reduces death following myocardial infarction. We evaluated if a sex gap in symptom-to-door ( STD ), door-to-balloon ( DTB ), and door-to- PCI time persists in contemporary patients, and its impact on mortality. Methods and Results From 2013 to 2016 the Victorian Cardiac Outcomes Registry prospectively recruited 13 451 patients (22.5% female) from 30 centers with ST-segment-elevation myocardial infarction ( STEMI , 47.8%) or non-ST-segment-elevation myocardial infarction (NSTEMI) (52.2%) who underwent PCI . Adjusted log-transformed STD and DTB time in the STEMI cohort and STD and door-to- PCI time in the NSTEMI cohort were analyzed using linear regression. Logistic regression was used to determine independent predictors of 30-day mortality. In STEMI patients, women had longer log- STD time (adjusted geometric mean ratio 1.20, 95% CI 1.12-1.28, P<0.001), log- DTB time (adjusted geometric mean ratio 1.12, 95% CI 1.05-1.20, P=0.001), and 30-day mortality (9.3% versus 6.5%, P=0.005) than men. Womens' adjusted geometric mean STD and DTB times were 28.8 and 7.7 minutes longer, respectively, than were mens' times. Women with NSTEMI had no difference in adjusted STD , door-to- PCI time, or early (<24 hours) versus late revascularization, compared with men. Female sex independently predicted a higher 30-day mortality (odds ratio 1.67, 95% CI 1.11-2.49, P=0.01) in STEMI but not in NSTEMI. Conclusions Women with STEMI have significant delays in presentation and revascularization with a higher 30-day mortality compared with men. The delay in STD time was 4-fold the delay in DTB time. Women with NSTEMI had no delay in presentation or revascularization, with mortality comparable to men. Public awareness campaigns are needed to address women's recognition and early action for STEMI .

Objectives: To evaluate the impact of preoperative atrial fibrillation (pre-op AF) on early and late mortality after isolated coronary artery bypass graft (CABG) surgery., Methods: Data obtained prospectively between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database Program were retrospectively analyzed. Patients who underwent concomitant atrial arrhythmia surgery/ablation were excluded. Demographic and operative data were compared between patients with and without pre-op AF. The independent association of pre-op AF on early mortality, perioperative complications, and late mortality was determined., Results: Isolated CABG surgery was performed in 21,534 patients; 1312 (6.1%) presented with pre-op AF. Pre-op AF patients were older (mean age, 71 years vs. 65 years, p<0.001) and had more comorbidities reflected in a higher additive EuroSCORE (8.4±3.5 vs. 6.5±3.2, p=0.001). Even after accounting for confounding factors, however, pre-op AF was associated with a 63% increase in 30-day mortality [4.2% vs. 1.4%; hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.17-2.29; p=0.004] and 39% increase in late mortality (5-year survival, 78% vs. 90%; HR, 1.39; 95% CI, 1.20-1.61; p<0.001)., Conclusion: Pre-op AF is an independent predictor of poor early and late outcomes. Pre-op AF should be considered, therefore, in the development or update of risk stratification models for CABG surgery., (Copyright © 2014. Published by Elsevier Ltd.)

Japanese encephalitis virus (JEV), which belongs to the genus Flavivirus of the family Flaviviridae, is a leading cause of meningo-encephalitis in Asian countries. The flavivirus non-structural protein 1 (NS1) plays a role in virus replication and in the elicitation of an immune response. The NS1' protein found among the members of the JEV subgroup is an extended form of NS1 and is generated by a -1 ribosomal frameshift. This protein is known to be involved in viral pathogenicity; however, its specific function is still unknown. Here, we describe an investigation of the molecular function of NS1' protein through the production of JEV NS1'-expressing and -non-expressing clones and their infection of avian and mammalian cells. Efficient NS1' protein expression was observed in avian cells and was found to facilitate JEV production in both avian cultured cells and embryonated chicken eggs. NS1' protein was observed to co-localize with NS5 protein and resulted in increased viral RNA levels in avian cells. These findings clearly indicate that NS1' enhances the production of JEV in avian cells and may facilitate the amplification/maintenance role of birds in the virus transmission cycle in nature.

