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Fully non-inductive second (2nd) harmonic electron cyclotron (EC) plasma current ramp-up was demonstrated with a newlly developed 28 GHz system in the QUEST spherical tokamak. A high plasma current of 54 kA was non-inductively ramped up and sustained stably for 0.9 s with a 270 kW 28 GHz wave. A higher plasma current of 66 kA was also non-inductively achieved with a slow ramp-up of the vertical field. We have achieved a significantly higher plasma current than those achieved previously with the 2nd harmonic EC waves. This fully non-inductive 2nd harmonic EC plasma ramp-up method might be useful for future burning plasma devices and fusion reactors, in particular for operations at half magnetic field with the same EC heating equipment. [ABSTRACT FROM AUTHOR]

This paper describes the recent progress in divertor simulation research using the GAMMA 10/PDX tandem mirror towards the development of divertors in fusion reactors. During a plasma flow generation experiment in the end cell of the GAMMA 10/PDX, ICRF heating in the anchor cell successfully extended the particle flux up to 3.3  ×  1023 m2 s−1. Superimposing the short pulse of the ECH also attained a maximum heat flux of ~30 MW m−2. We have succeeded in achieving and characterizing the detachment of the high-temperature plasma, which is equivalent to the SOL plasma of tokamaks, by using the divertor simulation experimental module (D-module) in the GAMMA 10/PDX end cell, in spite of using a linear device with a short magnetic field line connection length. Various gases (Ar, Xe, Ne and N2) are examined to evaluate the effect of radiation cooling against the plasma flow at the MW m−2 level in the divertor simulation region and the following results are obtained: (i) Xe gas was most effective in the reduction of heat and particle fluxes (1%, 3%, respectively) and has a stronger effect on electron cooling (down to ~1.6 eV) in the used gas species. (ii) Ne gas was less effective. On the other hand, (iii) N2 gas showed more favorable effects than Ar in the lower pressure range. These results will contribute to the progress in detached plasma operation and in clarifying the radiation cooling mechanism towards the development of future divertors. [ABSTRACT FROM AUTHOR]

Megawatt power gyrotrons are being developed for collaborative electron cyclotron heating (ECH) studies of advanced fusion devices and demonstration power plant (DEMO). (1) In the first experiment of a 300 GHz gyrotron, an output power above 0.5 MW in the TE32,18 single mode was achieved with a pulse width of 2 ms. This was the first observation of MW-scale oscillations in a DEMO-relevant gyrotron mode. It was also found that the reflection at the output window affected the determination of the oscillation mode. Furthermore, several single mode oscillations in the 226–254 GHz range were confirmed, which is important for the step-frequency tunable gyrotron in the sub-THz frequency range. (2) Based on the successful results of the 77 and 154 GHz large helical device (LHD) tubes, a new 154/116 GHz dual-frequency gyrotron with an output of over 1.5 MW is being designed. (3) A new record output of 1.38 MW was obtained using an existing 28 GHz gyrotron. A newly designed tube aimed at achieving a dual-frequency output power of 2 MW at 28 GHz (0.4 MW continuous wave) and 1 MW at 35 GHz was built. In the first experimental test, main mode oscillations were observed at the frequencies of 28.036 and 34.831 GHz with Gaussian-like output beams and output power of 1.27 and 0.48 MW, respectively. A total efficiency of 50% was achieved at 28 GHz operation. [ABSTRACT FROM AUTHOR]

Megawatt-class gyrotrons covering a wide frequency range (14 GHz–300 GHz) are in increasing demand for nuclear fusion. Recent electron cyclotron heating and electron cyclotron current drive experiments highlight a requirement of megawatt-scale gyrotrons at a relatively lower frequency (14–35 GHz) range of some plasma devices, like GAMMA 10/PDX of the University of Tsukuba, QUEST of Kyushu University, NSTX-U of Princeton Plasma Physics Laboratory, and Heliotron J of Kyoto University. Collaborative studies for designing a new 28 GHz/35 GHz dual-frequency gyrotron and a 14 GHz gyrotron have commenced. Operation above 1 MW of 28 GHz/35 GHz dual oscillation was demonstrated experimentally. Further in the design of dual-frequency gyrotron, operations with 2 MW 3 s and 0.4 MW CW (continuous wave) at 28 GHz, and power exceeding 1 MW for 3 s at 34.8 GHz have been shown to be feasible. The 14 GHz gyrotron is expected to operate above 1 MW. We are also developing higher frequency gyrotrons (77–300 GHz). The joint program of National Institute for Fusion Science and the University of Tsukuba developed two new 154 GHz gyrotrons for the large helical device after the demonstration of three 77 GHz gyrotrons. The 154 GHz gyrotrons achieved a maximum output power of 1.25 MW and quasi-CW operation of 0.35 MW for 30 min. [ABSTRACT FROM AUTHOR]

The transition of a detached to attached plasma experiment has been performed in GAMMA 10/PDX by applying an additional plasma heating pulse of electron cyclotron heating (ECH). In a plasma detachment experiment, a short pulse (25 ms) of ECH was applied at the east plug-cell to examine the effects of electron heating on the plasma parameters in the D-module. It was found that the ion flux increased significantly during ECH injection. In the ECH injection period, the ion flux increased with the increasing impurity injection, which indicates the impurity ion components are enhanced by ionization in the D-module due to the application of ECH. During ECH injection period, the increase of the ion flux near the corner of the target plate shows a clear dependence on the gas species. The 2D visible emission has been captured by the high-speed camera and a bright emission near the corner of the target has been observed. The spectroscopic measurement in the D-module shows that the impurity ion emission increases remarkably during ECH injection. These results indicate the detached plasma change to the attached state. Keywords: GAMMA 10/PDX, Divertor simulation experiment, Plasma detachment, Detached to attached transition

