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It is controversial whether children with isolated aortic valvular stenosis (vAS) initially undergo transcatheter or surgical aortic valvuloplasty (BAV or SAV). This multicenter retrospective case-control study aimed to explore outcomes after BAV or SAV for pediatric vAS. We studied children (aged < 15 years) with vAS treated at 4 tertiary congenital heart centers, and compared the rates of survival, reintervention, and valve replacement between patients with BAV and SAV. A total of 73 subjects (BAV: N = 52, SAV: N = 21) were studied. Age and aortic annulus z-score at the first presentation were 85 (26-530) days and - 0.45 (- 1.51-0.59), respectively. During the follow-up period of 121 (47-185) months, rates of 10-year survival (BAV: 88% vs. SAV: 92%, P = 0.477), reintervention (BAV: 58% vs. SAV: 31%, P = 0.626), and prosthetic/autograft valve replacement (BAV: 21% vs. SAV: 19%, P = 0.563) did not differ between the groups. Freedom from reintervention rate significantly correlated with aortic annulus z-score (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.49-0.88, P = 0.005), and freedom from prosthetic/autograft valve replacement rate significantly correlated to the degree of aortic regurgitation after the first intervention (HR: 4.58, 95% CI 1.19-17.71, P = 0.027). Propensity score-matched analysis (N = 16) did not show the differences in survival and reintervention rates between the groups. Long-term survival was acceptable, and the rates of freedom from reintervention and prosthetic/autograft valve replacement were comparable between children with vAS who underwent BAV and SAV., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

An efficient synthetic strategy for scabrolide F (7), a norcembranolide diterpene that was isolated from the Taiwanese soft coral Sinularia scabra , has only recently been reported by our group. Herein, we report details of the first total synthesis of 7. The tetrahydrofuran domain of 7 was stereoselectively constructed via the 5- endo-tet cyclization of a hydroxy vinyl epoxide. The reaction of alkyl iodide 30 with dithiane 38, followed by the introduction of an alkene moiety, afforded allylation precursor 41. The coupling of alkyl iodide 42 and allylic stannane 43 was examined as a model experiment of allylation. Because the desired allylated product 44 was not obtained, an alternative synthetic route toward 7 was investigated instead. In the second synthetic approach, fragment-coupling between alkyl iodide 56 and aldehyde 58, macrolactonization, and transannular ring-closing metathesis were used as the key steps to achieve the first total synthesis of 7. We hope that this synthetic strategy provides access to the total synthesis of other macrocyclic norcembranolides. We also evaluated the antifouling activity and toxicity of 7 and its synthetic intermediates toward the cypris larvae of the barnacle Amphibalanus amphitrite . This study is the first to report the antifouling activity of norcembranolides as well as the biological activity of 7.