Objectives: The use of the radial artery as a second arterial graft during coronary surgery has grown in popularity due to high patency and low harvest site complication rates. We sought to assess whether higher risk patients derive prognostic benefit., Methods: From 2001 to 2009, 11,388 patients underwent isolated primary multivessel coronary surgery. We identified a higher risk subgroup (n = 2581) according to emergent status, coronary instability, low ejection fraction and/or aortic counterpulsation. Among these, 1832 (71%) received at least one radial artery graft in addition to a left internal thoracic artery (LITA). The remaining 749 (29%) received LITA and veins only., Results: Patients not receiving a radial artery were more likely to be elderly, female, have poor left ventricular function or be of emergent status. These patients experienced higher unadjusted 30-day mortality (radial: 2% vs vein: 8%, P < 0.0001) with lower unadjusted 7-year survival (80 ± 1.3 vs 67 ± 2.4%, P < 0.0001). Subsequently, 515 patients in the radial group were propensity-matched to 515 receiving LITA + veins (mean logistic EuroSCORE, radial: 11.6 ± 9.7% vs vein: 11.6 ± 10.3%, P = 0.99). At 30 days, there were comparable rates of mortality (radial: 4% vs vein: 3%, P > 0.99), stroke (1 vs 1%, P > 0.99), myocardial infarction (1 vs 2%, P = 0.79), and any morbidity/mortality (34 vs 35%, P = 0.95). At 7 years, survival rates between the radial and vein groups were similar (radial: 75 ± 2.6% vs vein: 74 ± 2.9%, P = 0.65)., Conclusions: Patients with the greatest coronary instability, urgency of surgery or impairment of ventricular function are not disadvantaged in early outcomes or mid-term survival by the use of only a single arterial graft.

Background: There are limited data on the impact of smoking status on outcomes after isolated coronary artery bypass graft (CABG) surgery., Methods: Data obtained prospectively between June 2001 and December 2009 by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program were retrospectively analyzed. Demographic and operative data were compared between patients who were non-smokers, previous smokers, and current smokers. The independent impact of smoking status on 14 short-term complications and long-term mortality was determined using binary logistic and Cox regression, respectively., Results: Isolated CABG surgery was performed in 21 534 patients; smoking status was recorded in 21486 (99.8%). Of these, 7023 (32.6%) had no previous smoking history, 11183 (59.1%) were previous smokers, and 3290 (15.2%) were current smokers. The 30-day mortality rate was 1.8% in non-smokers, 1.5% in previous smokers, and 1.5% in current smokers (p=NS). The incidence of peri-operative complications was generally similar in the three groups, but current smokers were at an increased risk of pneumonia (p<0.001), and multisystem failure (p=0.003). The mean follow-up period for this study was 37 months (range, 0-106 months). After adjusting for differences in patient variables, the incidence of late mortality was higher in previous smokers [hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.47-2.05; p<0.001] or current smokers (HR, 1.41; 95% CI, 1.26-1.59; p<0.001) compared to non-smokers., Conclusion: Smoking status is not associated with early mortality after isolated CABG. It is, however, associated with an increased risk of pulmonary complications and reduced long-term survival., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: An increasing proportion of patients present for concomitant aortic valve replacement (AVR) and coronary artery bypass grafting (CABG) with left ventricular (LV) dysfunction. The aim of this study was to evaluate the early outcomes and late survival of patients with different degrees of LV function undergoing concomitant AVR and CABG., Methods: Between June 2001 and December 2009, patients undergoing concomitant AVR-CABG were identified from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program. Demographic, operative data and post-operative outcomes were compared between patients with normal (> 60%), moderately impaired (30- -60%), and severely impaired (< 30%) estimated LV ejection fraction (LVEF). Independent risk factors for short- and long-term mortality were identified using binary logistic and Cox regression, respectively., Results: AVR-CABG was performed in 2,563 patients with a mean follow up of 36 months (range 0-106). 144 (5.6%) had severely impaired LVEF, 983 (38.3%) had moderately impaired LVEF while the remaining 1377 (53.7%) had normal LVEF. The 30-day mortality in patients with severely impaired, moderately impaired and normal LVEF was 9.0%, 4.3% and 2.9%, respectively. This was significant on univariate (p < 0.001) but not multivariate analysis (p = NS). Severely impaired, moderately impaired and normal LVEF patients experienced 5-year survivals of 63.7%, 77.1% and 82.5%, respectively. Severely impaired LVEF was an independent multivariable predictor of late mortality (HR 1.71; 95% CI 1.22-2.40; p = 0.002)., Conclusions: Patients with severely impaired LVEF experience worse outcomes. However, in the era of modern surgery, this alone should not predicate exclusion, given the established benefits of surgery in this high-risk group.