Chronic kidney disease (CKD) is on the rise, and over 50% of patients die from cardiac causes. Patients develop heart failure due to unelucidated reno-cardiac interactions, termed type 4 cardiorenal syndrome (CRS4). The aim of this study is to establish and characterize a reliable model of CRS4 in swine with marked cardiac diastolic dysfunction. Yorkshire pigs (19.9 ± 1.7 kg, 4 females and 5 males) underwent staged renal artery embolization using autologous clot. Echocardiogram, aortic pressure (AoP), renal angiogram, and blood samples were assessed monthly. At 4 mo, animals were euthanized after measuring glomerular filtration rate (GFR) and left ventricular (LV) pressure-volume parameters. Heart and kidneys were collected for postmortem analyses. Size-matched swine ( n = 5; 43.7 ± 9.8 kg) served as controls. After three dose-titrated renal embolization, serum creatinine (SCr) and AoP increased by wk 10. At 4 mo, SCr (2.03 ± 0.45 vs. 1.34 ± 0.17 mg/dL, P = 0.013) and AoP (158 ± 16 vs. 121 ± 8 mmHg, P = 0.001) were higher, and GFR was lower (12 ± 3 vs. 131 ± 7 mL/min, P < 0.001) than size-matched controls. Although the LV ejection fraction was similar, the slope of the end-diastolic pressure-volume relationship was steeper in pigs after renal embolization (0.36 ± 0.09 vs. 0.17 ± 0.06, P = 0.003), indicating increased LV stiffness. LV mass index (2.73 ± 0.19 vs. 2.50 ± 0.13 g/kg, P = 0.043) and wall-thickness (11.4 ± 0.8 vs. 8.9 ± 1.2 mm, P = 0.003) increased. These were accompanied by histologically increased fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction. Repeat titrated renal embolization resulted in a model that exhibits advanced CKD and cardiac abnormalities consistent with CRS4. NEW & NOTEWORTHY Cardiac pathological changes consistent with heart failure with preserved ejection fraction can be induced in a large animal model by serial and titrated renal embolization of kidneys with autologous clot, leading to severe renal dysfunction and impaired cardiac diastolic function.

Pharmacologic beta-blockade is a well-established therapy for reducing adverse effects from sympathetic overactivity in cardiovascular diseases, such as heart failure. Despite decades of research efforts, in vivo cardiac functional studies utilizing genetic animal models remain scant. We generated a mouse model of cardiomyocyte-specific deletion of beta-1 adrenergic receptor (ADRB1) , the primary subtype expressed in cardiac myocytes, and demonstrated the role for ADRB1 in the maintenance of cardiac function at baseline and during exposure to increase in cardiac afterload by transient aortic occlusion and increasing heart rates (HRs) via atrial pacing. cKO hearts showed mildly depressed baseline left ventricular (LV) function, including slower HR, decreased contractility (dP/dtmax/IP) and prolonged relaxation (Tau) at baseline in both sexes. Exposure to increased LV afterload depressed LV function in either genotype similarly; however, the functional recovery following the removal of the afterload was severely impaired in cKO hearts, while cardiac function was immediately normalized in WT hearts. When HR was altered from 400 to 700bpm, cKO hearts were deficient in HR-dependent improvement of cardiac contractility and relaxation, known as positive force frequency relationship, that was evident in WT hearts. Enhanced phosphorylation of phospholamban by the HR increase was markedly blunted in cKO myocardium vs wild types, while CaMKII phosphorylation was comparable between the genotypes, suggesting the critical involvement of PKA. These results provide the first experimental evidence for the role of ADRB1 in cardiomyocytes for maintaining cardiac function at baseline and during acute stress, providing clinical perspective relating to the management of patients on beta-blockers.

