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Delayed afterdepolarizations (DADs) and spontaneous depolarizations (SDs) are typically triggered by spontaneous diastolic Ca 2+ release from the sarcoplasmic reticulum (SR) which is caused by an elevated SR Ca 2+ -ATPase (SERCA) uptake and dysfunctional ryanodine receptors. However, recent studies on the T-box transcription factor gene (TBX5) demonstrated that abnormal depolarizations could occur despite a reduced SERCA uptake. Similar findings have also been reported in experimental or clinical studies of diabetes and heart failure. To investigate the sensitivity of SERCA in the genesis of DADs/SDs as well as its dependence on other Ca 2+ handling channels, we performed systematic analyses using the Maleckar et al . model. Results showed that the modulation of SERCA alone cannot trigger abnormal depolarizations, but can instead affect the interdependency of other Ca 2+ handling channels in triggering DADs/SDs. Furthermore, we discovered the existence of a threshold value for the intracellular concentration of Ca 2+ ([Ca 2+ ] i ) for abnormal depolarizations, which is modulated by the maximum SERCA uptake and the concentration of Ca 2+ in the uptake and release compartments in the SR ([Ca 2+ ] up and [Ca 2+ ] rel ). For the first time, our modelling study reconciles different mechanisms of abnormal depolarizations in the setting of ‘lone’ AF, reduced TBX5, diabetes and heart failure, and may lead to more targeted treatment for these patients. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

Delayed afterdepolarizations (DADs) and spontaneous depolarizations (SDs) are typically triggered by spontaneous diastolic Ca2+ release from the sarcoplasmic reticulum (SR) which is caused by an elevated SR Ca2+-ATPase (SERCA) uptake and dysfunctional ryanodine receptors. However, recent studies on the T-box transcription factor gene (TBX5) demonstrated that abnormal depolarizations could occur despite a reduced SERCA uptake. Similar findings have also been reported in experimental or clinical studies of diabetes and heart failure. To investigate the sensitivity of SERCA in the genesis of DADs/SDs as well as its dependence on other Ca2+ handling channels, we performed systematic analyses using the Maleckar et al. model. Results showed that the modulation of SERCA alone cannot trigger abnormal depolarizations, but can instead affect the interdependency of other Ca2+ handling channels in triggering DADs/SDs. Furthermore, we discovered the existence of a threshold value for the intracellular concentration of Ca2+ ([Ca2+]i) for abnormal depolarizations, which is modulated by the maximum SERCA uptake and the concentration of Ca2+ in the uptake and release compartments in the SR ([Ca2+]up and [Ca2+]rel). For the first time, our modelling study reconciles different mechanisms of abnormal depolarizations in the setting of ‘lone’ AF, reduced TBX5, diabetes and heart failure, and may lead to more targeted treatment for these patients. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

Chlamydophila psittaci is found worldwide, but is particularly common among psittacine birds in tropical and subtropical regions. While investigating a human psittacosis outbreak that was associated with avian chlamydiosis in Hong Kong, we identified a novel adenovirus in epidemiologically linked Mealy Parrots, which was not present in healthy birds unrelated to the outbreak or in other animals. The novel adenovirus (tentatively named Psittacine adenovirus HKU1) was most closely related to Duck adenovirus A in the Atadenovirus genus. Sequencing showed that the Psittacine adenovirus HKU1 genome consists of 31,735 nucleotides. Comparative genome analysis showed that the Psittacine adenovirus HKU1 genome contains 23 open reading frames (ORFs) with sequence similarity to known adenoviral genes, and six additional ORFs at the 3' end of the genome. Similar to Duck adenovirus A, the novel adenovirus lacks LH1, LH2 and LH3, which distinguishes it from other viruses in the Atadenovirus genus. Notably, fiber-2 protein, which is present in Aviadenovirus but not Atadenovirus, is also present in Psittacine adenovirus HKU1. Psittacine adenovirus HKU1 had pairwise amino acid sequence identities of 50.3-54.0% for the DNA polymerase, 64.6-70.7% for the penton protein, and 66.1-74.0% for the hexon protein with other Atadenovirus. The C. psittaci bacterial load was positively correlated with adenovirus viral load in the lung. Immunostaining for fiber protein expression was positive in lung and liver tissue cells of affected parrots, confirming active viral replication. No other viruses were found. This is the first documentation of an adenovirus-C. psittaci co-infection in an avian species that was associated with a human outbreak of psittacosis. Viral-bacterial co-infection often increases disease severity in both humans and animals. The role of viral-bacterial co-infection in animal-to-human transmission of infectious agents has not received sufficient attention and should be emphasized in the investigation of disease outbreaks in human and animals.