Background: Several studies have shown that postoperative atrial fibrillation (POAF) is associated with poorer short-term and long-term outcomes after general cardiac operations. There is, however, a paucity of data on the impact of POAF on outcomes after isolated aortic valve replacement (AVR)., Methods: Data for all patients undergoing isolated first-time AVR between June 2001 and December 2009 was obtained from the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) National Cardiac Surgery Database Program and a retrospective analysis was conducted. Preoperative characteristics, early postoperative outcome, and late survival were compared between patients in whom POAF developed and those in whom it did not. Propensity score matching was performed to correct for differences between the 2 groups., Results: Excluding patients with preoperative arrhythmia, isolated first-time AVR was performed in 2,065 patients. POAF developed in 725 (35.1%) of them. Patients with POAF were significantly older (mean age, 72 versus 65 years; p < 0.001) and presented more often with comorbidities, including hypertension, respiratory disease, and hypercholesterolemia (all p < 0.05). From the initial study population, 592 propensity-matched patient pairs were derived; the overall matching rate was 81.7%. In the matched groups, 30-day mortality was not significantly different between the POAF and non-POAF groups (1.5% versus 1%; p = 0.48). Patients with POAF were, however, at an independently increased risk of perioperative complications, including new renal failure, gastrointestinal complications, and 30-day readmission (p < 0.05). Seven-year mortality was not significantly different between POAF and non-POAF groups (78% versus 83%; p = 0.63)., Conclusions: POAF is a risk factor for short-term morbidity but is not associated with a higher rate of early or late mortality after isolated AVR., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: The advent of percutaneous aortic valve implantation has increased interest in the outcomes of conventional aortic valve replacement in elderly patients. The current study critically evaluates the short-term and long-term outcomes of elderly (≥80 years) Australian patients undergoing isolated aortic valve replacement., Methods: Data obtained prospectively between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database Program were retrospectively analysed. Isolated aortic valve replacement was performed in 2791 patients; of these, 531 (19%) were at least 80 years old (group 1). The patient characteristics, morbidity and short-term mortality of these patients were compared with those of patients who were <80 years old (group 2). The long-term outcomes in elderly patients were compared with the age-adjusted Australian population., Results: Group 1 patients were more likely to be female (58.6% vs 38.0%, p<0.001) and presented more often with co-morbidities including hypertension, cerebrovascular disease and peripheral vascular disease (all p<0.05). The 30-day mortality rate was not independently higher in group 1 patients (4.0% vs 2.0%, p=0.144). Group 1 patients had an independently increased risk of complications including new renal failure (11.7% vs 4.2%, p<0.001), prolonged (≥24 h) ventilation (12.4% vs 7.2%, p=0.003), gastrointestinal complications (3.0% vs 1.3%, p=0.012) and had a longer mean length of intensive care unit stay (64 h vs 47 h, p<0.001). The 5-year survival post-aortic valve replacement was 72%, which is comparable to that of the age-matched Australian population., Conclusion: Conventional aortic valve replacement in elderly patients achieves excellent outcomes with long-term survival comparable to that of an age-adjusted Australian population. In an era of percutaneous aortic valve implantation, it should still be regarded as the gold standard in the management of aortic stenosis.

