Publications by authors named "Chih-Yuan Lin"

152 Publications

Phosphodiesterase-1 inhibitor modulates Ca regulation in sirtuin 1-deficient mouse cardiomyocytes.

Eur J Pharmacol 2021 Sep 7:174498. Epub 2021 Sep 7.

Grade Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Background: Phosphodiesterase inhibitors can be used to enhance second messenger signaling to regulate intracellular Ca cycling. This study investigated whether ITI-214, a selective phosphodiesterase-1 inhibitor, modulates intracellular Ca regulation, resulting in a positive inotropic effect in sirtuin 1 (Sirt1)-deficient cardiomyocytes.

Methods: Mice with cardiac-specific Sirt1 knockout (Sirt1) were used, with Sirt1 mice serving as controls. Electromechanical analyses of ventricular tissues were conducted, and we monitored intracellular Ca using Fluo-3 as well as reactive oxygen species production in isolated cardiomyocytes.

Results: Sirt1 ventricles showed prolonged action potential duration at 90% repolarization and increased contractile force after treatment with ITI-214. The rates and sustained durations of burst firing in ventricles were higher and longer, respectively, in Sirt1 ventricles than in controls. ITI-214 treatment decreased the rates and shortened the durations of burst firing in Sirt1 mice. Sirt1 cardiomyocytes showed reduced Ca transient amplitudes and sarcoplasmic reticulum (SR) Ca stores compared to those in control cardiac myocytes, which was reversed after ITI-214 treatment. SR Ca leakage was larger in Sirt1 cardiac myocytes than in control myocytes. ITI-214 reduced SR Ca leakage in Sirt1 cardiac myocytes. Increased levels of reactive oxygen species in Sirt1 cardiomyocytes compared to those in controls were reduced after ITI-214 treatment. Levels of Ca regulatory proteins, including ryanodine receptor 2, phospholamban, and sarcoplasmic/endoplasmic reticulum Ca ATPase 2a were not affected by ITI-214 administration.

Conclusions: Our results suggest that ITI-214 improves intracellular Ca regulation, which in turn exerts inotropic effects and suppresses arrhythmic events in Sirt1-deficient ventricular myocytes.
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http://dx.doi.org/10.1016/j.ejphar.2021.174498DOI Listing
September 2021

Investigation of entrance effects on particle electrophoretic behavior near a nanopore for resistive pulse sensing.

Electrophoresis 2021 Sep 1. Epub 2021 Sep 1.

Department of Mechanical Engineering, The University of Tokyo, Tokyo, Japan.

Resistive pulse sensing using solid-state nanopores provides a unique platform for detecting the structure and concentration of molecules of different types of analytes in an electrolyte solution. The capture of an entity into a nanopore is subject not only to the electrostatic force but also the effect of electroosmotic flow originating from the charged nanopore surface. In this study, we theoretically analyze spherical particle electrophoretic behavior near the entrance of a charged nanopore. By investigating the effects of pore size, particle-pore distance, and salt concentration on particle velocity, we summarize dominant mechanisms governing particle behavior for a range of conditions. In the literature, the Helmholtz-Smoluchowski equation is often adopted to evaluate particle translocation by considering the zeta potential difference between the particle and nanopore surfaces. We point out that, due to the difference of the electric field inside and outside the nanopore and the influence from the existence of the particle itself, the zeta potential of the particle, however, needs to be at least 30% higher than that of the nanopore to allow the particle to enter into the nanopore when its velocity is close to zero. Accordingly, we summarize the effective salt concentrations that enable successful particle capture and detection for different pore sizes, offering direct guidance for nanopore applications.
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http://dx.doi.org/10.1002/elps.202100162DOI Listing
September 2021

Restrictive cardiomyopathy caused by diffuse calcification of the left ventricle after 20 years of haemodialysis.

Cardiovasc J Afr 2021 Jul 5;32:1-3. Epub 2021 Jul 5.

Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan. Email:

Valvular and vascular calcifications are common among patients with end-stage renal disease, but diffuse calcification of the left ventricle is rarely reported. We report on a rare case of restrictive cardiomyopathy resulting from severe myocardial calcification and review the literature. A 77-year-old man was diagnosed with end-stage renal disease after having received regular haemodialysis for 20 years. He was referred to our emergency room due to exertional dyspnoea and exacerbated shortness of breath. A chest X-ray revealed severe pulmonary oedema and bilateral massive pleural effusion. Transthoracic echocardiography revealed impaired diastolic function of the left ventricle but preserved systolic function with a 50% ejection fraction. Repeat chest computed tomography demonstrated exacerbation of the calcification from the mitral annulus to the whole circular left ventricle. A coronary angiogram revealed non-significant stenosis, and right heart catheterisation demonstrated elevated pulmonary capillary wedge pressure. He was discharged after two weeks of conservative medication.
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http://dx.doi.org/10.5830/CVJA-2021-031DOI Listing
July 2021

Devices for Nanoscale Guiding of DNA through a 2D Nanopore.

ACS Sens 2021 07 6;6(7):2534-2545. Epub 2021 Jul 6.

Department of Physics and Astronomy, David Rittenhouse Laboratory, University of Pennsylvania, 209 South 33rd Street, Philadelphia, Pennsylvania 19104, United States.

