Three-dimensional residual channel attention networks denoise and sharpen fluorescence microscopy image volumes.

We demonstrate residual channel attention networks (RCAN) for the restoration and enhancement of volumetric time-lapse (four-dimensional) fluorescence microscopy data. First we modify RCAN to handle image volumes, showing that our network enables denoising competitive with three other state-of-the-art neural networks. We use RCAN to restore noisy four-dimensional super-resolution data, enabling image capture of over tens of thousands of images (thousands of volumes) without apparent photobleaching. Second, using simulations we show that RCAN enables resolution enhancement equivalent to, or better than, other networks. Third, we exploit RCAN for denoising and resolution improvement in confocal microscopy, enabling ~2.5-fold lateral resolution enhancement using stimulated emission depletion microscopy ground truth. Fourth, we develop methods to improve spatial resolution in structured illumination microscopy using expansion microscopy data as ground truth, achieving improvements of ~1.9-fold laterally and ~3.6-fold axially. Finally, we characterize the limits of denoising and resolution enhancement, suggesting practical benchmarks for evaluation and further enhancement of network performance.

Taiwan Society of Cardiology Heart Failure Registry 2020: Rationale and Design.

Background: Heart failure (HF) is a significant public health problem worldwide. Death and rehospitalization rates are similar across different HF phenotypes. However, the existing Taiwanese HF registries mainly enrolled inpatients with HF and reduced ejection fraction (HFrEF) before 2019, so their results may not apply to outpatients or patients with HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF) phenotypes. Methods: The Taiwan Society of Cardiology Heart Failure Registry 2020 is a prospective, multicenter, observational registry that will enroll patients with HF from 27 hospitals in Taiwan between 2020 and 2022 and will be followed for two years. Patients eligible for enrollment include those admitted due to acute decompensated heart failure or outpatients with a history of hospitalization for heart failure within the past six months. The registry will collect patient demographics, medical history, HF diagnosis, medication use, examination results, and comorbidities. The registry plans to enroll 3,370 patients, with the distribution of HFrEF/HFmrEF/HFpEF as 59%/13%/28%. Follow-up intervals will occur every six months for up to two years to monitor clinical outcomes and major cardiac interventions. The registry will conclude in December 2024. Conclusions: The Taiwan Society of Cardiology Heart Failure Registry 2020 is a comprehensive and meticulous effort to demonstrate the epidemiology, adherence to guidelines, clinical outcomes, and disease progression of Taiwanese patients with HF in contemporary clinical practice.

2024 Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ systemic syndrome that involves cardiac and extra-cardiac pathophysiological abnormalities. Its growing prevalence causes a major public concern worldwide. HFpEF is usually associated with multiple comorbidities, and non-cardiovascular death is common in patients with HFpEF. In Asia, patients with HFpEF has a younger age, higher prevalence of diabetes and chronic kidney disease than Western countries. A 2-step diagnostic algorithm is recommended in this guideline. In the first step, the diagnosis of HFpEF can be made if patients have symptoms and/or signs of heart failure, left ventricular ejection fraction ≥ 50%, increased natriuretic peptide, and objective evidence of left atrial or left ventricular abnormalities or raised left ventricular filling pressure. If diagnosis is still uncertain, invasive or noninvasive stress test can be performed in the second step. Comorbidities need to be controlled in HFpEF. Weight reduction for obesity and supervised exercise training are recommended for HFpEF. For pharmacological therapy, diuretic is used to relieve congestion and sodium-glucose cotransporter 2 inhibitor, empagliflozin or dapagliflozin, is recommended to improve prognosis of HFpEF. The research on HFpEF is advancing at a rapid pace. It is expected that newer modalities for diagnosis and management of HFpEF could appear in the near future.

Impact of Type 1 Versus Type 2 Diabetes on Developing Herpes Zoster and Post-herpetic Neuralgia: A Population-based Cohort Study.