Background: The proportion of elderly (≥80 years) patients undergoing coronary artery bypass surgery (CABG) is increasing., Methods: A retrospective analysis of data, collected by the Australasian Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program between June 2001 and December 2009 was performed. Isolated CABG was performed in 21,534 patients; of these, 1,664 (7.7%) were at least 80 years old (group 1). Patient characteristics, morbidity, and short-term mortality of these patients were compared with those aged less than 80 years (group 2). The long-term outcome of group 1 patients after CABG surgery was compared with an age and sex-matched Australian population., Results: Patients over 80 years old were more likely to be female (36.6% vs 17.3%, p < 0.001) and presented significantly more often with heart failure, hypertension, and triple-vessel disease (all p < 0.05). The 30-day mortality was higher in group 1 patients (4.2% vs 1.5%, p < 0.001). Group 1 patients also had an increased risk of complications, including prolonged (>24 hours) ventilation (14.2% vs 8.2%, p < 0.001), renal failure (7.3% vs 3.4%, p < 0.001), and mean intensive care unit stay (60.7 vs 42.5 hours, p < 0.001). The 5-year survival of elderly patients (73%) was comparable with the age-matched Australian population. Independent risk factors for 30-day mortality in group 1 patients included preoperative renal failure (p = 0.010), congestive heart failure (p = 0.014), and a nonelective procedure (p = 0.016)., Conclusions: Elderly patients who undergo isolated CABG have significantly lower perioperative risks than have been previously reported. The long-term survival of these patients is comparable with an age-adjusted population., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Mitral valve surgery may be regarded as less favourable for training, due to greater mortality risk, technical complexity, and difficulty for the supervisor to observe. We examined this perception by reviewing a multicentre experience., Methods: We analysed a multicentre database over a 7-year period containing 2216 isolated and combined mitral procedures. Of these, 2048 were performed by consultants and 168 by trainees (92% vs 8%) of varying seniority. Preoperative characteristics, early postoperative outcomes and 6-year survival were compared between groups. Propensity-score matching was performed to correct for group differences., Results: Trainees were less likely to operate on patients, who had previously undergone coronary surgery (consultant 4.3% vs trainee 1.2%, p=0.043) and those with moderate to severe mitral regurgitation (86% vs 81%, p=0.012). There were no other statistically significant differences in preoperative variables, such as urgency, endocarditis and left-ventricular dysfunction. There were similar rates of mitral valve repair (48% vs 51%, p=0.48). Trainees were more likely to operate on rheumatic valve pathology (20% vs 28%, p=0.012). Intra-operatively, trainees had longer aortic cross-clamp times (119 ± 52 vs 136 ± 50 min, p=0.0001). At 30 days, mortality was comparable (4.5% vs 3.6%, p=0.56) with a trend towards higher any mortality/morbidity in consultant procedures (33% vs 26%, p=0.059). At 6 years, survival was similar (79 ± 1.4% vs 78 ± 4.0%, p=0.73). After derivation of 142 propensity-score-matched patient pairs, trainees cases still experienced longer cross-clamp times (121 ± 58 vs 137 ± 52 min, p=0.023), but there was similar 30-day mortality (4.2% vs 3.5%, p>0.99) and any mortality/morbidity (28% vs 24%, p=0.52). Six-year survival between matched pairs was also similar (74 ± 7.2% vs 80 ± 4.4%, p=0.64). Trainee status did not predict early or late adverse events after multivariate Cox regression with and without propensity-score adjustment., Conclusions: Trainee outcomes are not inferior even when corrected for risk. This suggests that excellent operative training and supervision can be achieved in mitral valve surgery., (Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

We designed a new set of primers for reverse transcriptase loop-mediated isothermal amplification (RTLAMP) to specifically amplify the HA gene of avian influenza viruses subtype H5N1. By testing nine H5N1 virus strains and 41 clinical samples collected in Northern Vietnam, we found that the new primers showed higher sensitivity and specificity than the previously published RT-LAMP primers and were comparable to the RT-PCR method currently recommended by WHO. These results suggest that our RT-LAMP assay may be a better choice as a diagnostic tool for current H5N1 influenza virus infection.

Objectives: To determine the association between previous percutaneous coronary intervention (PCI) and results after coronary artery bypass graft surgery (CABG)., Background: Increasing numbers of patients undergoing CABG have previously undergone PCI., Methods: We analyzed consecutive first-time isolated CABG procedures within the Australasian Society of Cardiac and Thoracic Surgeons Database from June 2001 to May 2008. Logistic regression and propensity score analyses were used to assess the risk-adjusted impact of prior PCI on in-hospital mortality and major adverse cardiac events. Cox regression model was used to assess the effect of prior PCI on mid-term survival., Results: Of 13,184 patients who underwent CABG, 11,727 had no prior PCI and 1,457 had prior PCI. Mean follow-up was 3.3 +/- 2.1 years. Patients without prior PCI had a higher EuroSCORE value (4.4 +/- 3.3 vs. 3.6 +/- 3.0, p < 0.001), were older, and more likely to have left main stem stenosis and recent myocardial infarction. There was no difference in unadjusted in-hospital mortality (1.65% vs. 1.55%, p = 0.78) or major adverse cardiac events (3.0% vs. 3.0%, p = 0.99) between patients with or without prior PCI. After adjustment, prior PCI was not a predictor of in-hospital (odds ratio: 1.22, 95% confidence interval [CI]: 0.76 to 2.0, p = 0.41) or mid-term mortality at 6-year follow-up (hazard ratio: 0.94, 95% CI: 0.75 to 1.18, p = 0.62)., Conclusions: In this large registry study, prior PCI was not associated with increased short- or mid-term mortality after CABG. Good outcomes can be obtained in the group of patients undergoing CABG who have had previous PCI.