Monitoring and improving the quality of sleep are crucial from a public health perspective. In this study, we propose a change-point detection method using diffusion maps for a more accurate detection of respiratory arrest points. Conventional change-point detection methods are limited when dealing with complex nonlinear data structures, and the proposed method overcomes these limitations. The proposed method embeds subsequence data in a low-dimensional space while considering the global and local structures of the data and uses the distance between the data as the score of the change point. Experiments using synthetic and real-world contact-free sensor data confirmed the superiority of the proposed method when dealing with noise, and it detected apnea events with greater accuracy than conventional methods. In addition to improving sleep monitoring, the proposed method can be applied in other fields, such as healthcare, manufacturing, and finance. This study will contribute to the development of advanced monitoring systems that adapt to diverse conditions while protecting privacy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shirotori, Sugitani. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: A left thoracotomy approach is anatomically appropriate for childhood aortic coarctation; however, the pediatric femoral arteriovenous diameters are too small for cardiopulmonary bypass cannulation. We aimed to determine the safety of a partial cardiopulmonary bypass through the main pulmonary artery and the descending aorta in pediatric aortic coarctation repair., Methods: We retrospectively reviewed 10 patients who underwent coarctation repair under partial main pulmonary artery-to-descending aorta cardiopulmonary bypass with a left thoracotomy as the CPB group. During the same period, 16 cases of simple coarctation of the aorta repair, with end-to-end anastomosis through a left thoracotomy without partial CPB assistance, were included as the non-CPB group to evaluate the impact of partial CPB., Results: The median age and weight at surgery of the CPB group were 3.1 years (range, 9 days to 17.9 years) and 14.0 (range, 2.8-40.7) kg, respectively. Indications for the partial cardiopulmonary bypass with overlap were as follows: age > 1 year (n = 7), mild aortic coarctation (n = 3), and predicted ischemic time > 30 min (n = 5). Coarctation repair using autologous tissue was performed in seven cases and graft replacement in three. The mean partial cardiopulmonary bypass time, descending aortic clamp time, and cardiopulmonary bypass flow rate were 73 ± 37 min, 57 ± 27 min, and 1.6 ± 0.2 L/min/m 2 , respectively. Urine output during descending aortic clamping was observed in most cases in the CPB group (mean: 9.1 ± 7.9 mL/kg/h), and the total intraoperative urine output was 3.2 ± 2.7 mL/kg/h and 1.2 ± 1.5 mL/kg/h in the CPB and non-CPB group, respectively (p = 0.020). The median ventilation time was 1 day (range, 0-15), and the intensive care unit stay duration was 4 days (range, 1-16) with no surgical deaths. No major complications, including paraplegia or recurrent coarctation, occurred postoperatively during a median observation period of 8.1 (range, 3.4-17.5) years in the CPB group. In contrast, reoperation with recurrent coarctation was observed in 2 cases in the non-CPB group (p = 0.37)., Conclusions: Partial cardiopulmonary bypass through the main pulmonary artery and descending aorta via a left thoracotomy is a safe and useful option for aortic coarctation repair in children., (© 2024. The Author(s).)

Amplitude death has the potential to suppress unwanted oscillations in various engineering applications. However, in some engineering applications, such as dc microgrids, airfoil systems, and thermoacoustic systems, oscillation frequency is highly susceptible to external influences, leading to considerable variations. To maintain amplitude death amidst these frequency variations, we propose a design procedure that is robust against frequency variation for inducing amplitude death in delay-coupled oscillators. We first analytically derive the oscillator frequency band in which amplitude death can occur. The frequency bandwidth is maximized when the coupling strength is inversely proportional to the connection delay. Furthermore, our analysis reveals that the oscillator frequency band is influenced by the minimum eigenvalue of the normalized adjacency matrix (i.e., network topology) and that bipartite networks exhibit limited robustness to frequency variations. Our design procedure maintains the stability of amplitude death even under substantial frequency variations and is applicable to various network topologies. Numerical simulations confirm the validity of the proposed design.

The present paper analytically investigates the stability of amplitude death in a multiplex Stuart-Landau oscillator network with a delayed interlayer connection. The network consists of two frequency-mismatched layers, and all oscillators in each layer have identical frequencies. We show that, if the matrices describing the network topologies of each layer commute, then the characteristic equation governing the stability can be reduced to a simple form. This form reveals that the stability of amplitude death in the multiplex network is equally or more conservative than that in a pair of frequency-mismatched oscillators coupled by a delayed connection. In addition, we provide a procedure for designing the delayed interlayer connection such that amplitude death is stable for any commuting matrices and for any intralayer coupling strength. These analytical results are verified through numerical examples. Moreover, we numerically discuss the results for the case in which the commutative property does not hold.

Congenital pulmonary lymphangiectasia (CPL) is associated with fetal pulmonary venous obstructive physiology. The precise morbidity of CPL is unknown as CPL is generally fatal in neonates. Here, we report an infant with secondary CPL in total anomalous pulmonary venous connection (TAPVC). He developed severe pulmonary hypertension (PH) after corrective surgery for TAPVC. However, cardiac catheterization showed mild left pulmonary venous obstruction (PVO), which was deemed unnecessary for re-intervention. He died at 11 months-old due to an exacerbation of PH. Autopsy revealed medial hypertrophy of the pulmonary arteries, mild left PVO, and marked dilatation and proliferation of the pulmonary lymphatics which might have been involved in the PH, although CPL was not conclusively identified based on the previous biopsy findings. We should be aware of the possibility of CPL in addition to postoperative PVO when encountering patients with fetal pulmonary venous obstructive physiology. Furthermore, a cautious approach to the interpretation of lung biopsy results is warranted.