Background: Right ventricular (RV) function assessment by echocardiography can be challenging due to its complex morphology. Also, increasing use of sedation rather than general anesthesia for transfemoral approach transcatheter aortic valve replacement (TAVR) reduces the need for intraoperative transesophageal echocardiography (TEE). Recent clinical studies have demonstrated the importance of 3-dimensional (3D) echocardiography and a longitudinal strain for RV function assessment. In this study, we compared RV function echocardiographic assessment methodologies in TAVR and investigated its clinical utility., Methods: This was a prospective, observational study of TAVR at a large academic hospital. Inclusion criteria were adult patients undergoing TAVR requiring intraoperative TEE between April 2023 and October 2023. Exclusion criteria include an absolute contraindication to TEE, a pacemaker, or suboptimal intraoperative echocardiography images. The primary goal is to assess the correlation of 3D RV ejection fraction (EF) with RV fraction area change (FAC), and tricuspid annular plane systolic excursion (TAPSE). The secondary goal is to assess the correlation of RV free wall longitudinal strain (FWLS) with any newly diagnosed postoperative ventricular arrhythmia, including complete atrioventricular block (CAVB) and left bundle branch block (LBBB)., Results: Among 33 patients who underwent TAVR, 4 patients were excluded due to poor image quality, and 7 patients were excluded due to existing pacemaker. Thus, data for 22 patients were analyzed in this study. There was a good correlation between 3D RVEF and RV FAC (correlation coefficient 0.789. p = 0.0000482), but poor correlation between 3D RVEF and TAPSE (correlation coefficient 0.182. p = 0.444). Eight patients developed a new left or right BBB and CAVB postoperatively, and 3 patients required permanent pacemaker. Regression analysis of pre and post valve deployment showed RV free wall RVFWLS was each correlated with postoperative new BBB or CAVB (pre valve deployment: hazard ratio 1.272, 95% CI 1.075 to 1.505, p = 0.004981; post valve deployment: hazard ratio 1.134, 95% CI 1.001 to 1.286, p = 0.04846). No mortality was reported during the follow-up period, and no significant tricuspid regurgitation (more than moderate) was reported., Conclusion: 3D RVEF and RV FAC showed a good correlation. Intraoperative RVFWLS has the potential to predict postoperative new occurrence of BBB or CAVB., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Institutional Review Board of Thomas Jeferson University (IRB # iRISID-2022-0802) and verbal consent was obtained from all the participants before enrollment. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Following cardiac surgery, patients often require ventilatory support during transport to the intensive care unit (ICU). Manual ventilation using a bag valve mask (BVM) is commonly employed; however, mechanical ventilation may sometimes be preferred due to concerns regarding oxygenation, ventilation, and hemodynamic stability. The decision between manual and mechanical ventilation is typically based on clinical experience and surgical factors, as there is no established consensus or robust clinical evidence to guide this choice. The aim of this study was to compare oxygenation, ventilation, and hemodynamic parameters between manual ventilation with a BVM and mechanical ventilation using a transport ventilator., Design: A prospective, single-blinded clinical trial., Setting: A single-center tertiary academic hospital., Participants: A total of 48 patients who underwent cardiac surgery and were transported to the ICU between September 2023 and August 2024 were enrolled., Interventions: Patients meeting the inclusion criteria were randomly assigned to one of two groups: Patients in Arm 1received manual ventilation using a BVM during transport to the ICU; patients in Arm 2 received mechanical ventilation using a transport ventilator during transport to the ICU., Measurements and Main Results: Percentage changes in the PaO 2 /FiO 2 ratio and PaCO 2 pre- and post-transport were not significantly different between the two groups (p = 0.133 and 0.902, respectively). However, hypotension, defined as a >10% decrease in mean arterial pressure, was significantly more frequent in the BVM group than in the mechanical ventilation group (p = 0.00986)., Conclusions: In patients who have undergone cardiac surgery, hypotension occurred more frequently in the BVM group than in the mechanical ventilation group during transport to the ICU. However, oxygenation and ventilation parameters were comparable between the two groups., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Oestrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Oestrogen receptor α (ERα) non-nuclear signalling confers protection against heart failure remodelling, involving myocardial cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examine the cell type-specific role of ERα non-nuclear signalling in oestrogen-conferred protection against heart failure., Methods and Results: We first assessed the tissue-specific impacts of ERα on the cardiac benefits derived from oestrogen, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3 weeks of pressure overload [transverse aortic constriction (TAC)]. E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signalling in endothelial cells (ECs), employing animals with endothelial-specific inactivation of ERα non-nuclear signalling (ERαKI/KI/Tie2Cre+). Female ovariectomized mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which were associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed by CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+was rescued by myocardial PKG activation from chronic treatment with a soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial-cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required a co-existence of intact endothelial ERα signalling in a nitric oxide synthase-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of ECs., Conclusion: An endothelial oestrogen-myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure overload., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Adeno-associated virus-based gene therapy is a promising avenue in heart failure treatment, but has shown limited cardiac virus uptake in humans, requiring new approaches for clinical translation. Using a Yorkshire swine ischemic heart failure model, we demonstrate significant improvement in gene uptake with temporary coronary occlusions assisted by mechanical circulatory support. We first show that mechanical support during coronary artery occlusions prevents hemodynamic deterioration (n = 5 female). Subsequent experiments show that coronary artery occlusions during gene delivery improve gene transduction, while adding coronary sinus occlusion (Stop-flow) further improves gene expression up to >1 million-fold relative to conventional intracoronary infusion. Complete survival during and after delivery (n = 10 female, n = 10 male) further indicates safety of the approach. Improved cardiac gene expression correlates with virus uptake without an increase in extra-cardiac expression. Stop-flow delivery of virus-sized gold nanoparticles exhibits enhanced endothelial adherence and uptake, suggesting a mechanism independent of virus biology. Together, utilizing mechanical support for cardiac gene delivery offers a clinically-applicable strategy for heart failure-targeted therapies., Competing Interests: Competing interests: Part of this study was supported by a research grant from Abiomed, Inc. to the institution. K.I. serves as the principal investigator on the grant from Abiomed, Inc. K.I. received an honorarium from Abiomed, Inc. and served as a consultant for Pfizer, Inc., and Gordian Biotechnology. T.S. and T.K. were supported by A-CURE Research Fellowship supported by Abiomed, Inc.. K.I. and R.J.H. have a patent, “SYSTEMS AND METHODS FOR LEFT VENTRICULAR UNLOADING IN BIOLOGIC THERAPY OR VECTORED GENE THERAPY” Publication number: 20200305888. All other authors declare no competing interests., (© 2024. The Author(s).)

