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Key pointsA mathematical model of a small conductance Ca2+ -activated potassium (SK) channel was developed and incorporated into a physiologically detailed ventricular myocyte model. Ca2+ -sensitive K+ currents promote negative intracellular Ca2+ to membrane voltage (CAi2+ → Vm ) coupling. Increase of Ca2+ -sensitive K+ currents can be responsible for electromechanically discordant alternans and quasiperiodic oscillations at the cellular level. At the tissue level, Turing-type instability can occur when Ca2+ -sensitive K+ currents are increased.AbstractCardiac alternans is a precursor to life-threatening arrhythmias. Alternans can be caused by instability of the membrane voltage (Vm ), instability of the intracellular Ca2+ ( Ca i2+) cycling, or both. Vm dynamics and Ca i2+ dynamics are coupled via Ca2+ -sensitive currents. In cardiac myocytes, there are several Ca2+ -sensitive potassium (K+ ) currents such as the slowly activating delayed rectifier current (IKs ) and the small conductance Ca2+ -activated potassium (SK) current (ISK ). However, the role of these currents in the development of arrhythmias is not well understood. In this study, we investigated how these currents affect voltage and Ca2+ alternans using a physiologically detailed computational model of the ventricular myocyte and mathematical analysis. We define the coupling between Vm and Ca i2+ cycling dynamics ( Ca i2+→Vm coupling) as positive (negative) when a larger Ca2+ transient at a given beat prolongs (shortens) the action potential duration (APD) of that beat. While positive coupling predominates at baseline, increasing IKs and ISK promote negative Ca i2+→Vm coupling at the cellular level. Specifically, when alternans is Ca2+ -driven, electromechanically (APD-Ca2+ ) concordant alternans becomes electromechanically discordant alternans as IKs or ISK increase. These cellular level dynamics lead to different types of spatially discordant alternans in tissue. These findings help to shed light on the underlying mechanisms of cardiac alternans especially when the relative strength of these currents becomes larger under pathological conditions or drug administrations.

This paper proposes a method to reduce torque ripple in axial gap motors by multi objective optimization of permanent magnets (PMs) shape using genetic algorithm (GA). Torque ripple is a problem because it causes vibration and noise. Conventionally, torque ripple has been reduced by quantitatively designing the PMs in the shape of multiplicative wave. However, it is difficult to optimize the objective function only by quantitative evaluation through sensitivity analysis. Therefore, in this study, the functions constituting the PMs interface shape are expressed as a Fourier-based series. The PMs is optimized by optimizing combination of their coefficients with GA. As a result, the proposed model is almost equal to the average torque of the basic model and the torque ripple is significantly reduced. Furthermore, fillets are applied and the effect on each characteristic is verified. [ABSTRACT FROM AUTHOR]

Onychomycosis, a fungal nail infection, is a common dermatological condition in Japan, with a prevalence of approximately 5%–10%. Despite the introduction of new antifungal medications and updated treatment guidelines published in 2019, data on real‐world prescription trends and the associated medical costs are limited. This study aimed to investigate the prescription patterns and medical costs of topical and oral antifungal medications for onychomycosis in Japan from fiscal years 2014 to 2021 using the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data. We analyzed the annual prescription volumes and medical costs of four antifungal medications: efinaconazole, luliconazole, fosravuconazole, and terbinafine. The prescription volume of efinaconazole, a topical medication launched in 2014, rapidly increased and dominated the market share. Fosravuconazole, an oral medication introduced in 2018, showed an increasing trend, coinciding with a decline in efinaconazole prescriptions. Terbinafine, a well‐established oral medication, experienced a substantial decrease in prescription volume. The sex‐ and age‐adjusted prescription volume per 100 000 population was higher among older adults, particularly for efinaconazole. The total medical costs for onychomycosis treatment more than doubled in fiscal year 2015 compared with that for 2014, mainly driven by efinaconazole prescriptions, and exceeded 30 billion Japanese yen in fiscal years 2019–2021. The costs slightly decreased in fiscal years 2020 and 2021, possibly due to the introduction of fosravuconazole. The predominance of topical prescriptions, especially in older adults, raises concerns regarding adherence to the Japanese guidelines that recommend oral antifungals as the first‐line treatment for onychomycosis. The substantial increase in medical costs also highlights the economic burden of onychomycosis and the need for cost‐effective treatment strategies. This study provides valuable insights into the real‐world prescription trends and medical costs of onychomycosis treatment in Japan, suggesting an opportunity to assess potential gaps between guideline recommendations and clinical practice. [ABSTRACT FROM AUTHOR]