We fabricate on-chip solid-state nanofluidic-2D nanopore systems that can limit the range of motion for DNA in the sensing region of a nanopore. We do so by creating devices containing one or more silicon nitride pores and silicon nitride pillars supporting a 2D pore that orient DNA within a nanopore device to a restricted geometry, yet allow the free motion of ions to maintain a high signal-to-noise ratio. We discuss two concepts with two and three independent electrical connections and corresponding nanopore chip device architectures to achieve this goal in practice. Here, we describe device fabrication and transmission electron microscope (TEM) images, and provide simulated translocations based on the finite element analysis in 3D to demonstrate its merit. In both methods, there is a main 2D nanopore which we refer to as a "sensing" nanopore (monolayer MoS in this paper). A secondary layer is either an array of guiding pores sharing the same electrode pair as the sensing pore (Method 1) or a single, independently contacted, guiding pore (Method 2). These pores are constructed parallel to the "sensing" pore and serve as "guiding" elements to stretch and feed DNA into the atomically thin sensing pore. We discuss the practical implementation of these concepts with nanofluidic and Si-based technology, including detailed fabrication steps and challenges involved for DNA applications in solution.
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http://dx.doi.org/10.1021/acssensors.1c00829DOI Listing
July 2021

The Association between Migraine and Abdominal Aortic Aneurysms: A Nationwide Population-Based Cohort Study.

Int J Environ Res Public Health 2021 04 20;18(8). Epub 2021 Apr 20.

Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.

Previous studies have indicated that patients with migraine have a higher prevalence of risk factors known to be associated with cardiovascular diseases. There are also shared epidemiology and molecular mechanisms between migraine and abdominal aortic aneurysm (AAA). We hypothesized that patients with migraine could have an increased risk of AAA. To test this hypothesis, we used the National Health Insurance Research Database (NHIRD) to evaluate whether associations exist between migraine and AAA. The data for this nationwide population-based retrospective cohort study were obtained from the NHIRD in Taiwan. The assessed study outcome was the cumulative incidence of AAA in patients with migraine during a 15-year follow-up period. Among the 1,936,512 patients from the NHIRD, 53,668 (2.77%) patients were identified as having been diagnosed with migraine. The patients with migraine had a significantly higher cumulative risk of 3.558 of developing an AAA 5 years after the index date compared with the patients without migraine. At the end of the 15-year follow-up period, a significantly higher incidence of AAA (0.98%) was observed in the patients with migraine than in those without migraine (0.24%). We revealed an association between the development of migraine and AAA.
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http://dx.doi.org/10.3390/ijerph18084389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074774PMC
April 2021

Engineering adjustable two-pore devices for parallel ion transport and DNA translocations.

J Chem Phys 2021 Mar;154(10):105102

Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

We report ionic current and double-stranded DNA (dsDNA) translocation measurements through solid-state membranes with two TEM-drilled ∼3-nm diameter silicon nitride nanopores in parallel. Nanopores are fabricated with similar diameters but varying in effective thicknesses (from 2.6 to 10 nm) ranging from a thickness ratio of 1:1 to 1:3.75, producing distinct conductance levels. This was made possible by locally thinning the silicon nitride membrane to shape the desired topography with nanoscale precision using electron beam lithography (EBL). Two nanopores are engineered and subsequently drilled in either the EBL-thinned or the surrounding membrane region. By designing the interpore separation a few orders of magnitude larger than the pore diameter (e.g., ∼900 vs 3 nm), we show analytically, numerically, and experimentally that the total conductance of the two pores is the sum of the individual pore conductances. For a two-pore device with similar diameters yet thicknesses in the ratio of 1:3, a ratio of ∼1:2.2 in open-pore conductances and translocation current signals is expected, as if they were measured independently. Introducing dsDNA as analytes to both pores simultaneously, we detect more than 12 000 events within 2 min and trace them back with a high likelihood to which pore the dsDNA translocated through. Moreover, we monitor translocations through one active pore only when the other pore is clogged. This work demonstrates how two-pore devices can fundamentally open up a parallel translocation reading system for solid-state nanopores. This approach could be creatively generalized to more pores with desired parameters given a sufficient signal-to-noise ratio.
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http://dx.doi.org/10.1063/5.0044227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952139PMC
March 2021

Effectiveness of hospital emergency department regionalization and categorization policy on appropriate patient emergency care use: a nationwide observational study in Taiwan.

BMC Health Serv Res 2021 Jan 6;21(1):21. Epub 2021 Jan 6.

Institute of Health and Welfare Policy, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: Emergency department (ED) overcrowding is a health services issue worldwide. Modern health policy emphasizes appropriate health services utilization. However, the relationship between accessibility, capability, and appropriateness of ED use is unknown. Thus, this study aimed to examine the effect of hospital ED regionalization policy and categorization of hospital emergency capability policy (categorization policy) on patient-appropriate ED use.

Methods: Taiwan implemented a nationwide three-tiered hospital ED regionalization and categorization of hospital emergency capability policies in 2007 and 2009, respectively. We conducted a retrospective observational study on the effect of emergency care policy intervention on patient visit. Between 2005 and 2011, the Taiwan National Health Insurance Research Database recorded 1,835,860 ED visits from 1 million random samples. ED visits were categorized using the Yang-Ming modified New York University-ED algorithm. A time series analysis was performed to examine the change in appropriate ED use rate after policy implementation.

Results: From 2005 to 2011, total ED visits increased by 10.7%. After policy implementation, the average appropriate ED visit rate was 66.9%. The intervention had no significant effect on the trend of appropriate ED visit rate.

Conclusions: Although regionalization and categorization policies did increase emergency care accessibility, it had no significant effect on patient-appropriate ED use. Further research is required to improve data-driven policymaking.
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http://dx.doi.org/10.1186/s12913-020-06006-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787133PMC
January 2021

Association between abdominal aortic aneurysms and alcohol-related diseases.

Medicine (Baltimore) 2020 Oct;99(44):e22968

Department of Emergency Medicine.