Home-inhaled nitric oxide therapy was effective and feasible in the patients with intractable pulmonary arterial hypertension. We present the case of a child with severe pulmonary arterial hypertension associated with post-operative pulmonary venous obstruction who was treated with home-inhaled nitric oxide therapy.

The challenges and potential benefits of incorporating biomarkers into clinical trial designs have been increasingly discussed, in particular to develop new agents for immune-oncology or targeted cancer therapies. To more accurately identify a sensitive subpopulation of patients, in many cases, a larger sample size-and consequently higher development costs and a longer study period-might be required. This article discusses a biomarker-based Bayesian (BM-Bay) randomized clinical trial design that incorporates a predictive biomarker measured on a continuous scale with pre-determined cutoff points or a graded scale to define multiple patient subpopulations. We consider designing interim analyses with suitable decision criteria to achieve correct and efficient identification of a target patient population for developing a new treatment. The proposed decision criteria allow not only the take-in of sensitive subpopulations but also the ruling-out of insensitive ones on the basis of the efficacy evaluation of a time-to-event outcome. Extensive simulation studies are conducted to evaluate the operating characteristics of the proposed method, including the probability of correct identification of the desired subpopulation and the expected number of patients, under a wide range of clinical scenarios. For illustration purposes, we apply the proposed method to design a randomized phase II immune-oncology clinical trial., (© 2023 John Wiley & Sons Ltd.)

Objectives: To evaluate the impact of the COVID-19 pandemic on outpatient care in Japanese patients with neuromuscular diseases (NMDs)., Design: This retrospective cohort study included patients between January 2018 and February 2019; the follow-up period was divided into 'before COVID-19' (March 2019-February 2020) and 'during COVID-19' (March 2020-February 2021)., Setting: JMDC claims database study., Participants: Of the 10 655 557 patients identified, we included patients with spinal muscular atrophy (SMA; n=82), neuromyelitis optica (NMO; n=342), myasthenia gravis (MG; n=1347), Guillain-Barré syndrome (GBS; n=442) or autoimmune encephalitis/encephalopathy (AIE; n=133). Patients were required to have ≥1 month of data available, have a diagnosis of NMD during the enrolment period and be available for follow-up., Primary and Secondary Outcome Measures: We estimated the proportion of patients with >30% change in outpatient consultation and rehabilitation visits before versus during the COVID-19 pandemic., Results: Small reductions in the proportion of patients with outpatient consultation/rehabilitation visits were observed before versus during the pandemic. Compared with before the pandemic, 30.4%, 27.8%, 28.7%, 49.4% and 50.0% of patients showed a >30% decrease in outpatient consultation visits and 58.6%, 75.0%, 50.0%, 76.3% and 84.6% showed a >30% decrease in outpatient rehabilitation visits during the pandemic for SMA, NMO, MG, GBS and AIE, respectively. The median change in the number of outpatient consultation visits per year before versus during pandemic was -1.0 day for all NMDs, and that in outpatient rehabilitation visits per year was -6.0, -5.5, -1.5, -6.5 and -9.0 days for SMA, NMO, MG, GBS and AIE, respectively. The reduction in outpatient rehabilitation visits was greater in the absence versus presence of a neurology specialist., Conclusions: Outpatient consultation and rehabilitation visits during the COVID-19 pandemic were affected in Japanese patients with NMDs. Longer-term evaluations are required to understand if these reductions in outpatient care would affect patient prognosis., Competing Interests: Competing interests: TS serves as a consultant in Chugai Pharmaceutical Co, Ltd. YM-T, YS, JF-W and SS are employees of the company. TT is a full-time employee of JMDC Inc. MI received consultant fees from the company to supervise the study and draft the manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tuberous sclerosis complex (TSC) is an intractable inherited disease caused by a germline mutation in either the TSC complex subunit 1 ( TSC1 ) or TSC2 tumor suppressor genes. Recent progress in the treatment of TSC with rapamycin has provided benefits to patients with TSC. However, the complete elimination of tumors is difficult to achieve as regrowth often occurs after a drug is suspended; thus, more efficient medication and novel therapeutic targets are required. To overcome tumor remnants in the treatment of TSC, the present study investigated rapamycin-responsive signaling pathways in Tsc2 -deficient tumor cells, focusing on heat shock protein-related pathways. The expression levels of heat shock protein family B (small) member 1 (Hspb1; also known as HSP25/27) were increased by rapamycin treatment. The phosphorylation of Hspb1 was also increased. The knockdown of Hspb1 suppressed cell proliferation in the absence of rapamycin, and the overexpression of Hspb1 enhanced cell proliferation both in the presence and absence of rapamycin. Pathways associated with Hspb1 may present target candidates for treatment of TSC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kitano et al.)