Background Systemic sclerosis presents with a variety of cardiac manifestations, while myocarditis is usually a rare finding. Furthermore, there are no reports on the use of mitral transcatheter edge-to-edge repair (M-TEER) for the treatment of severe ventricular functional mitral regurgitation (vFMR) secondary to scleroderma myocarditis. Case summary A-79-year-old male was admitted to our hospital because of fever and fatigue. His physical examination revealed thickening of the fingertips' skin, Raynaud phenomenon, and mild pedal oedema. Positive anti-centromere antibodies indicated a diagnosis of a limited cutaneous systemic sclerosis. He presented with symptoms of heart failure, and moderate to severe lymphocytic infiltration was evident in his endomyocardial biopsy. He responded well to medical therapy and was discharged. However, one month after hospital discharge, he was readmitted to our institution because of worsening heart failure. Transthoracic echocardiography showed a decrease in left ventricular systolic function and progression of left ventricular remodelling, which caused severe vFMR. Endomyocardial biopsy revealed decreased lymphocytic infiltration and mild myocardial interstitial fibrosis, indicative of scleroderma myocarditis. As he was unable to be weaned off inotropes, we performed M-TEER for severe vFMR, which led to a significant reduction in MR volume and improvement of heart failure symptoms. A week after procedure, immunosuppressive therapy was initiated and the patient was discharged home in stable condition. Discussion Scleroderma myocarditis may manifest as heart failure with reduced ejection fraction with severe vFMR. Mitral transcatheter edge-to-edge repair for severe vFMR in the context of myocarditis can be one of the therapeutic options for haemodynamic stabilization. [ABSTRACT FROM AUTHOR]

Background and Aim: Changes in the number of surgeries for gastric cancer during the coronavirus disease 2019 (COVID‐19) pandemic have been reported, but data are insufficient to understand the impact at the national level. This study aimed to determine the impact of the COVID‐19 pandemic on gastric surgery in Japan. Methods: Insurance claims data registered from January 2015 to January 2021 were used. Changes in the number of endoscopic resections and gastrectomies for gastric cancer were estimated using an interrupted time‐series analysis. Results: The number of endoscopic resections significantly decreased in July 2020 (−1565; 95% confidence interval [CI]: −2022, −1108) and January 2021 (−539; 95% CI: −970, −109), and the number of laparoscopic surgeries significantly decreased in July 2020 (−795; 95% CI: −1097, −492), October 2020 (−313; 95% CI: −606, −19), and January 2021 (−507; 95% CI: −935, −78). Meanwhile, the number of open gastrectomies remained unchanged, and the number of robot‐assisted gastrectomies steadily increased since their coverage by public health insurance in April 2018. Conclusions: The decreased number of endoscopic resections and laparoscopic surgeries in Japan suggests a decline in early‐stage gastric cancer diagnosis, likely due to the suspension of gastric cancer screening and diagnostic testing during the pandemic. Meanwhile, the number of open and robot‐assisted gastrectomies remained unchanged and increased, respectively, indicating that these applications were not affected by the pandemic‐related medical crisis. These findings highlight that procedures for cancer diagnosis, including screening, should still be provided during pandemics. [ABSTRACT FROM AUTHOR]

Cardiac alternans has been linked to the onset of ventricular fibrillation and ventricular tachycardia, leading to life-threatening arrhythmias. Here, we investigated the effects of stretch-activated currents (ISAC) on alternans using a physiologically detailed model of the ventricular myocyte. We found that increasing ISAC suppresses alternans if the voltage-Ca coupling is positive or the alternans is voltage driven. However, for electromechanically discordant alternans, which occurs when the alternans is Ca driven with negative voltage-Ca coupling, increasing ISAC promotes Ca alternans. In addition, if action potential duration-Ca transients show quasiperiodicity, we observe a biphasic effect of ISAC, i.e., suppressing quasiperiodic oscillation at small stretch but promoting electromechanically discordant alternans at larger stretch. Our results demonstrate how ISAC interacts with coupled voltage-Ca dynamical systems with respect to alternans.

Calcium (Ca) sparks are the fundamental sarcoplasmic reticulum (SR) Ca release events in cardiac myocytes, and they have a typical duration of 20-40 ms. However, when a fraction of ryanodine receptors (RyRs) are blocked by tetracaine or ruthenium red, Ca sparks lasting hundreds of milliseconds have been observed experimentally. The fundamental mechanism underlying these extremely prolonged Ca sparks is not understood. In this study, we use a physiologically detailed mathematical model of subcellular Ca cycling to examine how Ca spark duration is influenced by the number of functional RyRs in a junctional cluster (which is reduced by tetracaine or ruthenium red) and other SR Ca handling properties. One RyR cluster contains a few to several hundred RyRs, and we use a four-state Markov RyR gating model. Each RyR opens stochastically and is regulated by cytosolic and luminal Ca. We varied the number of functional RyRs in the single cluster, diffusion within the SR network, diffusion between network and junctional SR, cytosolic Ca diffusion, SERCA uptake activity, and RyR open probability. For long-lasting Ca release events, opening events within the cluster must occur continuously because the typical open time of the RyR is only a few milliseconds. We found the following: 1) if the number of RyRs is too small, it is difficult to maintain consecutive openings and stochastic attrition terminates the release; 2) if the number of RyRs is too large, the depletion of Ca from the junctional SR terminates the release; and 3) very long release events require relatively small-sized RyR clusters (reducing flux as seen experimentally with tetracaine) and sufficiently rapid intra-SR Ca diffusion, such that local junctional intra-SR [Ca] can be maintained by intra-SR diffusion and overall SR Ca reuptake.