Renal outcomes with sodium-glucose cotransporter 2 inhibitors in Japanese people with grade 3 chronic kidney disease and type 2 diabetes: Analysis of medical administrative databases.

AIM: To evaluate whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with a reduction of renal events compared with other glucose-lowering drugs (oGLDs) among Japanese people with type 2 diabetes (T2D) and grade 3 (G3) chronic kidney disease (CKD) in a real-world clinical practice setting. MATERIALS AND METHODS: People with T2D who were newly prescribed an SGLT2i or an oGLD from April 2014 to November 2021 (without prior use of index drugs for ≥ 1 year prior to index date) and G3 CKD (estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) were selected from the Medical Data Vision database (MDV-DB) and the Real-World Data database (RWD-DB). SGLT2i and oGLD users were matched (1:1) using propensity score on patient background characteristics. The primary endpoint was a composite of the development of end-stage kidney disease or a sustained decline in eGFR of 50% or more. Hazard ratios (HRs) were estimated using the Cox proportional hazards model. RESULTS: Overall, 3190 (1595 per group) patients in the MDV-DB and 2572 (1286 per group) patients in the RWD-DB were included in the analyses. The composite outcome was significantly lower in the SGLT2i group than in the oGLD group in the MDV-DB (HR 0.49, 95% confidence interval [CI] 0.33 to 0.74, P < 0.001) and in the RWD-DB (HR 0.57, 95% CI 0.37 to 0.88, P = 0.011). CONCLUSIONS: Japanese people with T2D and G3 CKD initiating an SGLT2i had a lower risk of renal events than people initiating an oGLD.

Using oxygen/ozone nanobubbles for in situ oxidation of dissolved hydrogen sulfide at a residential tunnel-construction site.

Hydrogen sulfide (H2S) is a toxic gas, and considerable research has been conducted for its control and removal from industrial wastewater and sewage water. However, no simple and practical technology is available for degrading H2S in situ at tunnel constructing sites. On May 11, 2020, an H2S blowout accident occurred in underground soil at a residential sewer-tunnel construction site in Iwakuni City, Yamaguchi Prefecture, Japan, filling the tunnel with high concentrations of H2S gas, causing the fatality of one worker owing to emphysema. River water flowing near the site was immediately introduced into the tunnel to trap the H2S gas, generating 652-m3 water that contained high concentrations (120 mg/L) of dissolved H2S in the tunnel. To safely and quickly remove H2S in situ, the contaminated water was treated with high-density oxygen and ozone nanobubbles (O2/O3-HDNBs) generated using the ultrafine pore method. Consequently, H2S was removed from the contaminated water in 3 days. This is the first successful application of O2/O3-HDNB technology for the in situ oxidation of H2S in environmental water at a construction site. This study reports the practical application of this advanced technology and the system performance.

Large decrease in paediatric hospitalisations during the COVID-19 outbreak in Japan.

We evaluated the nationwide trends in paediatric hospitalisations including non-emergency hospitalisations during the COVID-19 pandemic in Japan. Using inpatient data from 272 acute-care hospitals covering 12.4% of total hospitalisations of all ages, we analysed the number of hospitalisations of children (aged 1-17 years) for weeks 9-21 of 2020 (during the outbreak) versus 2017-2019. Hospitalisation decreased during the outbreak by 38.4% (adjusted incidence rate ratio, 0.60; 95% CI, 0.53 to 0.69). There were reductions in communicable diseases and trauma, possibly through non-pharmaceutical interventions, but not in appendicitis. This study highlights the potential importance of reallocating paediatric care resources during the pandemic.

Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques.

BACKGROUND/AIMS: To investigate the utility of a data-driven deep learning approach in patients with inherited retinal disorder (IRD) and to predict the causative genes based on fundus photography and fundus autofluorescence (FAF) imaging. METHODS: Clinical and genetic data from 1302 subjects from 729 genetically confirmed families with IRD registered with the Japan Eye Genetics Consortium were reviewed. Three categories of genetic diagnosis were selected, based on the high prevalence of their causative genes: Stargardt disease (ABCA4), retinitis pigmentosa (EYS) and occult macular dystrophy (RP1L1). Fundus photographs and FAF images were cropped in a standardised manner with a macro algorithm. Images for training/testing were selected using a randomised, fourfold cross-validation method. The application program interface was established to reach the learning accuracy of concordance (target: >80%) between the genetic diagnosis and the machine diagnosis (ABCA4, EYS, RP1L1 and normal). RESULTS: A total of 417 images from 156 Japanese subjects were examined, including 115 genetically confirmed patients caused by the three prevalent causative genes and 41 normal subjects. The mean overall test accuracy for fundus photographs and FAF images was 88.2% and 81.3%, respectively. The mean overall sensitivity/specificity values for fundus photographs and FAF images were 88.3%/97.4% and 81.8%/95.5%, respectively. CONCLUSION: A novel application of deep neural networks in the prediction of the causative IRD genes from fundus photographs and FAF, with a high prediction accuracy of over 80%, was highlighted. These achievements will extensively promote the quality of medical care by facilitating early diagnosis, especially by non-specialists, access to care, reducing the cost of referrals, and preventing unnecessary clinical and genetic testing.