Heterogeneous associations exist between alcohol consumption and the initial presentation of cardiovascular diseases (CVDs). Studies regarding the association between abdominal aortic aneurysms (AAAs) and alcohol consumption are still limited and controversial. We hypothesize that patients with alcohol-related diseases are susceptible to AAA formation due to the presence of overlapping epidemiological factors and molecular mechanisms. We aimed to use a nationwide population-based retrospective cohort study to evaluate the association between alcohol-related diseases and AAA.The data were extracted from the National Health Insurance Research Database (NHIRD) in Taiwan. The study outcome assessed was the cumulative incidence of AAA in patients with alcohol-related diseases during a 14-year follow-up period.Our study included 22,878 patients who had alcohol-related diseases; these patients with alcohol-related diseases had a significantly higher cumulative risk of developing AAA 5 years after the index date than did the 91,512 patients without alcohol-related diseases. Patients with alcohol-related diseases also exhibited a significantly increased incidence of AAA compared with the incidence among patients without alcohol-related diseases, according to Cox regression analysis and Fine & Gray's competing risk model (adjusted hazard ratio = 2.379, 95% confidence interval = 1.653 -3.424, P < .001). In addition, male gender, older age, and chronic kidney disease were also associated with an increased risk of developing AAA. An interaction model showed that males with alcohol-related diseases had a 10.4-fold higher risk of AAA than did females without alcohol-related diseases.We observed an association between alcohol-related diseases and AAA even after adjusting for several comorbidities and medications in a nationwide population database.
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http://dx.doi.org/10.1097/MD.0000000000022968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598798PMC
October 2020

Persistent cardiac arrest caused by profound hypokalaemia after large-dose insulin injection in a young man with type 1 diabetes mellitus: successful rescue with extracorporeal membrane oxygenation and subsequent ventricular assist device.

Cardiovasc J Afr 2020 Nov-Dec;31(6):339-342. Epub 2020 Jul 6.

Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Email:

A 28-year-old man who had a history of type 1 diabetes mellitus with poor medication compliance was referred to the emergency department of our institute with suspected diabetic ketoacidosis. The patient developed sudden cardiac arrest following continuous insulin administration. Laboratory data revealed severe hypokalaemia. Cardiopulmonary resuscitation was performed immediately for 63 minutes. Although his spontaneous circulation resumed, the haemodynamics remained unstable. Peripheral extracorporeal membrane oxygenation was therefore employed for mechanical circulatory support. Echocardiography under these conditions revealed generalised hypokinesia of the bilateral ventricles. The left ventricular ejection fraction was only 10-15%. The chest film revealed bilateral pulmonary congestion. The patient developed multiple organ dysfunction, including acute kidney injury, liver congestion and persistent pulmonary oedema, although the hypokalaemia resolved. A temporary bilateral ventricular assist device (Bi-VAD) was used for superior systemic perfusion and unloading of the bilateral ventricles after 16 hours of extracorporeal membrane oxygenation support. After the start of maintenance using the Bi-VAD, extracorporeal membrane oxygenation was discontinued and the inotropic agents were tapered down immediately. Subsequently, the haemodynamics stabilised. All the visceral organs were well perfused with Bi-VAD support. Subsequent echocardiography demonstrated recovery from the myocardial stunning, with the left ventricular ejection fraction returning to 50-60%. The Bi-VAD was gradually weaned and successfully removed 12 days after implantation. The patient had an uneventful recovery and was discharged without organ injury. Over one year of follow up in our out-patient clinic, adequate cardiac function and improved diabetes control were found.
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http://dx.doi.org/10.5830/CVJA-2020-018DOI Listing
July 2021

Choosing and Doing wisely: triage level I resuscitation a possible new field for starting palliative care and avoiding low-value care - a nationwide matched-pair retrospective cohort study in Taiwan.

BMC Palliat Care 2020 Jun 20;19(1):87. Epub 2020 Jun 20.

Institute of Health and Welfare Policy, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: The association between palliative care and life-sustaining treatment following emergency department (ED) resuscitation is unclear. This study aims to analyze the usage of palliative care and life-sustaining treatments among ED triage level I resuscitation patients based on a nationally representative sample of patients in Taiwan.

Methods: A matched-pair retrospective cohort study was conducted to examine the association between palliative care and outcome variables using multivariate logistic regression and Kaplan-Meier survival analyses. Between 2009 and 2013, 336 ED triage level I resuscitation patients received palliative care services (palliative care group) under a universal health insurance scheme. Retrospective cohort matching was performed with those who received standard care at a ratio of 1:4 (usual care group). Outcome variables included the number of visits to emergency and outpatient departments, hospitalization duration, total medical expenses, utilization of life-sustaining treatments, and duration of survival following ED triage level I resuscitation.

Results: The mean survival duration following level I resuscitation was less than 1 year. Palliative care was administered to 15% of the resuscitation cohort. The palliative care group received significantly less life-sustaining treatment than did the usual care group.

Conclusion: Among patients who underwent level I resuscitation, palliative care was inversely correlated with the scope of life-sustaining treatments. Furthermore, triage level I resuscitation status may present a possible new field for starting palliative care intervention and reducing low-value care.
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http://dx.doi.org/10.1186/s12904-020-00590-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305586PMC
June 2020

Aldehyde dehydrogenase 2 protects against abdominal aortic aneurysm formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of vascular smooth muscle cells.

FASEB J 2020 07 28;34(7):9498-9511. Epub 2020 May 28.

Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies aldehydes by converting them to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress. Increased oxidative stress plays a pivotal role in abdominal aortic aneurysm (AAA) pathogenesis. Reactive oxygen species (ROS) promote degradation of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) apoptosis. Reducing oxidative stress by an ALDH2 activator could have therapeutic potential for limiting AAA development. We hypothesized that ALDH2 deficiency could increase the risk for AAA by decreasing ROS elimination and that an ALDH2 activator could provide an alternative option for AAA treatment. The National Center for Biotechnology (NCBI) Gene Expression Omnibus (GEO) database was used. Human aortic smooth muscle cells (HASMCs) were used for the in vitro experiments. Gene-targeted ALDH2*2 KI knock-in mice on a C57BL/6J background and apolipoprotein E knockout (ApoE KO) mice were obtained. An animal model of AAA was constructed using osmotic minipumps to deliver 1000 ng/kg/min angiotensin II (AngII) for 28 days. Patients with AAA had significantly lower ALDH2 expression levels than normal subjects. ALDH2*2 KI mice were susceptible to AngII administration, exhibiting significantly increased AAA incidence rates and increased aortic diameters. Alda-1, an ALDH2 activator, reduced AngII-induced ROS production, NF-kB activation, and apoptosis in HASMCs. Alda-1 attenuated AngII-induced aneurysm formation and decreased aortic expansion in ApoE KO mice. We concluded that ALDH2 deficiency is associated with the development of AAAs in humans and a murine disease model. ALDH2 deficiency increases susceptibility to AngII-induced AAA formation by attenuating anti-ROS effects and increasing VSMC apoptosis and vascular inflammation. Alda-1 was shown to attenuate the progression of experimental AAA in a murine model.
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http://dx.doi.org/10.1096/fj.201902550RRRDOI Listing
July 2020

Appropriateness of emergency care use: a retrospective observational study based on professional versus patients' perspectives in Taiwan.

BMJ Open 2020 05 11;10(5):e033833. Epub 2020 May 11.

Institute of Health and Welfare Policy, National Yang-Ming University School of Medicine, Taipei, Taiwan

Objective: The objectives of this study are to refine the measurement of appropriate emergency department (ED) use and to provide a natural observation of appropriate ED use rates based on professional versus patient perspectives.

Setting: Taiwan has a population of 23 million, with one single-payer universal health insurance scheme. Taiwan has no limitations on ED use, and a low barrier to ED use may be a surrogate for natural observation of users' perspectives in ED use.

Participants: In 7 years, there were 1 835 860 ED visits from one million random samples of the National Health Insurance Database.

Measures: Appropriate ED use was determined according to professional standards, measured by the modified Billings New York University Emergency Department (NYU-ED) algorithm, and further analysed after the addition of prudent patient standards, measured by explicit process-based and outcome-based criteria.

Statistical Analyses: The area under the receiver operating characteristic curve (AUC) was used to reflect the performance of appropriate ED use measures, and sensitivity analyses were conducted using different thresholds to determine the appropriateness of ED use. The generalised estimating equation model was used to measure the associations between appropriate ED use based on process and outcome criteria and covariates including sex, age, occupation, health status, place of residence, medical resources area, date and income level.

Results: Appropriate ED use based on professional criteria was 33.5%, which increased to 63.1% when patient criteria were added. The AUC, which combines both professional and patient criteria, was high (0.85).

Conclusions: The appropriate ED use rate nearly doubled when patient criteria were added to professional criteria. Explicit process-based and outcome-based criteria may be used as a supplementary measure to the implicit modified Billings NYU-ED algorithm when determining appropriate ED use.
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http://dx.doi.org/10.1136/bmjopen-2019-033833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223150PMC
May 2020

The effect of Sirt1 deficiency on Ca and Na regulation in mouse ventricular myocytes.

J Cell Mol Med 2020 06 27;24(12):6762-6772. Epub 2020 Apr 27.

Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

This study addressed the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca and Na regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac-specific Sirt1 knockout (Sirt1 ). Sirt1 mice were served as control. Sirt1 mice showed impaired cardiac ejection fraction with increased ventricular spontaneous activity and burst firing compared with those in control mice. The arrhythmic events were suppressed by KN93 and ranolazine. Reduction in Ca transient amplitudes and sarcoplasmic reticulum (SR) Ca stores, and increased SR Ca leak were shown in the Sirt1 mice. Electrophysiological measurements were performed using patch-clamp method. While L-type Ca current (I ) was smaller in Sirt1 myocytes, reverse-mode Na /Ca exchanger (NCX) current was larger compared with those in control myocytes. Late Na current (I ) was enhanced in the Sirt1 mice, alongside with elevated cytosolic Na level. Increased cytosolic and mitochondrial reactive oxygen species (ROS) were shown in Sirt1 mice. Sirt1 cardiomyocytes showed down-regulation of L-type Ca channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca  ATPase 2a (SERCA2a), but up-regulation of Ca /calmodulin-dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca and Na in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis.
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http://dx.doi.org/10.1111/jcmm.15327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299725PMC
June 2020

Ionic amplifying circuits inspired by electronics and biology.

Nat Commun 2020 03 26;11(1):1568. Epub 2020 Mar 26.

Department of Physics and Astronomy, University of California, 4129 Frederick Reines Hall, Irvine, CA, 92697, USA.

Integrated circuits are present in all electronic devices, and enable signal amplification, modulation, and relay. Nature uses another type of circuits composed of channels in a cell membrane, which regulate and amplify transport of ions, not electrons and holes as is done in electronic systems. Here we show an abiotic ionic circuit that is inspired by concepts from electronics and biology. The circuit amplifies small ionic signals into ionic outputs, and its operation mimics the electronic Darlington amplifier composed of transistors. The individual transistors are pores equipped with three terminals including a gate that is able to enrich or deplete ions in the pore. The circuits we report function at gate voltages < 1 V, respond to sub-nA gate currents, and offer ion current amplification with a gain up to ~300. Ionic amplifiers are a logical step toward improving chemical and biochemical sensing, separations and amplification, among others.
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http://dx.doi.org/10.1038/s41467-020-15398-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099069PMC
March 2020

Automated Hypofractionated IMRT treatment planning for early-stage breast Cancer.