Aims: Vein grafts are used for many indications, including bypass graft surgery and arteriovenous fistula (AVF) formation. However, patency following vein grafting or AVF formation is suboptimal for various reasons, including thrombosis, neointimal hyperplasia, and adverse remodelling. Recently, endothelial-to-mesenchymal transition (EndMT) was found to contribute to neointimal hyperplasia in mouse vein grafts. We aimed to evaluate the clinical potential of inhibiting EndMT and developed the first dedicated preclinical model to study the efficacy of local EndMT inhibition immediately prior to AVF creation., Methods and Results: We first undertook pilot studies to optimize the creation of a femoral AVF in pigs and verify that EndMT contributes to neointimal formation. We then developed a method to achieve local in vivo SMAD3 knockdown by dwelling a lentiviral construct containing SMAD3 shRNA in the femoral vein prior to AVF creation. Next, in Phase 1, six pigs were randomized to SMAD3 knockdown or control lentivirus to evaluate the effectiveness of SMAD3 knockdown and EndMT inhibition 8 days after AVF creation. In Phase 2, 16 pigs were randomized to SMAD3 knockdown or control lentivirus and were evaluated to assess longer-term effects on AVF diameter, patency, and related measures at 30 days after AVF creation. In Phase 1, compared with controls, SMAD3 knockdown achieved a 75% reduction in the proportion of CD31+ endothelial cells co-expressing SMAD3 (P < 0.001) and also a significant reduction in the extent of EndMT (P < 0.05). In Phase 2, compared with controls, SMAD3 knockdown was associated with an increase in the minimum diameter of the venous limb of the AVF (1.56 ± 1.66 vs. 4.26 ± 1.71 mm, P < 0.01) and a reduced degree of stenosis (P < 0.01). Consistent with this, neointimal thickness was reduced in the SMAD3 knockdown group (0.88 ± 0.51 vs. 0.45 ± 0.19 mm, P < 0.05). Furthermore, endothelial integrity (the proportion of luminal cells expressing endothelial markers) was improved in the SMAD3 knockdown group (P < 0.05)., Conclusion: EndMT inhibition in a preclinical AVF model by local SMAD3 knockdown using gene therapy led to reduced neointimal hyperplasia, increased endothelialization, and a reduction in the degree of AVF stenosis. This provides important proof of concept to pursue this approach as a clinical strategy to improve the patency of AVFs and other vein grafts., Competing Interests: Conflict of interest: J.C.K. is named as inventor on provisional patent 63/569 288 filed by Mount Sinai Innovation Partners on 25 March 2024 titled ‘Compositions for reducing SMAD3 expression in a blood vessel and methods of using’. The other authors have no relevant disclosures to declare. The data in this paper were used in a dissertation as partial fulfilment of the requirements for a PhD degree at the Graduate School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Acute mechanical left ventricular (LV) support has been suggested to improve infarct tissue perfusion. However, its regulatory mechanism remains unclear. We investigated the physiological mechanisms in six Yorkshire pigs, which were subjected to 90-min balloon occlusion of the left anterior descending artery. During the acute reperfusion phase, LV support using an Impella heart pump was initiated. LV pressure, coronary flow and pressure of the infarct artery were simultaneously recorded to evaluate the impact of LV support on coronary physiology. Coronary wave intensity was calculated to understand the forces regulating coronary flow. Significant increases in coronary flow velocity and its area under the curve were found after mechanical LV support. Among the coronary flow-regulating factors, coronary pressure was increased mainly during the late diastolic phase with less pulsatility. Meanwhile, LV pressure was reduced throughout diastole resulting in significant and consistent elevation of coronary driving pressure. Interestingly, the duration of diastole was prolonged with LV support. In the wave intensity analysis, the duration between backward suction and pushing waves was extended, indicating that earlier myocardial relaxation and delayed contraction contributed to the extension of diastole. In conclusion, mechanical LV support increases infarct coronary flow by extending diastole and augmenting coronary driving pressure. These changes were mainly driven by reduced LV diastolic pressure, indicating that the key regulator of coronary flow under mechanical LV support is downstream of the coronary artery, rather than upstream. Our study highlights the importance of LV diastolic pressure in infarct coronary flow regulation. KEY POINTS: Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Although mechanical left ventricular (LV) support has been suggested to improve infarct coronary flow, its specific mechanism remains to be clarified. LV support reduced LV pressure, and elevated coronary pressure during the late diastolic phase, resulting in high coronary driving pressure. This study demonstrated for the first time that mechanical LV support extends diastolic phase, leading to increased infarct coronary flow. Future studies should evaluate the correlation between improved infarct coronary flow and resulting infarct size., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Mechanical LV unloading for acute myocardial infarction (MI) is a promising supportive therapy to reperfusion. However, no data is available on exit strategy. We evaluated hemodynamic and cellular effects of reloading after Impella-mediated LV unloading in Yorkshire pigs. First, we conducted an acute study in normal heart to observe effects of unloading and reloading independent of MI-induced ischemic effects. We then completed an MI study to investigate optimal exit strategy on one-week infarct size, no-reflow area, and LV function with different reloading speeds. Initial studies showed that acute reloading causes an immediate rise in end-diastolic wall stress followed by a significant increase in cardiomyocyte apoptosis. The MI study did not result in any statistically significant findings; however, numerically smaller average infarct size and no-reflow area in the gradual reloading group prompt further examination of reloading approach as an important clinically relevant consideration., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for treating pain and inflammation. Spontaneous adverse drug reaction (ADR) reports represent a rich data source for the detection of unknown and rare ADRs. This cross-sectional study aimed to analyze the characteristics of ADRs due to NSAIDs in Thailand. All ADR reports of NSAIDs for systemic use from 2015 to 2019 were extracted from the national database in Thailand. Patient characteristics, drug use information, adverse event information, and source of senders in 32,857 reports were analyzed. The annual number of ADR reports due to NSAIDs decreased from 7,008 in 2015 to 5,922 in 2019. The most frequently reported drug was ibuprofen (n=12,645, 38.5%) followed by diclofenac (n=7,795, 23.7%), most patients were 40-59 years old, and the major adverse reaction was angioedema (n=7,513, 22.9%). Serious reactions were recorded in 20.7% (n=6,801) of the total ADRs. Most patients (n=20,593, 62.7%) recovered without sequelae, but there were 5,420 patients (16.5%) who could not recover and 3,109 patients (9.5%) who were recovering. Eight patients (0.02%) died of Stevens-Johnson syndrome (n=3), toxic epidermal necrolysis (n=4), and anaphylactic shock (n=1), which were possibly related to ADRs. The number of ADR reports due to NSAIDs decreased from 2015 to 2019 in Thailand. Serious ADRs and death cases accounted for 20.7% and 0.02%, respectively. Most fatal cases exhibited severe drug-induced skin reactions., Competing Interests: The authors have no conflicts of interest to declare that are relevant to the content of this article.

The intramolecular Diels-Alder reaction (IMDA) is a powerful method for regioselective and stereoselective construction of functionalised decalin skeletons, and the recent discovery of enzymes that catalyse IMDA cycloaddition in biosynthesis has generated considerable interest. This study focused on the role of the absolute configuration of the C-6 carbon of the substrate polyene in the stereocontrol of the IMDA reaction catalysed by Fsa2 and Phm7, which construct different enantiomeric decalin skeletons. Their enantiomeric precursor polyenes were synthesised and subjected to enzymatic or thermal IMDA reactions to isolate various diastereomeric decalines and determine their absolute configuration. Furthermore, density functional theory calculations were performed to elucidate the stereocontrol mechanism underlying the formation of decalin. The results showed that Fsa2 exhibits the same equisetin-type stereoselectivity for enantiomeric substrates regardless of the 6-methyl group configuration of the substrate, while Phm7 shows two types of stereoselectivity depending on the configuration of the 6-methyl group. We also found a unique stereochemistry-activity relationship in antibacterial activity for decalin diastereomers, including new derivatives. This study provides new insights into the stereoselectivity of DAase, which is important in the synthesis of natural product skeletons., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Long-term peritoneal dialysis (PD) is often associated with peritoneal dysfunction leading to withdrawal from PD. The characteristic pathologic features of peritoneal dysfunction are widely attributed to peritoneal fibrosis and angiogenesis. The detailed mechanisms remain unclear, and treatment targets in clinical settings have yet to be identified. We investigated transglutaminase 2 (TG2) as a possible novel therapeutic target for peritoneal injury. TG2 and fibrosis, inflammation, and angiogenesis were investigated in a chlorhexidine gluconate (CG)-induced model of peritoneal inflammation and fibrosis, representing a noninfectious model of PD-related peritonitis. Transforming growth factor (TGF)-β type I receptor (TGFβR-I) inhibitor and TG2-knockout mice were used for TGF-β and TG2 inhibition studies, respectively. Double immunostaining was performed to identify cells expressing TG2 and endothelial-mesenchymal transition (EndMT). In the rat CG model of peritoneal fibrosis, in situ TG2 activity and protein expression increased during the development of peritoneal fibrosis, as well as increases in peritoneal thickness and numbers of blood vessels and macrophages. TGFβR-I inhibitor suppressed TG2 activity and protein expression, as well as peritoneal fibrosis and angiogenesis. TGF-β1 expression, peritoneal fibrosis, and angiogenesis were suppressed in TG2-knockout mice. TG2 activity was detected by α-smooth muscle actin-positive myofibroblasts, CD31-positive endothelial cells, and ED-1-positive macrophages. CD31-positive endothelial cells in the CG model were α-smooth muscle actin-positive, vimentin-positive, and vascular endothelial-cadherin-negative, suggesting EndMT. In the CG model, EndMT was suppressed in TG2-knockout mice. TG2 was involved in the interactive regulation of TGF-β. As inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation associated with TGF-β and vascular endothelial growth factor-A suppression, TG2 may provide a new therapeutic target for ameliorating peritoneal injuries in PD., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