DNA methylation, one of the most important epigenetic modifications, plays a crucial role in various biological processes. The level of DNA methylation can be measured using whole-genome bisulfite sequencing at single base resolution. However, until now, there is a paucity of publicly available software for carrying out integrated methylation data analysis. In this study, we implemented Methy-Pipe, which not only fulfills the core data analysis requirements (e.g. sequence alignment, differential methylation analysis, etc.) but also provides useful tools for methylation data annotation and visualization. Specifically, it uses Burrow-Wheeler Transform (BWT) algorithm to directly align bisulfite sequencing reads to a reference genome and implements a novel sliding window based approach with statistical methods for the identification of differentially methylated regions (DMRs). The capability of processing data parallelly allows it to outperform a number of other bisulfite alignment software packages. To demonstrate its utility and performance, we applied it to both real and simulated bisulfite sequencing datasets. The results indicate that Methy-Pipe can accurately estimate methylation densities, identify DMRs and provide a variety of utility programs for downstream methylation data analysis. In summary, Methy-Pipe is a useful pipeline that can process whole genome bisulfite sequencing data in an efficient, accurate, and user-friendly manner. Software and test dataset are available at http://sunlab.lihs.cuhk.edu.hk/methy-pipe/.

Background and objectives: Hypernatremia can be community or hospital-acquired, and there may be specific factors unique to the hospital environment, such as intravenous fluid treatment, which contribute to hypernatremia. The aim of this study was to determine the factors associated with the progression from moderate to severe hospital-acquired hypernatremia among patients admitted under general medicine. Materials and Methods: In this retrospective, single-center cohort study (2012 to 2017), we used ICD-10 coding and medical records to identify adult patients who developed moderate hypernatremia and followed them for progression to severe hypernatremia. We profiled the serum biochemistry and the volume and composition of prescribed intravenous fluids. We applied logistic regression to determine the factors associated with the progression to severe hypernatremia, using the patients with moderate hypernatremia as reference. Results: Of the 180 medical inpatients (median age of 81 years) with moderate hospital-acquired hypernatremia, 9.4% progressed to severe hypernatremia. Normal saline comprised 76% of intravenous fluid volume administered prior to onset of moderate hypernatremia. After the onset, 38% of fluid volume prescribed remained normal saline. The factors independently associated with progression to severe hypernatremia included chronic kidney disease stage (odds ratio 2.38, 95% CI: 1.26–4.50, P = 0.008) and serum creatinine increase (per 10 µmol/L, OR 1.29, 95% CI: 1.07–1.57, P = 0.009). Conclusions: Patients with chronic kidney disease and acute kidney injury may have an increased risk of severe hospital-acquired hypernatremia.

Although institutional theorists maintain that the widespread diffusion of ISO 9000 is the result of institutional forces, they have neglected the potential gains to top management in the perpetuation of the standard. Based on a long-horizon event study with control firms to detect long-term abnormal financial gains, we investigate the impact of ISO 9000 adoption on CEO compensation in the U.S. manufacturing industry from 1994 to 2006. We find that the CEOs' total cash compensation was positively adjusted when their firms received ISO 9000 certification, and they received higher-value stock options when their firms embarked on ISO 9000 certification. However, the performance of the ISO 9000 certified firms was not improved throughout this period. Our further analyses suggest that it is likely that the CEO influences the board to obtain higher compensation under an institutionalized environment. Contrary to the traditional institutional theory-based view, we argue that a highly institutionalized environment does provide political opportunities for organizational actors to garner personal advantages.