Trends in intensive neonatal care during the COVID-19 outbreak in Japan.

The reduction in the use of neonatal intensive care units (NICUs) during the COVID-19 outbreak has been reported, but whether this phenomenon is widespread across countries is unclear. Using a large-scale inpatient database in Japan, we analysed the intensive neonatal care volume and the number of preterm births for weeks 10-17 vs weeks 2-9 (during and before the outbreak) of 2020 with adjustment for the trends during the same period of 2019. We found statistically significant reductions in the numbers of NICU admissions (adjusted incidence rate ratio (aIRR), 0.76; 95% CI, 0.65 to 0.89) and neonatal resuscitations (aIRR, 0.37; 95% CI, 0.25 to 0.55) during the COVID-19 outbreak. Along with the decrease in the intensive neonatal care volume, preterm births before 34 gestational weeks (aIRR, 0.71) and between 34 0/7 and 36 6/7 gestational weeks (aIRR, 0.85) also showed a significant reduction. Further studies about the mechanism of this phenomenon are warranted.

The effect of diabetes mellitus on the Two-Step value for gait ability.

OBJECTIVE: Impaired glucose tolerance is a factor that can affect locomotive syndrome. This study aimed to elucidate the impact of diabetes mellitus (DM) on the value of the Two-Step Test as an index of gait ability in locomotive syndrome. The present study focused on DM patients who did not have diabetic polyneuropathy (DP) and discussed the effect of DM on the Two-Step value. METHODS: This cross-sectional study compared the Two-Step values between DM patients without DP (32 male, 28 female; mean age 62.2 years) and regional residents without DM (25 male, 18 female; mean age 61.8 years). RESULTS: Body mass index was significantly higher in the DM patients than in the regional residents. The Two-Step value was lower in DM patients than in individuals without DM among females but not among males. Therefore, the Two-Step value was lower in female DM patients than in female regional residents of the same age. CONCLUSION: This study presents a new observation: The gait ability in female DM patients can be impaired, even before the development of DP.

Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor.

BACKGROUND: Mitochondrial K(ATP) channel activation is an essential component of ischemic preconditioning. These channels are selectively opened by diazoxide and may be up-regulated by adenosine and nitric oxide. Therefore, pharmacological preconditioning with diazoxide in combination with adenosine and a nitric oxide donor (triple-combination pharmacological preconditioning) may enhance cardioprotection. METHODS AND RESULTS: Isolated and perfused rat hearts underwent ischemic preconditioning with 3 cycles of 5 minutes of ischemia and 5 minutes of reperfusion before 5 minutes of oxygenated potassium cardioplegia and 35 minutes of ischemia. Pharmacological preconditioning was performed by adding adenosine, diazoxide, and a nitric oxide donor S-nitroso-N-acetyl-penicillamine each alone or in combinations for 25 minutes followed by 10 minutes washout before cardioplegic arrest. Only triple-combination pharmacological preconditioning conferred significant cardioprotection as documented by highly improved left ventricular function and limited creatine kinase release during reperfusion that was comparable to that afforded by ischemic preconditioning. Mitochondrial K(ATP) channel activity assessed by flavoprotein oxidation was increased by diazoxide, but no further increase in flavoprotein oxidation was obtained by ischemic preconditioning and triple-combination pharmacological preconditioning. Significant activation of protein kinase C-epsilon was observed in only ischemic preconditioning and triple-combination pharmacological preconditioning. Pretreatment with the mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate or the protein kinase C inhibitor chelerythrine abrogated activation of protein kinase C-epsilon and cardioprotection afforded by ischemic preconditioning and triple-combination pharmacological preconditioning. CONCLUSIONS: Integrated pharmacological preconditioning is not simply mediated by enhanced mitochondrial K(ATP) channel activation, but is presumably mediated through amplified protein kinase C signaling promoted by coordinated interaction of adenosine, mitochondrial K(ATP) channel activation, and nitric oxide.