The system to collect information on mortality statistics in Lao PDR is not well established, accurate and timely death information is therefore not available. This article reports the system and process to make the mortality statistical data of Lao PDR. The country has a paper-based resident registration system, using a death notification document, a death certificate, and a family census book. The death notification document is important as it provides the cause of death, which is issued from a health facility and the village office. In the event of a death occurring at home, the family representative needs to report to the village office verbally to obtain a death notification document. On the other hand, if the death occurred in a medical facility, a death notification document from a health facility is provided. The family representative should bring the death notification document to the district Home Affairs office to register the death and obtain a death certificate. After that, the family representative needs to bring the death certificate to the district Public Security office for an amendment in the family census book. ICD-10 is under development regarding death notification from health facilities under the Ministry of Health. However, it is unclear how death notification from village offices can adopt ICD-10 as the majority of deaths occur outside health facilities. A comprehensive and integrated mortality reporting system is necessary in order to create a holistic health policy and welfare for the country., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this study.

Using the Cre-loxP system, we generated the first mouse model in which estrogen receptor-α non-nuclear signaling was inactivated in endothelial cells. Estrogen protection against mechanical vascular injury was impaired in this model. This result indicates the pivotal role of endothelial estrogen receptor-α non-nuclear signaling in the vasculoprotective effects of estrogen., Competing Interests: This work was supported by the Japan Foundation for Applied Enzymology, Japan Heart Foundation Research Grant, SENSHIN Medical Research Foundation, Kobayashi Foundation (Dr Takimoto), Takeda Science Foundation (Drs Ueda and Takimoto), National Institutes of Health HL 052233, National Institutes of Health HL 136962, DK 062729 (Dr Liao), AHA Northeast Research Consortium Postdoctoral Fellowship, Uehara Research Fellowship (Dr Hiroi), and Tri-Service General Hospital Medical Research Foundation Grant TSGH-PH-E-111017 (Dr Liu). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

The reaction of 2-alkynylazetidines and alcohols with a gold catalyst is described. A variety of substituted δ-amino-α,β-unsaturated ketones were synthesized via gold-promoted nucleophilic attack of alcohols followed by ring-opening of azetidine ring.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant N G -nitro-l-arginine methyl ester administration, and a pressure-overload hypertrophy (PO) model was produced by surgical constriction of the transverse aorta (TAC). Heart rate (HR) was slowed below 400 beats/min by intraperitoneal injection of ivabradine. PV loop data were acquired and analyzed at HR incrementing from 400 to 700 beats/min via atrial pacing using a miniature pacing catheter inserted into the esophagus, and comparisons were made among control, HFpEF, and PO mice. At baseline without pacing, no diastolic abnormalities were detected in either PO or HFpEF models. Frequency-diastolic relations, however, revealed the significant diastolic impairment specific to the HFpEF model; both relaxation time constant (Tau) and end-diastolic pressure-volume relationship (EDPVR) were worsened as heart rate increased. Peak positive first derivative of left ventricular pressure (dP/d t max ) was significantly lower in HFpEF versus controls only at a high HR of 700 beats/min. A pacing-controlled protocol would be a feasible and potent method to detect diastolic dysfunction specific to a mouse HFpEF model. NEW & NOTEWORTHY We developed a pacing-controlled PV loop protocol for the assessment of diastolic function at different heart rates in mice, which is a feasible and potent method for the characterization of diastolic dysfunction in a murine HFpEF model whose diastolic dysfunction might be difficult to be detected under resting conditions without pacing.

Introduction: Fibroblast growth factor-2 (FGF-2) has been reported to promote periodontal tissue regeneration. However, no study has investigated the long-term prognosis of periodontal regenerative therapy using FGF-2 to date. The aim of this study was to observe the long-term outcomes as well as to investigate the factors affecting the prognosis of periodontal regenerative therapy using FGF-2., Methods: Sixty intrabony defects were prospectively investigated for three years after periodontal regenerative therapy with recombinant human FGF-2 (rhFGF-2) by evaluating probing pocket depth (PPD) and radiographic bone defect depth (RBD). The factors influencing RBD were assessed by conducting a multivariate linear regression analysis after adjusting for confounders., Results: The mean age of the participants was 62.4 ± 13.4 years, and baseline PPD and RBD were 6.1 ± 1.9 mm and 4.5 ± 1.8 mm, respectively. At six months, one year, and three years after surgery, PPD and RBD had significantly improved to 4.2 ± 1.7, 3.7 ± 1.4, 4.0 ± 1.9 mm and to 3.08 ± 2.05, 2.73 ± 1.90, 2.51 ± 2.15 mm, respectively. At the three-year examination, a significant positive association was deteced between RBD reduction and RBD at baseline, while the association was not significant between RBD reduction and the radiographic bony angle, number of bony walls of the defect, or the furcation involvement at baseline., Conclusions: rhFGF-2 was effective for alveolar bone regeneration in patients with periodontitis and maintained the improved parameters over the three-year observation period. The radiographic bone defect depth at baseline was found to be the factor affecting the periodontal regenerative therapy using rhFGF-2 in the intrabony defects., Trial Registration Number: UMIN000027979., Competing Interests: None declared., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Competing Interests: Conflict of Interest None.