Type 2 diabetes is associated with an increased risk of herpes zoster and postherpetic neuralgia. However, the association of type 1 diabetes with herpes zoster or postherpetic neuralgia remains unclear. This retrospective cohort study using Taiwan's Health Insurance Research Database included 199,566 patients with type 1 diabetes and 1,458,331 with type 2 diabetes, identified during the period 2000 to 2012. Patients with type 1 diabetes had a significantly higher risk of developing herpes zoster than those with type 2 diabetes (p < 0.001). Across all age groups, the impact of diabetes on herpes zoster was greater in type 1 than in type 2 diabetes. Patients with both type 1 and type 2 diabetes had a 1.45-fold higher risk of post-herpetic neuralgia than those without diabetes (hazard ratio 1.45, 95% confidence interval 1.28-1.65; hazard ratio 1.45, 95% confidence interval 1.37-1.52, respectively), and there was no difference between the 2 types of diabetes (hazard ratio 1.06; 95% confidence interval 0.93-1.21). The results recommend consideration of herpes zoster vaccination at an earlier age in patients with type 1 diabetes.

2023 Expert Consensus of the Taiwan Society of Cardiology on the Diagnosis and Treatment of Cardiac Amyloidosis.

Cardiac amyloidosis is one form of systemic amyloidosis caused by abnormal amyloid fibrils deposited in the extracellular space of the myocardium causing heart failure because of restrictive cardiomyopathy and conduction disturbances. The incidence and prevalence of cardiac amyloidosis are higher than previously noted, particularly among special populations. The most common forms of cardiac amyloidosis are light chain and transthyretin amyloid cardiomyopathy. Even though more than 70% of patients with systemic amyloidosis have cardiac amyloidosis, the diagnosis is often delayed, suggesting significant gaps in the knowledge of cardiac amyloidosis and a lack of multidisciplinary teamwork in our daily practice. The Taiwan Society of Cardiology Heart Failure Committee organized experts to draft the "Expert Consensus on the diagnosis and treatment of cardiac amyloidosis." This statement aims to help clinicians and healthcare professionals improve early diagnosis and management of cardiac amyloidosis in Taiwan. The expert panel met virtually to review the data and discuss the consensus statements. Our review provided practical information about diagnostic methods and algorithms, clinical clues and red-flag signs, cardiac amyloidosis per se and its comorbidities treatment modalities, and follow-up plans for asymptomatic transthyretin gene carriers. We especially innovate two acronyms, "HFpEF MUTED CALL" and "HFmrEF MUST COUNT", to help in the early diagnosis and screening of transthyretin amyloid cardiomyopathy as shown in the Central Illustration.

Assessing the facilities and healthcare services for heart failure: Taiwan versus European countries.

BACKGROUND/PURPOSE: The present study was designed to evaluate the local cardiology infrastructure and services for heart failure (HF) care in Taiwan hospitals and to compare the HF care with the hospitals in European countries. METHODS: Available data from a total of 98 medical centers and regional hospitals in Taiwan were analyzed. Each facility was given a single copy of the questionnaire between September and December 2019, and service records were extracted from the National Health Insurance Database. European data were adopted from the 2017 European Society of Cardiology Atlas. RESULTS: The number of cardiologists per million populations in Taiwan was 57.4, and it was lower than the European median (72.8). The median percentages of interventional and electrophysiologists among cardiologists were 64% and 15% in Taiwan, which were both higher than the European median values (12% and 5%, respectively). The accessibility rates to implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) in Taiwan were both higher (3.4 and 3.0 centers per million populations) comparing to those in European countries (median 1.6 and 1.5 centers per million populations). Comparing to 67 hospitals without HF care teams in Taiwan, 31 hospitals (31.6%) with HF teams have significantly more cardiology staff, enhanced procedural capabilities with more alternatives on oral or intravenous HF relevant medications. CONCLUSION: Our analysis clearly demonstrated discrepancies in cardiology subspecialties and CRT/ICD accessibilities between European countries and Taiwan. Variations in HF-focused services and facilities plus HF-directed medications have demonstrated significant differences among Taiwanese hospitals with or without HF care team.

Contribution of Different Subbands of ECG in Sleep Apnea Detection Evaluated Using Filter Bank Decomposition and a Convolutional Neural Network.