Background: Reoperative coronary artery bypass grafting (redo CABG) shows improving outcomes, but with varying degrees of improvement. We assessed contemporary outcomes after redo CABG to determine if redo status is still a risk factor for early postoperative complications and midterm survival., Methods: Isolated CABG procedures (June 1, 2001 to May 31, 2008) within the Australasian Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database were included. Redo status as a predictor for early outcomes was assessed with logistic regression analysis. Midterm survival was determined from the National Death Index. Effect of redo status on midterm survival was assessed using a Cox proportional hazards model., Results: Inclusion criteria were met by 13,436 patients, and 458 (3.4%) underwent redo CABG. Operative mortality was 4.8% for redo CABG and 1.8% for first-time CABG (p < 0.001). After adjustment, redo status remained a predictor for operative mortality (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.3 to 3.6), myocardial infarction (OR, 2.8; 95% CI, 1.6 to 6.0), and prolonged ventilation (OR, 1.5; 95% CI, 1.1 to 2.0). Unadjusted survival was lower for the redo CABG group vs the first-time CABG group at up to 6 years (p = 0.01, log-rank test. After adjusting for differences in patient variables, redo status was not a predictor of midterm survival (OR, 1.03; 95% CI, 0.78 to 1.35; p = 0.85)., Conclusions: Early postoperative outcomes of redo CABG are encouraging. Midterm survival is excellent; however, redo remains a significant risk factor for operative mortality in contemporary practice.

Influenza A virus has the ability to overcome immunity from previous infections through the acquisition of genetic changes. Thus, understanding the evolution of the viruses in humans is important for the surveillance and the selection of vaccine strains. A total of 30 influenza A/H3N2 viruses and 35 influenza A/H1N1 viruses that were collected in Vietnam from 2001 to 2006 were used to analyze the evolution of the hemagglutinin (HA), neuraminidase (NA), and matrix protein (M) genes. Phylogenetic analysis of individual gene segments revealed that the HA and the NA genes of the influenza A viruses evolved in a sequential way. However, the evolutionary pattern of the M gene proved to be nonlinear and was not linked with that of the HA and NA genes. Genetic drift in HA1 segments, especially in the antigenic sites of A/H3N2 viruses, occurred more frequently in A/H3N2 viruses than it did in A/H1N1 viruses. Two reassortants, one influenza A/H3N2 strain and one A/H1N1 strain, were found on the basis of the phylogenetic analysis of the three genes. While both genetic mutation and reassortment contributed to their evolution, the frequency of genetic changes and reassortment events differs between the two subtypes. As influenza viruses circulate throughout the year, we emphasize the importance of surveillance in tropical and subtropical zones, where the emergence of new strains may be detected earlier than it is in temperate zones.

The tissue distribution, cellular localization, and level of expression of angiotensin II (Ang II) receptors were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by in vitro autoradiography, immunohistochemistry, and radioligand binding studies. In the normal human prostate, Ang II receptors were of the AT(1) subtype and localized predominantly to periurethral stromal smooth muscle. The AT(1) receptor antagonist losartan totally displaced specific [(125)I]-[Sar(1),Ile(8)]Ang II binding, in a concentration-dependent manner, whereas the AT(2) receptor antagonist PD123319 was without effect. There was no significant difference in receptor affinity, but AT(1) receptor density was markedly reduced in BPH compared with that in normal prostate. In rat prostate, Ang II (0.01-1 microM) produced a concentration-dependent increase in [(3)H]-noradrenaline release from sympathetic nerves. The findings of the present study suggest that angiotensin AT(1) receptors predominate in the human prostate. The high concentration of AT(1) receptors in the periurethral region suggests a role for Ang II in modulating cell growth, smooth muscle tone, and possibly micturition. Furthermore, down-regulation of AT(1) receptors in BPH may be due to receptor hyperstimulation by increased local levels of Ang II in BPH. Finally, Ang II may play a functional role in modulating sympathetic transmission in the prostate. These data support the novel concept that activation of the renin-angiotensin system may be involved in the pathophysiology of BPH.