The Center for Child and Adolescent Mental Health (CCAMH) is one of the centers that have psychiatric specialists for children in Cambodia. This study aims to understand the characteristics of children with neuro-developmental disorders, especially autism spectrum disorder (ASD), at CCAMH. This study included 440 cases that were randomly chosen from 2,147 new patients at CCAMH in 2018-2019 and were aged 0-12 years. Socio-demographic factors, parent's information, obstetrical factors, and clinical data were collected from patients' records. A logistic regression analysis and Pearson's chi-square test were used to compare the characteristics between children who were finally diagnosed with ASD and the others (non-ASD). Of the 440 patients, most were male (75.2%), 0-4 years old (57.7%), and diagnosed with ASD (50.0%). Common symptoms were delay of speech, playing alone, and hyperactivity. ASD was significantly more prevalent in male patients compared to females and in the 0-4 years age group compared to the 5-12 years age group. Parents who lived in Phnom Penh and had high education were more likely to visit the CCAMH with their children who were diagnosed with ASD. Regarding treatment, approximately half of all 440 patients had family counselling and psychosocial education. ASD patients had more speech therapy, special education and structured teaching, and networking and coordination therapy compared to non-ASD patients. To provide education and therapy to children with ASD and their parents from the early stage, information about the center and ASD should be widely distributed to all parents in Cambodia., Competing Interests: The authors declare no conflicts of interest in this study.

Introduction: This study aimed to examine the reporting rate and the factors associated with serious outcomes of patient safety incidents at public hospitals in Malaysia., Methods: All patient safety incidents reported in the e-Incident-Reporting System from January to December 2019 were included in the study. A descriptive study was used to describe the characteristics of incidents, and logistic models were used to identify factors associated with low reporting rates and severe harm or death outcomes of incidents., Results: There were 9431 patient safety incidents reported in the system in 2019. The mean reporting rate was 2.1/1000 patient bed-days or 1.5% of hospital admissions. The major category of incidents was drug-related incidents (32.4%). No-harm incidents contributed to 56.1% of all the incidents, while 1.1% resulted in death. More hospitals in the eastern (odds ratio [OR], 12.1) and southern regions (OR, 6.1) had low reporting rates compared to the central region. Incidents with severe harm or death outcomes were associated with more males (OR, 1.4) than females and with the emergency department (OR, 10.6), internal medicine (OR, 5.7), obstetrics and gynecology (OR, 2.4), and surgical department (OR, 5.0) more than the pharmacy department. Compared to drug-related incidents, operation-related (OR, 3.0), procedure-related (OR, 3.5), and therapeutic-related (OR, 4.8) incidents had significantly more severe harm or death outcomes, and patient falls (OR, 0.4) had less severe harm or death outcomes., Conclusion: The mean reporting rate was 2.1/1000 patient bed-days or 1.5% of hospital admissions. More hospitals in the eastern and southern regions had low reporting rates. Certain categories of incidents had significantly more severe outcomes., Competing Interests: Conflict of interest: None.

Left atrial (LA) dysfunction is one of the predictive factors of worse outcomes after mitral valve surgery for mitral regurgitation (MR). We aimed to investigate the effect of MR etiology on progression of LA remodeling in swine MR models. MR was induced in 14 Yorkshire pigs using catheter-based procedures. Seven pigs underwent simultaneous occlusions of the left circumflex artery and the diagonal branch, which resulted in ischemic mitral regurgitation (IMR group). The other seven pigs underwent chordal severing to induce leaflet prolapse simulating degenerative mitral regurgitation (DMR group). Changes in LA volume and function were assessed at baseline, 1 mo, and 3 mo using echocardiography and hemodynamic evaluations. Histopathological assessments were conducted to evaluate LA hypertrophy and fibrosis. At 3 mo, quantitative MR severity was comparable and severe in both groups. Despite the similar degree of MR, minimum LA volume index increased significantly more in the IMR group (IMR: 11.9 ± 6.4 to 73.2 ± 6.4 mL/m 2 , DMR: 10.7 ± 6.4 to 29.5 ± 6.4 mL/m 2 , P interaction = 0.004). Meanwhile, increase in maximum LA volume index was similar between the groups, resulting in lower LA emptying function in the IMR group (IMR: 60.1 ± 3.1 to 29.4 ± 3.1%; DMR: 62.4 ± 3.1 to 58.2 ± 3.1%, P interaction = 0.0003). LA reservoir strain assessed by echocardiography was also significantly lower in the IMR group. Histological analyses revealed increased LA cellular hypertrophy and fibrosis in the IMR group. In conclusion, ischemic MR is associated with aggressive remodeling and reduced emptying function compared with the MR due to leaflet prolapse. Earlier intervention might be necessary for ischemic MR to prevent LA remodeling. NEW & NOTEWORTHY We show different LA structural and functional remodeling patterns between ischemic MR and MR due to leaflet prolapse. Severe ischemic MR was accompanied by extensive LA remodeling, which may be associated with poor clinical outcomes. Our data suggest that detailed structural and functional LA remodeling assessment is important for managing IMR and to determine the presence of LA ischemia.

Background: The concept of customer satisfaction is gaining hold in all corporate sectors worldwide, and a satisfaction survey is used as a tool to discover service problems and as a chance for customers to rate their experience with health care services. A high degree of patient satisfaction with the services given has been found in numerous studies conducted in Malaysian public health care facilities. However, there is limited information available on caregiver satisfaction with pediatric clinics run by the Ministry of Health (MoH) of Malaysia., Objective: This was the first research performed at a public hospital's pediatric clinic, which was the first hospital to adopt the public-private-partnership model under the MoH, with the aim of discovering the prevalence and factors affecting the satisfaction of caregivers at the national referral center., Methods: Cross-sectional research using the standard self-administered SERVQUAL questionnaire was conducted among caregivers accompanying their children to the clinic. The questionnaire consists of 16 paired statements to evaluate their expectations and experiences with the clinic services., Results: A total of 459 caregivers were involved in this study with a majority aged between 30 and 39 years (n=254, 55.4%). Caregivers from the Indian community (adjusted odds ratio [AOR] 2.91, 95% CI 1.37-6.18) and lower income groups (AOR 2.94, 95% CI 1.87-4.64), and those with lower educational backgrounds (AOR 3.58, 95% CI 1.19-10.72) were more likely to be satisfied with the quality of pediatric clinic services. Housewives/househusbands (AOR 0.48, 95% CI 0.25-0.90), on the other hand, appeared less likely to be satisfied with the services provided during their visit to the clinic. Looking at overall patient satisfaction, 50.5% (n=232) of caregivers demonstrated satisfaction with the quality of services, compared to 49.5% (n=227) of dissatisfied respondents., Conclusions: This paper suggests that, although most caregivers are satisfied with the services, greater emphasis must be placed on delivering reliable service in response to the MoH's mission to provide quality and integrated people-centered health services in Malaysia., (©Thinakaran M Selvarajah, Eiko Yamamoto, Yu Mon Saw, Tetsuyoshi Kariya, Nobuyuki Hamajima. Originally published in JMIRx Med (https://med.jmirx.org), 25.05.2022.)