Radiat Oncol 2020 Mar 17;15(1):67. Epub 2020 Mar 17.

Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan.

Background: Hypofractionated whole-breast irradiation is a standard adjuvant therapy for early-stage breast cancer. This study evaluates the plan quality and efficacy of an in-house-developed automated radiotherapy treatment planning algorithm for hypofractionated whole-breast radiotherapy.

Methods: A cohort of 99 node-negative left-sided breast cancer patients completed hypofractionated whole-breast irradiation with six-field IMRT for 42.56 Gy in 16 daily fractions from year 2016 to 2018 at a tertiary center were re-planned with an in-house-developed algorithm. The automated plan-generating C#-based program is developed in a Varian ESAPI research mode. The dose-volume histogram (DVH) and other dosimetric parameters of the automated and manual plans were directly compared.

Results: The average time for generating an autoplan was 5 to 6 min, while the manual planning time ranged from 1 to 1.5 h. There was only a small difference in both the gantry angles and the collimator angles between the autoplans and the manual plans (ranging from 2.2 to 5.3 degrees). Autoplans and manual plans performed similarly well in hotspot volume and PTV coverage, with the autoplans performing slightly better in the ipsilateral-lung-sparing dose parameters but were inferior in contralateral-breast-sparing. The autoplan dosimetric quality did not vary with different breast sizes, but for manual plans, there was worse ipsilateral-lung-sparing (V) in larger or medium-sized breasts than in smaller breasts. Autoplans were generally superior than manual plans in CI (1.24 ± 0.06 vs. 1.30 ± 0.09, p < 0.01) and MU (1010 ± 46 vs. 1205 ± 187, p < 0.01).

Conclusions: Our study presents a well-designed standardized fully automated planning algorithm for optimized whole-breast radiotherapy treatment plan generation. A large cohort of 99 patients were re-planned and retrospectively analyzed. The automated plans demonstrated similar or even better dosimetric quality and efficacy in comparison with the manual plans. Our result suggested that the autoplanning algorithm has great clinical applicability potential.
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http://dx.doi.org/10.1186/s13014-020-1468-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077022PMC
March 2020

Cardiac calcium dysregulation in mice with chronic kidney disease.

J Cell Mol Med 2020 03 16;24(6):3669-3677. Epub 2020 Feb 16.

Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Cardiovascular complications are leading causes of morbidity and mortality in patients with chronic kidney disease (CKD). CKD significantly affects cardiac calcium (Ca ) regulation, but the underlying mechanisms are not clear. The present study investigated the modulation of Ca homeostasis in CKD mice. Echocardiography revealed impaired fractional shortening (FS) and stroke volume (SV) in CKD mice. Electrocardiography showed that CKD mice exhibited longer QT interval, corrected QT (QTc) prolongation, faster spontaneous activities, shorter action potential duration (APD) and increased ventricle arrhythmogenesis, and ranolazine (10 µmol/L) blocked these effects. Conventional microelectrodes and the Fluo-3 fluorometric ratio techniques indicated that CKD ventricular cardiomyocytes exhibited higher Ca decay time, Ca sparks, and Ca leakage but lower [Ca ] transients and sarcoplasmic reticulum Ca contents. The CaMKII inhibitor KN93 and ranolazine (RAN; late sodium current inhibitor) reversed the deterioration in Ca handling. Western blots revealed that CKD ventricles exhibited higher phosphorylated RyR2 and CaMKII and reduced phosphorylated SERCA2 and SERCA2 and the ratio of PLB-Thr17 to PLB. In conclusions, the modulation of CaMKII, PLB and late Na current in CKD significantly altered cardiac Ca regulation and electrophysiological characteristics. These findings may apply on future clinical therapies.
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http://dx.doi.org/10.1111/jcmm.15066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131917PMC
March 2020

Charge Inversion and Calcium Gating in Mixtures of Ions in Nanopores.

J Am Chem Soc 2020 02 30;142(6):2925-2934. Epub 2020 Jan 30.

Department of Physics and Astronomy , University of California , Irvine , California 92697 , United States.

Calcium ions play important roles in many physiological processes, yet their concentration is much lower than the concentrations of potassium and sodium ions. The selectivity of calcium channels is often probed in mixtures of calcium and a monovalent salt, e.g., KCl or NaCl, prepared such that the concentration of cations is kept constant with the mole fraction of calcium varying from 0 and 1. In biological channels, even sub-mM concentration of calcium can modulate the channels' transport characteristics; this effect is often explained via the existence of high affinity Ca binding sites on the channel walls. Inspired by properties of biological calcium-selective channels, we prepared a set of nanopores with tunable opening diameters that exhibited a similar response to the presence of calcium ions as biochannels. Nanopores in 15 nm thick silicon nitride films were drilled using focused ion beam and e-beam in a transmission electron microscope and subsequently rendered negatively charged through silanization. We found that nanopores with diameters smaller than 20 nm were blocked by calcium ions such that the ion currents in mixtures of KCl and CaCl and in CaCl were even ten times smaller than the ion currents in KCl solution. The ion current blockage was explained by the effect of local charge inversion where accumulated calcium ions switch the effective surface charge from negative to positive. The modulation of surface charge with calcium leads to concentration and voltage dependent local charge density and ion current. The combined experimental and modeling results provide a link between calcium ion-induced changes in surface charge properties and resulting ionic transport.
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http://dx.doi.org/10.1021/jacs.9b11537DOI Listing
February 2020

Association between surgical repair of aortic aneurysms and the diagnosis of subsequent cardiovascular diseases.

J Cardiol 2020 06 30;75(6):621-627. Epub 2019 Dec 30.

Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Background: Cardiovascular diseases (CVDs) and aortic aneurysms (AAs) share several clinical risk factors. However, the potential effects on future CVDs of surgical treatments involving the open surgical repair (OSR) of AAs are unknown. We hypothesize that the OSR of AAs is associated with subsequent CVDs.

Methods: The data for this nationwide population-based retrospective cohort study were obtained from the National Health Insurance Research Database in Taiwan. The outcome assessed in this study was the cumulative incidence of CVDs in patients with AAs during a 14-year follow-up period, which was further stratified according to those who underwent OSR, endovascular aneurysm repair (EVAR), and nonsurgical treatment (NST).

Results: Our analysis included 11,764 patients with AAs, of whom 2,524 received surgery and 2,524 were propensity score-matched controls. Compared to the controls, patients who received OSR exhibited a significantly decreased incidence of CVD development [adjusted hazard ratio (HR)=0.89,p=0.006]. Furthermore, compared to patients who received NST, patients who received OSR had a significantly lower incidence of subsequent acute myocardial infarction (adjusted HR=0.793, p=0.037).

Conclusions: Compared to NST, OSR of AAs could be associated with a lower incidence of subsequent CVDs.
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http://dx.doi.org/10.1016/j.jjcc.2019.12.005DOI Listing
June 2020

An ultrathin ionomer interphase for high efficiency lithium anode in carbonate based electrolyte.

Nat Commun 2019 12 20;10(1):5824. Epub 2019 Dec 20.

Department of Chemical Engineering, National Taiwan University, Taipei, 10617, Taiwan.

High coulombic efficiency and dendrite suppression in carbonate electrolytes remain challenges to the development of high-energy lithium ion batteries containing lithium metal anodes. Here we demonstrate an ultrathin (≤100 nm) lithium-ion ionomer membrane consisting of lithium-exchanged sulfonated polyether ether ketone embedded with polyhedral oligosilsesquioxane as a coating layer on copper or lithium for achieving efficient and stable lithium plating-stripping cycles in a carbonate-based electrolyte. Operando analyses and theoretical simulation reveal the remarkable ability of the ionomer coating to enable electric field homogenization over a considerably large lithium-plating surface. The membrane coating, serving as an artificial solid-electrolyte interphase filter in minimizing parasitic reactions at the electrolyte-electrode interface, enables dendrite-free lithium plating on copper with outstanding coulombic efficiencies at room and elevated (50 °C) temperatures. The membrane coated copper demonstrates itself as a promising current collector for manufacturing high-quality pre-plated lithium thin-film anode.
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http://dx.doi.org/10.1038/s41467-019-13783-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925282PMC
December 2019

Electrodiffusioosmosis-Induced Negative Differential Resistance in pH-Regulated Mesopores Containing Purely Monovalent Solutions.

ACS Appl Mater Interfaces 2020 Jan 31;12(2):3198-3204. Epub 2019 Dec 31.

Department of Chemical Engineering , National Taiwan University of Science and Technology , Taipei 10607 , Taiwan.

Negative differential resistance (NDR) refers to a unique electrical property where current decreases with increasing voltage. Herein, we report experimental evidence showing that the NDR effect can be observed in mesopores that feature charged pore walls and are subjected to a KCl concentration gradient. NDR in our system originates from the solution and ion flows driven by the synergistic effects of electroosmosis [electroosmotic flow (EOF)] and diffusioosmosis, the so-called electrodiffusioosmosis. Experiments reveal that in addition to the ion current rectification, the mesopores considered here exhibit the NDR phenomenon that is dependent on the magnitude and direction of the salinity gradient and on pH. The NDR behavior can be observed only at conditions at which the EOF and diffusioosmosis occur in the opposite directions: diffusioosmosis fills the tip opening with a high concentration solution, while EOF brings a low concentration solution to the pore. All experimental findings are supported by our numerical model, which takes into account the interfacial site reactions of acidic and basic functional groups on the entire pore membrane surfaces. Our results provide an important insight into how liquid pH, salinity gradients, interfacial site reactions, and pore geometries can influence the current-voltage characteristics of mesopores, enriching transport modes that can be induced by voltage.
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http://dx.doi.org/10.1021/acsami.9b18524DOI Listing
January 2020

Tunable Current Rectification and Selectivity Demonstrated in Nanofluidic Diodes through Kinetic Functionalization.

J Phys Chem Lett 2020 Jan 13;11(1):60-66. Epub 2019 Dec 13.

Department of Chemical Engineering , National Taiwan University , Taipei 10617 , Taiwan.

The possibility of tuning the current rectification and selectivity in nanofluidic diodes is demonstrated both experimentally and theoretically through dynamically functionalizing a conical nanopore with poly-l-lysine. We identified an optimum functionalization time equivalent to optimum modification depth that assures the highest rectification degrees. Results showed that the functionalization time-dependent rectification behavior of nanofluidic diodes is dominated by the properties of current at positive voltages that in our electrode configuration indicate the "on" state of the diode and accumulation of ions in the nanopore. The functionalization time also tunes the ion selectivity of the diode. If the functionalization time is sufficiently short, an unusual depletion of counterions near the bipolar interface results in a cation-selective nanopore. However, a further increase in the duration of functionalization renders a nanopore that is an anion-selective nanopore. The dynamic functionalization presented in this Letter enables tuning ion selectivity of nanopores.
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http://dx.doi.org/10.1021/acs.jpclett.9b03344DOI Listing
January 2020

Inequality in outpatient resource utilization among older adults during the 2007-2008 financial crisis: findings from Taiwan.

BMC Health Serv Res 2019 Sep 2;19(1):621. Epub 2019 Sep 2.

Department of Living Science, National Open University, No.172, Zhongzheng Rd., Luzhou Dist.,, New Taipei City, 247, Taiwan, Republic of China.