A variety of feature extraction and classification approaches have been proposed using electrocardiogram (ECG) and ECG-derived signals for improving the performance of detecting apnea events and diagnosing patients with obstructive sleep apnea (OSA). The purpose of this study is to further evaluate whether the reduction of lower frequency P and T waves can increase the accuracy of the detection of apnea events. This study proposed filter bank decomposition to decompose the ECG signal into 15 subband signals, and a one-dimensional (1D) convolutional neural network (CNN) model independently cooperating with each subband to extract and classify the features of the given subband signal. One-minute ECG signals obtained from the MIT PhysioNet Apnea-ECG database were used to train the CNN models and test the accuracy of detecting apnea events for different subbands. The results show that the use of the newly selected subject-independent datasets can avoid the overestimation of the accuracy of the apnea event detection and can test the difference in the accuracy of different subbands. The frequency band of 31.25-37.5 Hz can achieve 100% per-recording accuracy with 85.8% per-minute accuracy using the newly selected subject-independent datasets and is recommended as a promising subband of ECG signals that can cooperate with the proposed 1D CNN model for the diagnosis of OSA.

Effects of Ivabradine on Patients with Depressed Left Ventricular Function after Cardiac Resynchronization Therapy.

Background: The potential synergistic effect of ivabradine and cardiac resynchronization therapy (CRT) in heart failure (HF) patients has rarely been studied. We aimed to evaluate the clinical benefits of ivabradine in patients with left ventricular dysfunction following CRT implantation. Methods: Two hundred and thirty-one patients receiving CRT were consecutively enrolled between January 2014 and December 2018 from two HF centers. A total of 123 patients had left ventricular ejection fraction (LVEF) < 40% and resting sinus heart rate (HR) ≥ 75 bpm after six months of CRT implantation. Among these patients, 45 were treated with ivabradine (Group 1), and 78 did not receive ivabradine treatment (Group 2). Results: Baseline characteristics and prescription rates of HF medications other than ivabradine were similar between the two groups. In Group 1, the mean HR decreased from 82.2 ± 11.4 bpm to 76.3 ± 10.5 bpm (p = 0.012), and the mean LVEF increased from 29.9 ± 6.5% to 38.8 ± 12.4% (p < 0.001). Atrial pacing percentage, biventricular pacing percentage, and burden of atrial fibrillation (AF) were not significantly different between the two groups during the study period. The patients' daily physical activity increased significantly in Group 1 compared to Group 2 (Δ daily activity 0.4 ± 0.7 hours/day vs. -0.1 ± 7.2 hours/day, p < 0.001). Conclusions: Ivabradine could effectively reduce HR and improve physical activity. It was safe to use and did not increase AF burden or affect biventricular pacing percentage in CRT recipients.

Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.

BACKGROUND: With emerging evidence on the efficacy of adding dapagliflozin to standard care for patients with heart failure with reduced ejection fraction (HFrEF), this study assessed the cost-effectiveness of add-on dapagliflozin to standard care versus standard care alone for HFrEF from the perspective of healthcare systems in the Asia-Pacific region. METHODS: A Markov model was applied to project the outcomes of treatment in terms of lifetime medical cost and quality-adjusted life-years. The transition probabilities between health states in the model were obtained from the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction trial. Country-specific costs and utilities were extracted for modeling. The incremental cost-effectiveness ratio against a country-specific willingness-to-pay threshold was applied to determine the cost-effectiveness of treatment. A series of sensitivity analyses were performed to ensure the robustness of the study results. Costs are presented in 2020 United States dollars. RESULTS: The incremental cost-effectiveness ratios for add-on dapagliflozin versus standard care alone were $5277, $9980, $12,305, $16,705, and $23,227 per quality-adjusted life-year gained in Korea, Australia, Taiwan, Japan, and Singapore, respectively. When using add-on dapagliflozin to standard care versus standard care alone, ~ 100% of simulations were cost-effective at a willingness-to-pay threshold of one gross domestic product per capita of the given Asia-Pacific country; however, the probability of being cost-effective for using add-on dapagliflozin decreased when the time horizon for simulation was restricted to 18 months and when the cardiovascular mortality for the two treatments (43.8% and 33.0%, respectively) was assumed to be the same. The cost-effectiveness results were most sensitive to cardiovascular mortality of treatment. CONCLUSIONS: Adding dapagliflozin to standard care is cost-effective for HFrEF in healthcare systems in the Asia-Pacific region, which supports the rational use of dapagliflozin for HFrEF in this region.

Simultaneous polymerization and adhesion under hypoxia in sickle cell disease.