Background Similarity-based retrieval of Electronic Health Records (EHRs) from large clinical information systems provides physicians the evidence support in making diagnoses or referring examinations for the suspected cases. Clinical Terms in EHRs represent high-level conceptual information and the similarity measure established based on these terms reflects the chance of inter-patient disease co-occurrence. The assumption that clinical terms are equally relevant to a disease is unrealistic, reducing the prediction accuracy. Here we propose a term weighting approach supported by PubMed search engine to address this issue. Methods We collected and studied 112 abdominal computed tomography imaging examination reports from four hospitals in Hong Kong. Clinical terms, which are the image findings related to hepatocellular carcinoma (HCC), were extracted from the reports. Through two systematic PubMed search methods, the generic and specific term weightings were established by estimating the conditional probabilities of clinical terms given HCC. Each report was characterized by an ontological feature vector and there were totally 6216 vector pairs. We optimized the modified direction cosine (mDC) with respect to a regularization constant embedded into the feature vector. Equal, generic and specific term weighting approaches were applied to measure the similarity of each pair and their performances for predicting inter-patient co-occurrence of HCC diagnoses were compared by using Receiver Operating Characteristics (ROC) analysis. Results The Areas under the curves (AUROCs) of similarity scores based on equal, generic and specific term weighting approaches were 0.735, 0.728 and 0.743 respectively (p < 0.01). In comparison with equal term weighting, the performance was significantly improved by specific term weighting (p < 0.01) but not by generic term weighting. The clinical terms “Dysplastic nodule”, “nodule of liver” and “equal density (isodense) lesion” were found the top three image findings associated with HCC in PubMed. Conclusions Our findings suggest that the optimized similarity measure with specific term weighting to EHRs can improve significantly the accuracy for predicting the inter-patient co-occurrence of diagnosis when compared with equal and generic term weighting approaches.

We observed an independent association between vitamin D insufficiency and higher carotid intima-media thickness in a cross-sectional analysis of 139 HIV-infected persons. If confirmed, these findings support a clinical trial of vitamin D supplementation to reduce cardiovascular events in HIV-infected persons.

Chlamydophila psittaci is found worldwide, but is particularly common among psittacine birds in tropical and subtropical regions. While investigating a human psittacosis outbreak that was associated with avian chlamydiosis in Hong Kong, we identified a novel adenovirus in epidemiologically linked Mealy Parrots, which was not present in healthy birds unrelated to the outbreak or in other animals. The novel adenovirus (tentatively named Psittacine adenovirus HKU1) was most closely related to Duck adenovirus A in the Atadenovirus genus. Sequencing showed that the Psittacine adenovirus HKU1 genome consists of 31,735 nucleotides. Comparative genome analysis showed that the Psittacine adenovirus HKU1 genome contains 23 open reading frames (ORFs) with sequence similarity to known adenoviral genes, and six additional ORFs at the 3' end of the genome. Similar to Duck adenovirus A, the novel adenovirus lacks LH1, LH2 and LH3, which distinguishes it from other viruses in the Atadenovirus genus. Notably, fiber-2 protein, which is present in Aviadenovirus but not Atadenovirus, is also present in Psittacine adenovirus HKU1. Psittacine adenovirus HKU1 had pairwise amino acid sequence identities of 50.3-54.0% for the DNA polymerase, 64.6-70.7% for the penton protein, and 66.1-74.0% for the hexon protein with other Atadenovirus. The C. psittaci bacterial load was positively correlated with adenovirus viral load in the lung. Immunostaining for fiber protein expression was positive in lung and liver tissue cells of affected parrots, confirming active viral replication. No other viruses were found. This is the first documentation of an adenovirus-C. psittaci co-infection in an avian species that was associated with a human outbreak of psittacosis. Viral-bacterial co-infection often increases disease severity in both humans and animals. The role of viral-bacterial co-infection in animal-to-human transmission of infectious agents has not received sufficient attention and should be emphasized in the investigation of disease outbreaks in human and animals.

We describe two cases of progressive abducens nerve palsy secondary to a compressive lesion in the Dorello canal. Blood tests, lumbar puncture, nasopharyngeal examination, computed tomography, magnetic resonance imaging, and angiography were performed, but the etiology could not be identified. After consultation with a neuroradiologist, fine-cut magnetic resonance imaging along the course of the abducens nerve with gadolinium and constructive interference in steady state sequences was performed, and the diagnosis was made. In cases of small intracranial pathology, the use of thinner slices or specific sequences is suggested to better visualize the course of cranial nerves.