Background: Equity in medical resource utilization is a crucial concern in countries with national health insurance systems. From the perspective of an active aging framework, public health insurance is one of the pillars of economic security, as suggested by the World Bank, to achieve the goal of social security for older adults. This study thus sought to quantify income-related inequality in national health insurance systems, especially during the global economic crisis of 2007-2008.

Methods: By employing the Taiwan National Health Interview Surveys (2005 and 2009) datasets, we analyzed the socioeconomic inequality of outpatient service utilization for older Taiwanese adults during the financial crisis of 2007-2008. We used corrected concentration indices (CCIs) to examine inequalities over time. Furthermore, we decomposed socioeconomic inequalities to reveal the contributions of determinant factors. The dependent variables related to whether participants had used outpatient services in the previous month, and the independent factors included individual's needs, enabling, predisposing, and environmental factors proposed by Andersen model.

Results: The sample consisted of 2415 observations in 2005 and 2554 observations in 2009. The income-related health care inequality was minor from pro-rich to pro-poor across the study duration, although the difference was insignificant (women: from a concentration index [CI] of 0.0256 in 2005 to a CI of - 0.0098 in 2009; men: from a CI of 0.0379 in 2005 to a CI of 0.0310 in 2009). We used a probit model to analyze the effect of explanatory factors on outpatient resource utilization by men and women. After other factors were controlled for, we found that that the income variable had a positive and significant effect on outpatient service utilization in 2009 and the absolute contribution of income to inequality notably increased from 0.0480 in 2005 to 0.3247 in 2009 for older women.

Conclusions: In conclusion, Taiwan's National Health Insurance system guarantees the accessibility of health care services to older adults, but slight income-related inequality was maintained in the outpatient resource utilization of women during the 2007-2008 financial crisis. Close attention should be paid to the vulnerability of women during times of economic insecurity.
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http://dx.doi.org/10.1186/s12913-019-4466-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721238PMC
September 2019

Male With Dyspnea.

Ann Emerg Med 2019 09;74(3):454-461

Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

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http://dx.doi.org/10.1016/j.annemergmed.2019.03.004DOI Listing
September 2019

Modulation of Charge Density and Charge Polarity of Nanopore Wall by Salt Gradient and Voltage.

ACS Nano 2019 09 31;13(9):9868-9879. Epub 2019 Jul 31.

Department of Chemical Engineering , National Taiwan University , Taipei 10617 , Taiwan.

Surface charge plays a very important role in biological processes including ionic and molecular transport across a cell membrane. Placement of charges and charge patterns on walls of polymer and solid-state nanopores allowed preparation of ion-selective systems as well as ionic diodes and transistors to be applied in building biological sensors and ionic circuits. In this article, we show that the surface charge of a 10 nm diameter silicon nitride nanopore placed in contact with a salt gradient is not a constant value, but rather it depends on applied voltage and magnitude of the salt gradient. We found that even when a nanopore was in contact with solutions of pH equivalent to the isoelectric point of the pore surface, the pore walls became charged with voltage-dependent charge density. Implications of the charge gating for detection of proteins passing through a nanopore were considered, as well. Experiments performed with single 30 nm long silicon nitride nanopores were described by continuum modeling, which took into account the surface reactions on the nanopore walls and local modulation of the solution pH in the pore and at the pore entrances. The results revealed that manipulation of surface charge can occur without changing pH of the background electrolyte, which is especially important for applications where maintaining pH at a constant and physiological level is necessary. The system presented also offers a possibility to modulate polarity and magnitude of surface charges in a two-electrode setup, which previously was accomplished in more complex multielectrode systems.
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http://dx.doi.org/10.1021/acsnano.9b01357DOI Listing
September 2019

Association between acute aortic dissection and the distribution of aortic calcification.

PLoS One 2019 11;14(7):e0219461. Epub 2019 Jul 11.

Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Objective: Aortic calcification (AC) is associated with increased risks of cardiovascular events and mortality. Numerous studies have explored the association between calcification and abdominal artery aneurysm. However, evidence regarding the association between AC and acute aortic dissection (AAD) is limited. We aimed to evaluate the association between AC-related variables and the development of intimal tear (IT) in patients with AAD.

Methods: We conducted a retrospective observational study involving 64 patients with type A AAD and 32 patients with type B AAD from February, 2011 to January, 2017 at a tertiary referral medical center in Taiwan. We used the default analysis module "calcification score analysis" to calculate all the calcification variables, including AC scores and volume.

Results: We identified an association between AC and AAD. Patients with AAD had a greater AC volume in the aortic arch and greater AC scores for both the ascending aorta and the aortic arch than did patients without AAD. However, hypertension and coronary artery disease, rather than AC remained to be the independent risk factor for AAD in multivariate analysis. Patients with type A AAD had greater mean and cumulative AC volumes in the aortic arch, greater cumulative AC volumes in the whole aorta and higher cumulative AC scores in the aortic arch than did patients with type B AAD. ACs were superimposed on ITs in nearly half of the patients with AAD. In patients with type A AAD, AC was more commonly located distal to the IT and farther from the IT.

Conclusions: We identified the associations between AC-related variables and the location of IT in patients with AAD. However, AC was not an independent risk factor for AAD. The distribution of AC was different between patients with type A and type B AAD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219461PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622544PMC
March 2020

Electrokinetic Phenomena in Organic Solvents.

J Phys Chem B 2019 Jul 2;123(28):6123-6131. Epub 2019 Jul 2.