Objectives: ERC/mesothelin is a glycosylphosphatidylinositol (GPI)-anchor protein expressed in mesothelioma. A precursor protein is cleaved by proteases and an N-terminal fragment (N-ERC) is extracellularly secreted. A remaining C-terminal fragment (C-ERC) is tethered on cellular membranes by the GPI-anchor, but C-ERC is also released after cleavage by proteases. We and other groups reported that serum N-/C-ERC levels are associated with stages of mesothelioma and suggested the possibility of their usefulness as diagnostic markers. However, the N-ERC level is also influenced by renal functions that are not directly associated with conditions of mesothelioma. It is not known whether other clinical factors influence serum N-/C-ERC values. Furthermore, their relationship to the amount of ERC/Mesothelin in mesothelioma is not yet validated. The objective of this study is to clarify the relationship of serum N-/C-ERC levels and the status of mesothelioma and several clinical factors., Materials and Methods: We analyzed relations of serum N-/C-ERC levels and ages, gender and other clinical factors in 522 patients without mesothelioma and examined their relation to the amount of ERC/Mesothelin in mesothelioma tissues in 13 mesothelioma cases., Results: Serum N-ERC levels were influenced by renal functions. On the contrary, those of C-ERC were not influenced by any clinical factors examined in this study and were significantly correlated with the amount of ERC/Mesothelin in mesothelioma., Conclusion: Although both markers are good indicators of treatment-responses in individual patients with mesothelioma, only C-ERC reflected the amount of ERC/Mesothelin in mesothelioma among multiple patients, possibly because N-ERC was influenced by renal functions., Competing Interests: The Authors declare that there are no conflicts of interest., (© 2023 The Juntendo Medical Society.)

Objective: This study aimed to explore anatomical and hemodynamic features of atrial septal defect, which was treated by transcatheter device closure late after completion of biventricular circulation in patients with pulmonary atresia and intact ventricular septum (PAIVS) or critical pulmonary stenosis (CPS)., Methods: We studied echocardiographic and cardiac catheterization data, including defect size, retroaortic rim length, single or multiple defects, the presence of malalignment atrial septum, tricuspid and pulmonary valve diameters, and cardiac chamber sizes, in patients with PAIVS/CPS who underwent transcatheter closure of atrial septal defect (TCASD), and compared to control subjects., Results: A total of 173 patients with atrial septal defect, including 8 patients with PAIVS/CPS, underwent TCASD. Age and weight at TCASD were 17.3 ± 18.3 years and 36.6 ± 13.9 kg, respectively. There was no significant difference in defect size (13.7 ± 4.0 vs. 15.6 ± 5.2 mm, p = 0.317) and the retro-aortic rim length (3.7 ± 4.3 vs. 3.6 ± 0.3.1 mm, p = 0.948) between the groups; however, multiple defects (50% vs. 5%, p < 0.001) and malalignment atrial septum (62% vs. 14%. p < 0.001) were significantly frequent in patients with PAIVS/CPS compared to control subjects. The ratio of pulmonary to systemic blood flow in patients with PAIVS/CPS was significantly lower than that in the control patients (1.2 ± 0.4 vs. 2.0 ± 0.7, p < 0.001); however, four out of eight patients with atrial septal defect associated with PAIVS/CPS had right-to-left shunt through a defect, who were evaluated by the balloon occlusion test before TCASD. The indexed right atrial and ventricular areas, the right ventricular systolic pressure, and mean pulmonary arterial pressure did not differ between the groups. After TCASD, the right ventricular end-diastolic area remained unchanged in patients with PAIVS/CPS, whereas it significantly decreased in control subjects., Conclusions: Atrial septal defect associated with PAIVS/CPS had more complex anatomy, which would be a risk for device closure. Hemodynamics should be individually evaluated to determine the indication for TCASD because PAIVS/CPS encompassed anatomical heterogeneity of the entire right heart., (© 2023 Wiley Periodicals LLC.)