Thrombus formation after aortic valvular replacement using Björk-Shiley valve occluding the right coronary orifice.

We describe a patient with unstable angina due to occlusion of the orifice of the right coronary artery by thrombus formation after aortic valvular replacement using a Björk-Shiley valve. After strict anticoagulant treatment, transesophageal echocardiography demonstrated disappearance of the thrombus formation around the orifice of the right coronary artery.

Fusiform coronary aneurysm in the left circumflex artery with recurrent myocardial infarction and idiopathic thrombopenia.

The authors describe the rare case of a patient with fusiform coronary aneurysm with myocardial infarction in the left circumflex artery complicated by idiopathic thrombopenia. Medical treatment with a combination of warfarin and aspirin could not prevent recurrence of angina pectoris and myocardial infarction, but surgical ligation of the proximal site of the fusiform aneurysm and coronary bypass to the distal site of the fusiform aneurysm prevented further myocardial infarction and angina pectoris.

Surgical experience with right atrial-aortic fistula and penetration of the superior vena cava by a protruding Accufix atrial J-shaped retention wire.

A 57-year-old woman who had a dual chamber pacemaker implanted in June 1990 for sick sinus syndrome had developed heart failure since 1993. Although fluoroscopy revealed that the proximal J-shaped retention wire of the lead had fractured and had protruded through the outer insulation in 1994, and also that the distal J-shaped retention wire of the lead had protruded through the outer insulation in 1997, a transthoracic echocardiographic examination diagnosed tricuspid valve regurgitation, suggesting that the right atrial-aortic fistula might have been overlooked. In an attempt to avoid migration of the J-shaped retention wire from the lead and to repair the tricuspid regurgitation, it was decided that an operation be performed; however, intraoperative transesophageal echocardiography showed a right atrial-aortic fistula. Intraoperative inspection also revealed that the right atrial-aortic fistula and penetration of the superior vena cava had been caused by the Accufix atrial J-shaped retention wire. Under total cardiopulmonary bypass and induced cardiac arrest, a right atriotomy was performed and the atrial and ventricular leads were removed from the tips. The atrial orifice of the fistula and the aortic orifice were closed. Finally, a new dual-chamber pacing system with bipolar epicardial pacing leads was implanted. Postoperative inspection revealed that the proximal retention wire had fractured, the tip of the retention wire had protruded through the outer insulation, and the distal J-shaped outer insulation was damaged.

Nitric oxide induces caspase-dependent apoptosis and necrosis in neonatal rat cardiomyocytes.

Excessive nitric oxide (NO) production has been implicated in the pathophysiology of cardiomyocyte (CMC) apoptosis and necrosis induced by ischemia/reperfusion, inflammation and NO-donating chemicals. Although caspases are known to be involved in apoptosis, the present study examined whether caspases also play a role in NO-induced CMC necrosis. Neonatal rat CMCs were labeled with Annexin-V and propidium iodide, and apoptosis and necrosis were analyzed by confocal images and fluorescence activated cell sorter analysis. CMC apoptosis and necrosis were also evaluated by determining DNA fragmentation in the cell and the supernatant fractions. Treatment of CMCs with the NO donor, diethylenetriamine NO (DETA/NO) or S-nitroso-N-acetyl-penicillamine (SNAP) at concentrations of 10 and 100 microM for 24h induced predominantly apoptosis over necrosis, but a higher concentration (1mM) of DETA/NO or SNAP provoked both apoptosis and necrosis. The lower doses of DETA/NO-induced apoptosis was associated with a gradual increase in caspase-3 activity over 24h without appreciable activation of poly ADP-ribose polymerase (PARP), while the higher dose of DETA/NO induced a marked increase in caspase-3 activity and CMC apoptosis until 2h after the treatment, and increased necrotic CMCs thereafter associated with robust activation of PARP. The caspase inhibitor Z-DEVD-FMK but not the poly ADP-ribose polymerase (PARP) inhibitor 3-aminobenzamide (3-AB) abolished caspase-3 activation and CMC apoptosis induced by 100 microM DETA/NO. However, both Z-DEVD-FMK and 3-AB abolished PARP activation and CMC necrosis induced by 1mM DETA/NO. The amount of nicotinamide adenine dinucleotide (NAD) and adenine nucleotides in CMCs was not significantly affected by treatment with 10 and 100 microM DETA/NO, but was significantly reduced by treatment with 1mM DETA/NO without a decline of adenylate energy charge. The depletion of NAD and adenine nucleotides was abrogated by Z-DEVD-FMK and 3-AB. These results suggest that caspase activation play a crucial role in CMC apoptosis induced by lower concentrations of NO as well as in CMC necrosis induced by a higher concentration of and a longer exposure to NO. NO-induced CMC necrosis is likely mediated by PARP activation which occurs as a consequence of caspase activation.