Polymerization and adhesion, dynamic processes that are hallmarks of sickle cell disease (SCD), have thus far been studied in vitro only separately. Here, we present quantitative results of the simultaneous and synergistic effects of adhesion and polymerization of deoxygenated sickle hemoglobin (HbS) in the human red blood cell (RBC) on the mechanisms underlying vasoocclusive pain crisis. For this purpose, we employ a specially developed hypoxic microfluidic platform, which is capable of inducing sickling and unsickling of RBCs in vitro, to test blood samples from eight patients with SCD. We supplemented these experimental results with detailed molecular-level computational simulations of cytoadherence and biorheology using dissipative particle dynamics. By recourse to image analysis techniques, we characterize sickle RBC maturation stages in the following order of the degree of adhesion susceptibility under hypoxia: sickle reticulocytes in circulation (SRs) → sickle mature erythrocytes (SMEs) → irreversibly sickled cells (ISCs). We show that (i) hypoxia significantly enhances sickle RBC adherence; (ii) HbS polymerization enhances sickle cell adherence in SRs and SMEs, but not in ISCs; (iii) SRs exhibit unique adhesion dynamics where HbS fiber projections growing outward from the cell surface create multiple sites of adhesion; and (iv) polymerization stimulates adhesion and vice versa, thereby establishing the bidirectional coupling between the two processes. These findings offer insights into possible mechanistic pathways leading to vasoocclusion crisis. They also elucidate the processes underlying the onset of occlusion that may involve circulating reticulocytes, which are more abundant in hemolytic anemias due to robust compensatory erythropoiesis.

The Characteristics and Outcomes of Patients with Heart Failure and Reduced Ejection Fraction: The Eligibility of Novel Heart Failure Medications.

BACKGROUND: Renin-angiotensin system inhibitors and beta-blockers are the initial treatment of choice for heart failure with reduced ejection fraction (HFrEF), whereas sacubitril/valsartan (SAC/VAL) and ivabradine are considered to second-line therapies. The eligibility of SAC/VAL and ivabradine according to the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) labels, Taiwan National Health Insurance (TNHI) reimbursement regulations, and European Society of Cardiology (ESC) heart failure (HF) guidelines are diverse, and they may not fulfill the needs of real-world HFrEF patients. METHODS: Patients hospitalized for HF with left ventricular ejection fraction (LVEF) ≤ 40% were recruited from 21 hospitals in Taiwan between 2013 and 2014. The criteria for SAC/VAL and ivabradine according to the different regulations were applied. RESULTS: Of 1,474 patients, 86.8%, 29.4%, and 9.5% met the EMA/FDA label criteria, TNHI-regulation, and ESC guidelines for SAC/VAL, compared to 47.1%, 37.2%, and 45.6% for ivabradine, respectively. Ineligible reasons for the TNHI regulations included LVEF > 35% (19.9%, for SAC/VAL and ivabradine) and sinus rate < 75 beats per minute (bpm) (29.9%, for ivabradine). Although not meeting the TNHI regulations, patients with LVEF 35-40% had a similar 1-year mortality rate (15.6% vs. 15.8%, p = 0.876) to those with LVEF ≤ 35%, whereas patients with a sinus rate 70-74 bpm had a similar 1-year mortality rate (15.3% vs. 16.1%, p = 0.805) to those with a sinus rate ≥ 75 bpm. CONCLUSIONS: Approximately 70% and 63% of TSOC-HFrEF registry patients were ineligible for SAC/VAL and ivabradine, respectively, according to current TNHI regulations. Regardless of the eligibility for novel HFrEF medications, the high incidence of adverse events suggests that all patients should be treated cautiously.

Risk factors of acute renal impairment after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Acute renal impairment (ARI) is a major complication after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for cancer patients with peritoneal metastases. This study aimed to investigate the incidence and identify the risk factors of post-HIPEC creatinine increased. METHODS: From April 2015 to December 2019, demographic and perioperative data of 169 patients undergoing CRS/HIPEC with a preoperative creatinine level <1.5 mg/dL were retrospectively reviewed. Renal impairment was defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The risk factors of creatinine increased were analyzed using univariate and multiple logistic regression analyses. RESULTS: Among the 169 enrolled patients, 21 (12.4%) had postoperative creatinine increased (ARI group) and 148 (87.6%) did not (non-ARI group). Significantly more of the ARI group received a cisplatin HIPEC regimen than the non-ARI group (71.4 vs. 37.8%, p = 0.004). Multiple logistic regression analysis revealed that the patients who received a cisplatin HIPEC regimen (adjusted odds ratio [AOR] = 11.38, p < 0.001) and peritoneal dialysis solution as HIPEC perfusate (AOR = 7.07, p = 0.002) were more likely to develop post-HIPEC creatinine increased. CONCLUSIONS: Identifying the risk factors of post-HIPEC creatinine increased can help to improve patient selection, a dose of HIPEC regimens modification and perioperative care. We also identified the detrimental renal effect of peritoneal dialysis solution as HIPEC perfusate. More prospective studies are warranted to confirm these findings.