Coronary anomalies encompass different conditions in terms of anomalous origin, coursing, and branching, which are occasionally associated with congenital heart disease. This study aimed to explore coronary anomalies associated with ventricular septal defect that was a stereotypical congenital heart disease. We retrospectively reviewed angiographic findings in patients with ventricular septal defect who required corrective surgery, and identified coronary abnormalities, including anomalous origin, coursing, and branching of coronary arteries based on angiography. We studied the prevalence and types of coronary anomalies among them. A total of 998 patients with ventricular septal defect was studied. Age and weight were 2.0 (2.1-15.2) months and 5.7 (4.1-8.7) kg, respectively. There were 115 patients (12%) with syndrome or genetic disorder, and 34 patients (3%) with extracardiac major organ anomalies. The overall prevalence of coronary anomalies was 6.2%. All coronary anomalies were anomalous origin and coursing, among 3 patients accompanied anomalous intrinsic coronary anatomy. Originating within aortic root above the Valsalva sinus was the most common coronary anomaly. Coronary anomalies were independently correlated with bicuspid aortic valve (odds ratio [OR]: 8.02, 95% confidence interval [CI]: 2.34-23.4) and persistent left superior caval vein (OR: 5.02, 95% CI: 1.93-11.7). We showed the possibility that minor cardiac variants, such as bicuspid aortic valve and persistent left superior caval vein, contribute to higher prevalence of coronary anomalies in patients with ventricular septal defect., (© 2022. Springer Japan KK, part of Springer Nature.)

Aim: Early life stress is associated with overgrowth of the amygdala, which plays a key role in the processing and memory of emotional responses. Herein, we aimed to explore the amygdala volume in children with single-ventricle congenital heart disease who experience repeated admissions during the neonatal period and infancy. Methods: We compared the amygdala volume measured using brain magnetic resonance imaging (MRI) between 40 patients after completion of the Fontan procedure and 40 age- and sex-matched control subjects Results: Age at the MRI study were 9.2 (8.5-11.1) and 10.2 (9.2-10.3) years in the Fontan and control groups, respectively. The maximum amygdala volume in the Fontan group was significantly larger than in the control group (1232 [983-1392] mm 3 /m 2 vs. 980 [728-1166] mm 3 /m 2 , P < 0.001). The amygdala volume did not correlate to cardiac index (r  =  0.260) and central venous pressure (r = -0.107) in the Fontan group. Conclusions: Children with single-ventricle congenital heart disease exhibited amygdala overgrowth.