Complementary role of extracellular ATP and adenosine in ischemic preconditioning in the rat heart.

Although adenosine is an important mediator of ischemic preconditioning (IPC), its relative contribution to IPC remains unknown. Because adenosine is formed through the hydrolysis of ATP, the present study investigated the role of ATP and adenosine in IPC. Isolated and buffer-perfused rat hearts underwent IPC by three cycles of 5-min ischemia and 5-min reperfusion before 25 min of global ischemia. The rate-pressure product (RPP) 30 min after reperfusion was taken as an endpoint of functional protection. Interstitial fluid (ISF) adenine nucleotides and adenosine were measured by cardiac microdialysis techniques. Inhibition of IPC-induced recovery of RPP was partial by the adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (SPT; 100 microM) or by the structurally distinct P2Y purinoceptor antagonists suramin (300 microM) or reactive blue (RB; 10 microM) but was additive when SPT was given with suramin or RB. The P2X antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium (50 microM) had no effect on functional protection. The improved functional recovery was not significantly affected by an ecto-5'-nucleotidase inhibitor, alpha,beta-methylene adenosine diphosphate (AMP-CP; 100 microM), alone but was inhibited by AMP-CP plus SPT, suramin, or RB. ISF ATP and adenosine increased temporarily by 10-fold during IPC. AMP-CP augmented the increase in ISF ATP associated with the decrease in ISF adenosine. There was a reciprocal correlation between the ISF concentration of ATP and adenosine in preconditioned hearts. In addition, there was a significant correlation between ISF adenosine and ATP and the inhibitory potency of SPT and suramin or RB against functional protection conferred by IPC. These results suggest that extracellular ATP and adenosine play a complementary role in IPC through P2Y purinoceptors and adenosine receptors, respectively.

Enhanced IPC by activation of pertussis toxin-sensitive and -insensitive G protein-coupled purinoceptors.

Extracellular ATP plays an important role in ischemic preconditioning (IPC) through the activation of P(2y) purinoceptors. This study examined whether ATP-stimulated P(2y) purinoceptors are coupled to pertussis toxin (PTX)-insensitive G protein and whether activation of this pathway enhances myocardial protection afforded by IPC. The rat was treated with PTX for 48 h, and the heart was then isolated and buffer perfused. The heart underwent IPC by three cycles of 5-min ischemia and 5-min reperfusion before 25 min of global ischemia. Isovolumic left ventricular function was measured, and functional recovery at 30 min after reperfusion was taken as an end point of myocardial protection. PTX pretreatment partially inhibited functional protection by IPC. Treatment with 100 microM 8-(p-sulfophenyl) theophylline (SPT) during IPC had no further effect on PTX-induced inhibition of functional protection by IPC, whereas suramin (300 microM) or reactive blue (RB) (10 microM) completely abolished myocardial protection in the preconditioned heart pretreated with PTX. Supplementation with adenosine (30 microM), ATP (30 microM), or UTP (50 microM) significantly enhanced IPC-induced functional protection, although preconditioning with these nucleotides without IPC had no protective effect. Adenosine-enhanced IPC was inhibited by pretreatment with PTX and SPT but not by suramin or RB, whereas ATP-enhanced IPC was inhibited by suramin or RB in combination with PTX pretreatment. On the other hand, UTP-enhanced IPC was not affected by PTX pretreatment but was inhibited by suramin or RB. Adenosine supplemented IPC without PTX pretreatment and ATP supplemented IPC with PTX pretreatment were not affected by nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (100 microM). Although the protein kinase C inhibitor Ro318425 (0.3 microM) or tyrosine kinase inhibitor genistein (50 microM) had no significant effect on the functional protection afforded by adenosine-supplemented IPC without PTX pretreatment and ATP-supplemented IPC with PTX pretreatment, the combination of Ro318425 and genistein attenuated functional protection afforded by both the purinoceptor agonist-supplemented IPC. These results suggest the crucial involvement of PTX-sensitive and -insensitive G protein coupled purinoceptors in enhanced IPC by supplementation with adenosine, ATP, and UTP.