Solid/liquid interfaces play a key role in separation processes, energy storage devices, and transport in nanoscale systems. Nanopores and mesopores with well-defined geometry and chemical characteristics have been a valuable tool to unravel electrochemical properties of interfaces, but the majority of studies have been focused on aqueous solutions. Here, we present experiments and numerical modeling aimed at characterizing effective surface charge of polymer pores in mixtures of water and alcohols as well as in propylene carbonate and acetone. The charge properties of pore walls are probed through analysis of current-voltage curves recorded in the presence of salt concentration gradients. The presence and direction of electro-osmotic flow lead to asymmetric current-voltage curves, with rectification characteristics determined by the polarity of surface charge. The results suggest that the effective surface charge of the pore walls depends not only on the type of solvent but also on the concentration of the electrolyte and voltage. We identified conditions at which polymer pores that are negatively charged in aqueous solutions become positively charged in propylene carbonate and acetone. The findings are of importance for nonaqueous separations, fundamental knowledge on solid/liquid interfaces in organic media, and preparation of porous devices with tunable surface charge characteristics.
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http://dx.doi.org/10.1021/acs.jpcb.9b04969DOI Listing
July 2019

Association between surgical repair of aortic aneurysms and the diagnosis of intracranial aneurysms.

J Vasc Surg 2020 02 14;71(2):481-489. Epub 2019 Jun 14.

Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Objective: Aortic aneurysms (AAs) and intracranial aneurysms (IAs) share several clinical risk factors, a genetic predisposition, and molecular signaling pathways. Nonetheless, associations between IAs and AAs remain to be thoroughly validated in large-scale studies. In addition, no effective medical therapies exist for unruptured IAs or AAs.

Methods: Data for this nationwide, population-based, retrospective, cohort study described herein were obtained from the National Health Insurance Research Database in Taiwan. The study outcomes assessed were (1) the cumulative incidence of IAs, which was compared between AA and patients without an AA and (2) the cumulative incidence of IAs in patients with AAs during the 13-year follow-up period, which was further compared among those who underwent open surgical repair (OSR), endovascular aneurysm repair or nonsurgical treatment (NST).

Results: Our analyses included 20,280 patients with an AA and 20,280 propensity score-matched patients without an AA. Compared with the patients without an AA, patients with AA exhibited a significantly increased risk of an IA diagnosis (adjusted hazard ratio [HR], 3.395; P < .001). Furthermore, 6308 patients with AAs were treated with surgical intervention and another 6308 propensity score-matched patients with AAs were not. Patients with an AA who underwent OSR had a significantly lower risk of being diagnosed with an IA than patients with an AA who underwent endovascular aneurysm repair or NST (adjusted HR, 0.491 [P < .001] and adjusted HR, 0.473 [P < .001], respectively).

Conclusions: We demonstrated an association between IAs and AAs, even after adjusting for several comorbidities. We also found that OSR was associated with fewer recognized IAs than NST.
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http://dx.doi.org/10.1016/j.jvs.2019.04.466DOI Listing
February 2020

Electrokinetic ion transport in an asymmetric double-gated nanochannel with a pH-tunable zwitterionic surface.

Phys Chem Chem Phys 2019 Apr 28;21(15):7773-7780. Epub 2019 Mar 28.

Department of Chemical Engineering, National Taiwan University, Taipei, 10617, Taiwan.

Bioinspired, artificial functional nanochannels for intelligent molecular and ionic transport control have versatile potential applications in nanofluidics, energy conversion, and controlled drug release. To simulate the gating and rectification functions of biological ion channels, we model the electrokinetic ion transport phenomenon in an asymmetric double-gated nanochannel having a pH-regulated, zwitterionic surface. Taking account of the effect of electroosmotic flow (EOF), the conductance of the nanochannel and its ion current rectification (ICR) behavior are investigated and the associated mechanisms interpreted. In particular, the influences of the solution pH, the bulk salt concentration, and the base opening radius and the surface curvature of the nanochannel on these behaviors are examined. We show that through adjusting the base opening radius and the surface curvature of a nanochannel, its ICR behavior can be tuned effectively. In addition to proposing underlying mechanisms for the phenomena observed, the results gathered in this study also provide necessary information for designing relevant devices.
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http://dx.doi.org/10.1039/c9cp00266aDOI Listing
April 2019

The association between heat stroke and subsequent cardiovascular diseases.

PLoS One 2019 13;14(2):e0211386. Epub 2019 Feb 13.

Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background: Recent studies have indicated that several critical illnesses are associated with an increased risk of cardiovascular diseases (CVDs). Nonetheless, studies of the association between heat-related illnesses (HRIs) and subsequent CVDs are still limited. We sought to evaluate whether heat stroke (HS) was associated with an increased CVD incidence.

Methods: The data from the nationwide, population-based, retrospective, cohort study described herein were obtained from the National Health Insurance Research Database in Taiwan. The outcome evaluated in this study was the cumulative incidence of CVDs, which was compared between patients with HS, patients with other HRIs and a control group during a 14-year follow-up period.

Results: Our analyses included 150 HS cases, 150 patients with other HRIs and 150 patients without HRIs. The HS patients had a significantly higher incidence of developing CVDs than the other HRI and control patients (32.67% vs. 23.33% vs. 16.67%, p = 0.005). Patients with HS had an increased incidence of acute myocardial infarction (AMI) compared with that of the controls (6% vs. 2.67%, p = 0.042) and an increased incidence of acute ischemic stroke (AIS) compared with those of the other HRI and control patients (12% vs. 6% vs. 4.67%, p = 0.038). An increased risk of chronic kidney disease (CKD) was also found in the patients with HS and other HRIs compared to that in the controls (17.33% vs. 14.67% vs. 6.67%, p = 0.016).

Conclusion: Prior HS was associated with an increased incidence of CVDs, particularly AMI and AIS, and an increased incidence of CKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211386PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373898PMC
November 2019
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