A disappointing number of new therapies for pulmonary hypertension (PH) have been successfully translated to the clinic. Adeno-associated viral (AAV) gene therapy has the potential to treat the underlying pathology of PH, but the challenge remains in efficient and safe delivery. The aims of this study were (1) to test the efficacy of endobronchial aerosolization delivery for AAV1-mediated sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a ( SERCA2a ) gene therapy in a PH pig model and (2) to identify the most efficient airway administration modality for in-lung gene therapy in PH. We hypothesized that delivery to the distal bronchi increases lung viral uptake and avoids virus loss in off-target compartments. In part 1 of the study, PH was induced in pigs by surgically banding the pulmonary veins. Two months postsurgery, 1 × 10 13 viral genomes (vg) of AAV1. SERCA2a or saline was endobronchially aerosolized using a bronchoscope. Two months after aerosolization, high vg copies (vgc) were detected in the lungs, accompanied by functional and morphometrical amelioration of PH. In part 2 of the study, we directly compared the endobronchial aerosolization gene delivery to the intratracheal aerosolization in PH pigs. Endobronchial delivery demonstrated higher viral expression (6,719 ± 927 vs. 1,444 ± 402 vgc/100 ng DNA, p  = 0.0017), suggesting this delivery modality is a promising method for clinical AAV gene therapy for PH.

In Lao PDR, Ministry of Health introduced District Health Information Software 2 (DHIS2) in 2013. Although DHIS2 includes cause of death, Lao government did not request to report cause of death through DHIS2, resulting in no information on frequency of underlying cause of death even for the deaths at medical facility. This study aimed to collect the information on the underlying cause of death at all medical facilities in Xaiyabouli province, a rural area in Lao PDR. As well as the point estimate of the proportion, a 95% confidence interval (CI) based on a binomial distribution was calculated for each cause of death. According to the local government request, 226 deaths (128 males and 98 females) in 2019 were reported from all medical facilities in the province. Among them, infectious diseases were the most frequent (33.6%, 95% CI 27.5-40.2%); sepsis (16.8%, 95% CI 12.2-22.3%), pneumonia (8.8%, 95% CI 5.5-13.3%), and meningitis (4.9%, 95% CI 2.5-8.5%). Heart diseases were 15.9% (95% CI 11.4-21.4%) including heart failure and myocardial infarction. Injury was 10.2% (95% CI 6.2-14.4%) including brain injury. Neonatal death was 10.6% (95% CI 6.9-15.4%). Among those, preterm death was common (8.8%, 95% CI 5.3-13.3%). Renal failure was 8.0% (95% CI 4.8-12.3%). According to civil registration covering all deaths both at facilities and outside facilities, deaths at facilities were 16.8% of the whole deaths (1,372 deaths) in Xaiyabouli province. Although deaths outside facilities were not included, this is the first report demonstrating cause of death in one province in Lao PDR., Competing Interests: The authors declare that they have no competing interests.

Although diagnosis and treatment of tuberculosis (TB) have been improved in many countries, delays in the diagnosis and treatment remain problematic in resource-limited countries. This study aimed to identify factors affecting delays in TB care in Mongolia. Data on TB cases registered from January 2016 to December 2017 were obtained from the national registry of TB at the Department of TB Surveillance and Research in National Center for Communicable Disease. The total number of TB cases registered in these two years was 8,166, including 3,267 cases of newly diagnosed pulmonary TB. Pulmonary TB cases (1,836 males and 1,431 females) were analyzed to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Patient delays longer than the median (28 days) were significantly associated with patient age >32 years (aOR=1.31, 95%CI: 1.14-1.51), residence in areas other than Ulaanbaatar (aimags) (aOR=1.38, 95%CI: 1.20-1.59), and smear-negative (aOR=0.57, 95%CI: 0.47-0.69). Health system delays longer than the median (7 days) were significantly associated with patient age >32 years (aOR=1.16, 95%CI: 1.00-1.33), residence in aimags (aOR=0.82, 95%CI: 0.71-0.95), special facilities including a prison hospital (aOR=4.40, 95%CI: 2.42-7.83), registration in 2017 relative to 2016 (aOR=0.83, 95%CI: 0.71-0.95), and smear-negative (aOR=1.72, 95%CI: 1.42-2.07). Total delays longer than the median (45 days) were significantly associated with patient age >32 years (aOR=1.39, 95%CI: 1.21-1.60), residence in aimags (aOR=1.27, 95%CI: 1.11-1.47), and smear-negative (aOR=0.74, 95%CI: 0.62-0.90). To shorten the total delay, improvement of the access to medical facilities in aimags is necessary., Competing Interests: The author declares no conflicts of interest for this study.

As the aging population grows worldwide, the problem of age-related health is becoming an important public health concern. Dementia is a devastating disease that places a significant physical, emotional, and financial burden on patients, their caregivers, and society. It is predicted to increase in developing countries. The Revised Hasegawa's Dementia Scale (HDS-R) has been used in many Asian countries to measure cognitive function. However, there is still no Vietnamese version of the HDS-R. Therefore, this paper describes the development of the HDS-R scale and manual in Vietnamese language. Two Vietnamese researchers translated the HDS-R from English to Vietnamese. To confirm the accuracy of the translation, two other Vietnamese researchers conducted a back-translation. Another pair of Vietnamese researchers compared the back-translated English version to the original one. All six researchers discussed the inconsistencies between English HDS-R scale and manual and derived the most suitable version for the Vietnamese context. In Questions 4 and Question 7, we changed the words from "cherry blossom" and "train" to "daisy flower" and "bicycle" for the first option, and from "plum blossom" to "rose" for the second option. We also changed the expressions in some places in the manual to fit the Vietnamese language. Future studies are needed to validate this version to be able to access cognitive function in both clinical and public healthcare settings., Competing Interests: Authors have declared that no conflict of interest for the present study.