A Sleep Apnea Detection System Based on a One-Dimensional Deep Convolution Neural Network Model Using Single-Lead Electrocardiogram.

Many works in recent years have been focused on developing a portable and less expensive system for diagnosing patients with obstructive sleep apnea (OSA), instead of using the inconvenient and expensive polysomnography (PSG). This study proposes a sleep apnea detection system based on a one-dimensional (1D) deep convolutional neural network (CNN) model using the single-lead 1D electrocardiogram (ECG) signals. The proposed CNN model consists of 10 identical CNN-based feature extraction layers, a flattened layer, 4 identical classification layers mainly composed of fully connected networks, and a softmax classification layer. Thirty-five released and thirty-five withheld ECG recordings from the MIT PhysioNet Apnea-ECG Database were applied to train the proposed CNN model and validate its accuracy for the detection of the apnea events. The results show that the proposed model achieves 87.9% accuracy, 92.0% specificity, and 81.1% sensitivity for per-minute apnea detection, and 97.1% accuracy, 100% specificity, and 95.7% sensitivity for per-recording classification. The proposed model improves the accuracy of sleep apnea detection in comparison with several feature-engineering-based and feature-learning-based approaches.

Quantifying Shear-Induced Deformation and Detachment of Individual Adherent Sickle Red Blood Cells.

Vaso-occlusive crisis, a common painful complication of sickle cell disease, is a complex process triggered by intercellular adhesive interactions among blood cells and the endothelium in all human organs (e.g., the oxygen-rich lung as well as hypoxic systems such as liver and kidneys). We present a combined experimental-computational study to quantify the adhesive characteristics of sickle mature erythrocytes (SMEs) and irreversibly sickled cells (ISCs) under flow conditions mimicking those in postcapillary venules. We employed an in vitro microfluidic cell adherence assay, which is coated uniformly with fibronectin. We investigated the adhesion dynamics of SMEs and ISCs in pulsatile flow under well-controlled hypoxic conditions, inferring the cell adhesion strength by increasing the flow rate (or wall shear stress (WSS)) until the onset of cell detachment. In parallel, we performed simulations of individual SMEs and ISCs under shear. We introduced two metrics to quantify the adhesion process, the cell aspect ratio (AR) as a function of WSS and its rate of change (the dynamic deformability index). We found that the AR of SMEs decreases significantly with the increase of WSS, consistent between the experiments and simulations. In contrast, the AR of ISCs remains constant in time and independent of the flow rate. The critical WSS value for detaching a single SME in oxygenated state is in the range of 3.9-5.5 Pa depending on the number of adhesion sites; the critical WSS value for ISCs is lower than that of SMEs. Our simulations show that the critical WSS value for SMEs in deoxygenated state is above 6.2 Pa (multiple adhesion sites), which is greater than their oxygenated counterparts. We investigated the effect of cell shear modulus on the detachment process; we found that for the same cell adhesion spring constant, the higher shear modulus leads to an earlier cell detachment from the functionalized surface. These findings may aid in the understanding of individual roles of sickle cell types in sickle cell disease vaso-occlusion.

2019 Focused Update of the Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure.

Heart failure is a growing epidemic, especially in Taiwan because of the aging population. The 2016 Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry showed that the guideline-recommended therapies were prescribed suboptimally both at the time of hospital discharge and during follow-up. We, therefore, conducted this 2019 focused update of the guidelines of the Taiwan Society of Cardiology for the diagnosis and treatment of heart failure to reinforce the importance of new diagnostic and therapeutic modalities of heart failure. The 2019 focused update discusses new diagnostic criteria, pharmacotherapy, non-pharmacological management, and certain co-morbidities of heart failure. Angiotensin receptor neprilysin inhibitor and If channel inhibitor is introduced as new and recommended medical therapies. Latest criteria of cardiac resynchronization therapy, implantable cardioverter-defibrillator, heart transplantation, and ventricular assist device therapy are reviewed in the non-pharmacological management chapter. Co-morbidities in heart failure are discussed including chronic kidney disease, diabetes, chronic obstructive pulmonary disease, and sleep-disordered breathing. We also explain the adequate use of oxygen therapy and non-invasive ventilation in heart failure management. A particular chapter for chemotherapy-induced cardiac toxicity is incorporated in the focused update to emphasize the importance of its recognition and management. Lastly, implications from the TSOC-HFrEF registry and post-acute care of heart failure are discussed to highlight the importance of guideline-directed medical therapy and the benefits of multidisciplinary disease management programs. With guideline recommendations, we hope that the management of heart failure can be improved in our society.