Objective: To assess the incidence of bevacizumab-associated gastrointestinal (GI) perforation during first-line treatment of patients with ovarian, fallopian tube, or peritoneal cancer receiving neoadjuvant chemotherapy (NAC) in Japanese real-world clinical practice., Methods: A retrospective study was conducted using a healthcare claims database owned by Medical Data Vision Co., Ltd. (study period, 2008-2020). Patients who initiated first-line treatment of ovarian, fallopian tube, or peritoneal cancer were identified and divided into NAC and primary debulking surgery (PDS) groups. The incidence of bevacizumab-associated GI perforation was compared within the NAC group and between the groups., Results: Paclitaxel + carboplatin (TC) was most commonly used as first-line treatment (39.5% and 59.6% in the NAC and PDS groups, respectively). TC + bevacizumab was used in 9.3% and 11.6% of patients in the NAC and PDS groups, respectively. In the NAC group receiving TC, the proportion of patients with risk factors for GI perforation was lower among patients with versus without concomitant bevacizumab. The incidence of GI perforation in the NAC group was 0.38% (1/266 patients) in patients receiving TC + bevacizumab and 0.18% (2/1,131 patients) in patients receiving TC without bevacizumab (risk ratio=2.13; 95% confidence interval [CI]=0.19 to 23.36; risk difference=0.20; 95% CI=-0.58 to 0.97). None of the 319 patients in the PDS group receiving TC + bevacizumab had GI perforation., Conclusion: No notable increase was observed in GI perforation associated with NAC containing bevacizumab. We conclude that bevacizumab is prescribed with sufficient care in Japan to avoid GI perforation., Competing Interests: Takayuki Enomoto has received honoraria for lectures and presentations from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., MSD K.K., and Takeda Pharmaceutical Company Limited outside the submitted work. Yasuo Sugitani, Kiyoko Ogino, and Shuichi Kamijima are full-time employees of Chugai Pharmaceutical Co., Ltd., (© 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

During brain development, neural precursor cells (NPCs) expand initially, and then switch to generating stage-specific neurons while maintaining self-renewal ability. Because the NPC pool at the onset of neurogenesis crucially affects the final number of each type of neuron, tight regulation is necessary for the transitional timing from the expansion to the neurogenic phase in these cells. However, the molecular mechanisms underlying this transition are poorly understood. Here, we report that the telencephalon-specific loss of PAR3 before the start of neurogenesis leads to increased NPC proliferation at the expense of neurogenesis, resulting in disorganized tissue architecture. These NPCs demonstrate hyperactivation of hedgehog signaling in a smoothened-dependent manner, as well as defects in primary cilia. Furthermore, loss of PAR3 enhanced ligand-independent ciliary accumulation of smoothened and an inhibitor of smoothened ameliorated the hyperproliferation of NPCs in the telencephalon. Thus, these findings support the idea that PAR3 has a crucial role in the transition of NPCs from the expansion phase to the neurogenic phase by restricting hedgehog signaling through the establishment of ciliary integrity., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

The first total synthesis of scabrolide F, a norcembranolide isolated from the soft coral Sinularia scabra , is described. Hydroxycarboxylic acid, which is the key synthetic intermediate, was synthesized in a convergent manner by fragment coupling. The obtained hydroxycarboxylic acid was subjected to macrolactonization and subsequent transannular ring-closing metathesis (RCM) to furnish scabrolide F. The synthetic protocol can be extended to the total synthesis of other norcembranolides.

Pulmonary hypertension associated with congenital heart disease (CHD-PH) encompasses different conditions confounded by the left-to-right shunt, left heart obstruction, ventricular dysfunction, hypoxia due to airway obstruction, dysplasia/hypoplasia of the pulmonary vasculature, pulmonary vascular obstructive disease, and genetic variations of vasoactive mediators. Pulmonary input impedance consists of the pulmonary vascular resistance (Rp) and capacitance (Cp). Rp is calculated as the transpulmonary pressure divided by the pulmonary cardiac output, whereas Cp is calculated as the pulmonary stroke volume divided by the pulmonary arterial pulse pressure. The plots of Rp and Cp demonstrate a unique hyperbolic relationship, namely, the resistor-capacitor coupling curve, which represents the pulmonary vascular condition. The product of Rp and Cp is the exponential pressure decay, which refers to the time constant. Alterations in Cp are more considerable in CHD patients at an early stage of developing pulmonary hypertension or with excessive pulmonary blood flow due to a left-to-right shunt. The importance of Cp has gained attention because recent reports have shown that low Cp potentially reflects poor prognosis in patients with CHD-PH and idiopathic pulmonary hypertension. It is also known that Cp levels decrease in specific populations, such as preterm infants and trisomy 21. Therefore, both Rp and Cp should be individually evaluated in the management of children with CHD-PH who have different disease conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Muneuchi, Ezaki, Sugitani and Watanabe.)