Background: Carotid artery manipulation is not a special technique but reports of intraoperative ventricular fibrillation are rare. The risk of fatal arrhythmias may be hidden behind routine surgical techniques and anesthetic management. We focused on QT prolongation and QT dispersion., Case Presentation: A 77-year-old man underwent carotid endarterectomy and bailout stenting. Although there were no obvious preoperative risk factors for intraoperative ventricular tachyarrhythmia, ventricular fibrillation (VF) had occurred during a maneuver of the carotid artery under hypercapnia. QTc was prolonged from 317 ms before surgery to 458 ms before the onset of VF. QTc dispersion between leads II and III was also increased to 50 ms. Hypomagnesemia was noted after resuscitation by electrical defibrillation, adrenaline, and noradrenaline., Conclusions: We considered that the combination of multiple risk factors led to the development of ventricular fibrillation. It should be noted that carotid artery manipulation has the potential to cause arrhythmias., (© 2022. The Author(s).)

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor γ co-activator-1α (PGC1α) in the PDE5i-conferred cardioprotection, utilizing PGC1α null mice. In PGC1α +/+ hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1α -/- hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG-PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure., (© 2021 Federation of European Biochemical Societies.)

Background: Cardiac surgery is performed worldwide, and acute kidney injury (AKI) following cardiac surgery is a risk factor for mortality. However, the optimal blood pressure target to prevent AKI after cardiac surgery remains unclear. We aimed to investigate whether relative hypotension and other hemodynamic parameters after cardiac surgery are associated with subsequent AKI progression., Methods: We retrospectively enrolled adult patients admitted to 14 intensive care units after elective cardiac surgery between January and December 2018. We defined mean perfusion pressure (MPP) as the difference between mean arterial pressure (MAP) and central venous pressure (CVP). The main exposure variables were time-weighted-average MPP-deficit (i.e., the percentage difference between preoperative and postoperative MPP) and time spent with MPP-deficit > 20% within the first 24 h. We defined other pressure-related hemodynamic parameters during the initial 24 h as exploratory exposure variables. The primary outcome was AKI progression, defined as one or more AKI stages using Kidney Disease: Improving Global Outcomes' creatinine and urine output criteria between 24 and 72 h. We used multivariable logistic regression analyses to assess the association between the exposure variables and AKI progression., Results: Among the 746 patients enrolled, the median time-weighted-average MPP-deficit was 20% [interquartile range (IQR): 10-27%], and the median duration with MPP-deficit > 20% was 12 h (IQR: 3-20 h). One-hundred-and-twenty patients (16.1%) experienced AKI progression. In the multivariable analyses, time-weighted-average MPP-deficit or time spent with MPP-deficit > 20% was not associated with AKI progression [odds ratio (OR): 1.01, 95% confidence interval (95% CI): 0.99-1.03]. Likewise, time spent with MPP-deficit > 20% was not associated with AKI progression (OR: 1.01, 95% CI 0.99-1.04). Among exploratory exposure variables, time-weighted-average CVP, time-weighted-average MPP, and time spent with MPP < 60 mmHg were associated with AKI progression (OR: 1.12, 95% CI 1.05-1.20; OR: 0.97, 95% CI 0.94-0.99; OR: 1.03, 95% CI 1.00-1.06, respectively)., Conclusions: Although higher CVP and lower MPP were associated with AKI progression, relative hypotension was not associated with AKI progression in patients after cardiac surgery. However, these findings were based on exploratory investigation, and further studies for validating them are required. Trial Registration UMIN-CTR, https://www.umin.ac.jp/ctr/index-j.htm , UMIN000037074., (© 2021. The Author(s).)

Objectives: The authors devised a hepatic vein flow index (HVFi), using intraoperative transesophageal echocardiography and graft weight, and investigated its predictive value for postoperative graft function in orthotopic liver transplant., Design: Prospective clinical trial., Setting,: Single-center tertiary academic hospital., Participants: Ninety-seven patients who had orthotopic liver transplant with the piggy-back technique between February 2018 and December 2019., Measurements and Main Results: HVFi was defined with HV flow/graft weight. Patients who developed early graft dysfunction (EAD) had low HVFi in systole (HVFi sys, 1.23 v 2.19 L/min/kg, p < 0.01), low HVFi in diastole (HVFi dia, 0.87 v 1.54 L/min/kg, p < 0.01), low hepatic vein flow (HVF) in systole (HVF sys, 2.04 v 3.95 L/min, p < 0.01), and low HVF in diastole (HVF dia, 1.44 v 2.63 L/min, p < 0.01). More cardiac death, more vasopressors at the time of measurement, more acute rejection, longer time to normalize total bilirubin (TIME t-bil), longer surgery time, longer neohepatic time, and more packed red blood cell transfusion were observed in the EAD patients. All HVF parameters were negatively correlated with TIME t-bil (HVFi sys R = -0.406, p < 0.01; HFVi dia R = -0.442, p < 0.01; HVF sys R = -0.44, p < 0.01; HVF dia R = -0.467, p < 0.01). The receiver operating characteristic curve analysis determined the best cut-off levels of HVFi to predict occurrence of EAD (HVFi sys <1.608, HVFi dia <0.784 L/min/kg), acute rejection (HVFi sys <1.388, HVFi dia <1.077 L/min/kg), and prolonged high total bilirubin (HVFi sys <1.471, HVFi dia <1.087 L/min/kg)., Conclusions: The authors' devised HVFi has the potential to predict the postoperative graft function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In humans, atypical endometrial hyperplasia (AEH) is considered as a precancerous lesion of endometrial adenocarcinoma (EA), from which it must be distinguished. Precancerous lesions have not been reported in cats with EA. We now document the histopathological features of endometrial lesions in six cats, which histopathologically resembled human AEH and had a good prognosis following ovariohysterectomy. Grossly, one cat presented with papillomatous nodules and three cats had pyometra. Histopathologically, proliferation of endometrial epithelial cells without atypia was observed in all cases. In some regions of the endometrium, cells had increased atypia and were arranged in stratified layers, which formed irregular ducts and papillary structures. No invasive behaviour or vascular invasion was observed. On the basis of these findings, the cats were diagnosed with non-invasive or early-stage adenocarcinoma. Immunohistochemistry for oestrogen receptor and progesterone receptor revealed an inverse correlation with the severity of the endometrial lesions and degree of malignancy of tumour cells. Ki67 labelling revealed that mitotic activity increased as the lesion developed. All cats survived, with a median survival time of 385 days (range: 229-744 days). The distribution of the histopathological endometrial changes and the non-invasive behaviour in these feline cases resemble cases of AEH in humans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)