Quantifying Platelet Margination in Diabetic Blood Flow.

Patients with type 2 diabetes mellitus (T2DM) develop thrombotic abnormalities strongly associated with cardiovascular diseases. In addition to the changes of numerous coagulation factors such as elevated levels of thrombin and fibrinogen, the abnormal rheological effects of red blood cells (RBCs) and platelets flowing in blood are crucial in platelet adhesion and thrombus formation in T2DM. An important process contributing to the latter is the platelet margination. We employ the dissipative particle dynamics method to seamlessly model cells, plasma, and vessel walls. We perform a systematic study on RBC and platelet transport in cylindrical vessels by considering different cell shapes, sizes, and RBC deformabilities in healthy and T2DM blood, as well as variable flowrates and hematocrit. In particular, we use cellular-level RBC and platelet models with parameters derived from patient-specific data and present a sensitivity study. We find T2DM RBCs, which are less deformable compared to normal RBCs, lower the transport of platelets toward the vessel walls, whereas platelets with higher mean volume (often observed in T2DM) lead to enhanced margination. Furthermore, increasing the flowrate or hematocrit enhances platelet margination. We also investigated the effect of platelet shape and observed a nonmonotonic variation with the highest near-wall concentration corresponding to platelets with a moderate aspect ratio of 0.38. We examine the role of white blood cells (WBCs), whose count is increased notably in T2DM patients. We find that WBC rolling or WBC adhesion tends to decrease platelet margination due to hydrodynamic effects. To the best of our knowledge, such simulations of blood including all blood cells have not been performed before, and our quantitative findings can help separate the effects of hydrodynamic interactions from adhesive interactions and potentially shed light on the associated pathological processes in T2DM such as increased inflammatory response, platelet activation and adhesion, and ultimately thrombus formation.

Linagliptin and cardiovascular outcomes in type 2 diabetes after acute coronary syndrome or acute ischemic stroke.

BACKGROUND: The cardiovascular safety and efficacy of linagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus (T2DM) after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) are unclear. The aim of our real-world cohort study was to evaluate the cardiovascular outcomes of linagliptin in patients with T2DM after ACS or AIS. METHODS: An open observational noncrossover retrospective cohort study was conducted between June 1, 2012 and December 31, 2013 utilizing Taiwan National Health Insurance Research Database. A total of 1203 patients with T2DM after ACS or AIS were selected as the study cohort. Cardiovascular safety and efficacy of linagliptin were evaluated by comparing outcomes of 401 subjects receiving linagliptin after ACS or AIS to 802 matched control subjects not receiving any incretin-based therapy after ACS or AIS. The primary composite outcome included cardiovascular death, non-fatal myocardial infarction and non-fatal ischemic stroke. RESULTS: The primary composite outcome after 15-month follow-up was 7% (28 patients) in the linagliptin group compared with 6.1% (49 patients) in the control group [hazard ratio (HR) 1.06; 95% confidence interval (CI) .66-1.68]. The linagliptin group also had similar risks of all-cause mortality, hospitalization for heart failure, percutaneous coronary intervention and coronary artery bypass grafting compared to the control group in terms of the secondary outcomes. CONCLUSIONS: In T2DM patients after ACS or AIS, treatment with linagliptin was not associated with increased risks of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke.

Modeling of Biomechanics and Biorheology of Red Blood Cells in Type 2 Diabetes Mellitus.

Erythrocytes in patients with type-2 diabetes mellitus (T2DM) are associated with reduced cell deformability and elevated blood viscosity, which contribute to impaired blood flow and other pathophysiological aspects of diabetes-related vascular complications. In this study, by using a two-component red blood cell (RBC) model and systematic parameter variation, we perform detailed computational simulations to probe the alteration of the biomechanical, rheological, and dynamic behavior of T2DM RBCs in response to morphological change and membrane stiffening. First, we examine the elastic response of T2DM RBCs subject to static tensile forcing and their viscoelastic relaxation response upon release of the stretching force. Second, we investigate the membrane fluctuations of T2DM RBCs and explore the effect of cell shape on the fluctuation amplitudes. Third, we subject the T2DM RBCs to shear flow and probe the effects of cell shape and effective membrane viscosity on their tank-treading movement. In addition, we model the cell dynamic behavior in a microfluidic channel with constriction and quantify the biorheological properties of individual T2DM RBCs. Finally, we simulate T2DM RBC suspensions under shear and compare the predicted viscosity with experimental measurements. Taken together, these simulation results and their comparison with currently available experimental data are helpful in identifying a specific parametric model-the first of its kind, to our knowledge-that best describes the main hallmarks of T2DM RBCs, which can be used in future simulation studies of hematologic complications of T2DM patients.

MD/DPD Multiscale Framework for Predicting Morphology and Stresses of Red Blood Cells in Health and Disease.

Healthy red blood cells (RBCs) have remarkable deformability, squeezing through narrow capillaries as small as 3 microns in diameter without any damage. However, in many hematological disorders the spectrin network and lipid bilayer of diseased RBCs may be significantly altered, leading to impaired functionality including loss of deformability. We employ a two-component whole-cell multiscale model to quantify the biomechanical characteristics of the healthy and diseased RBCs, including Plasmodium falciparum-infected RBCs (Pf-RBCs) and defective RBCs in hereditary disorders, such as spherocytosis and elliptocytosis. In particular, we develop a two-step multiscale framework based on coarse-grained molecular dynamics (CGMD) and dissipative particle dynamics (DPD) to predict the static and dynamic responses of RBCs subject to tensile forcing, using experimental information only on the structural defects in the lipid bilayer, cytoskeleton, and their interaction. We first employ CGMD on a small RBC patch to compute the shear modulus, bending stiffness, and network parameters, which are subsequently used as input to a whole-cell DPD model to predict the RBC shape and corresponding stress field. For Pf-RBCs at trophozoite and schizont stages, the presence of cytoadherent knobs elevates the shear response in the lipid bilayer and stiffens the RBC membrane. For RBCs in spherocytosis and elliptocytosis, the bilayer-cytoskeleton interaction is weakened, resulting in substantial increase of the tensile stress in the lipid bilayer. Furthermore, we investigate the transient behavior of stretching deformation and shape relaxation of the normal and defective RBCs. Different from the normal RBCs possessing high elasticity, our simulations reveal that the defective RBCs respond irreversibly, i.e., they lose their ability to recover the normal biconcave shape in successive loading cycles of stretching and relaxation. Our findings provide fundamental insights into the microstructure and biomechanics of RBCs, and demonstrate that the two-step multiscale framework presented here can be used effectively for in silico studies of hematological disorders based on first principles and patient-specific experimental input at the protein level.

Atrial fibrillation originating from superior vena cava with atrial flutter-electrocardiogram pattern.

BACKGROUNDS: Substrate property is related to the genesis and maintenance of atrial fibrillation (AF). The aim of the study was to investigate the impact of substrate property on the electrocardiogram (ECG) in patients with AF originating from the superior vena cava (SVC). METHODS AND RESULTS: Seventy-six patients with AF originating from SVC who underwent catheter ablation were included from 2004 to 2013. Of these patients, 16 had a presentation of atrial flutter (AFL)-pattern ECG during AF (group 1), and 60 patients did not (group 2). There was no significant difference in clinical characteristics between the groups. The percentage of low voltage zone (LVZ) in SVC below the level of pulmonary artery in group 1 was significantly larger than that in group 2. The polarities of the flutter wave in 12-lead ECG were compared with another 26 subjects with reverse typical AFL. The ECG morphology was characterized by negative or biphasic P waves in lead V1 in most of the patients in group 1 (62.5%), which was analogous to that in reverse typical AFL. The negative polarity of flutter waves in aVL might distinguish SVC AF with an AFL-pattern from reverse typical AFL. CONCLUSION: The ECG characteristics of AF originating from SVC can mimic atypical AFL. LVZ in the SVC may be associated with the presentation of AFL-pattern ECG.