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RESUMO: Os benefícios obtidos pela oxigenoterapia de longa duração (OLD) em doentes com DPOC e hipoxemia em repouso (PaO2 inferior a 60 mmHg) estão bem documentados por inúmeros estudos. Nestes doentes a OLD prolonga a so-brevida, reduz o número de internamentos e o desenvolvimento de hipertensão pulmonar secundária, melhora a capacidade para realizar as actividades da vida diária e promove a melhoria da qualidade de vida relacionada com a saúde. Não está contudo claramente estabelecido se a oxigenoterapia é benéfica em doentes com DPOC e hipoxemia ligeira a moderada. Alguns estudos demonstraram que a administração de oxigénio durante o exercício resultou na melhoria da tolerância ao esforço e na redução da dispneia em alguns doentes com DPOC e hipoxemia ligeira em repouso. Não ficou claro qual o tipo de doentes com DPOC que mais beneficiará desta terapêutica. Neste trabalho os autores estudaram os efeitos da oxigenoterapia na capacidade para o exercício e na hemodinâmica pulmonar durante o esforço em doentes com DPOC com hipoxemia ligeira (PaO2 superior a 60 mmHg) e normocapnia em repouso e obstrução brônquica ligeira a grave. Estudaram 75 doentes do sexo masculino, dos quais 16 tinham obstrução brônquica ligeira (FEV1 > 50 % do teórico), 25 tinham obstrução brônquica moderada (FEV1: 35-50 % do teórico) e 34 tinham obstrução brônquica grave (FEV1â¤50 % do teórico). A capacidade para o exercício foi avaliada através da prova de marcha de 6 minutos. O estudo da hemodinâmica pulmonar (pressão da artéria pulmonar, pressão de oclusão da artéria pulmonar, pressão da aurícula direita e débito cardíaco) foi realizada em 43 doentes, através da cateterização de uma veia antecubital com cateter de Swan-Ganz, enquanto estes doentes realizavam uma prova de esforço com carga constante de 25 watts em cicloergómetro em posição supina. Para ambos os modos de exercício (prova de marcha e prova de carga constante em cicloergómetro) foi administrado oxigénio suplementar ou ar comprimido a 2 litros por minuto. Obtiveram os seguintes resultados:A administração de oxigénio durante a prova de marcha resultou num aumento significativo da distância percorrida em todos os grupos de doentes sendo significativamente superior nos doentes com obstrução moderada a grave e nos doentes que apresentaram maior dessaturação durante a prova de marcha sob ar comprimido.Durante a prova de carga constante em cicloergómetro verificaram um aumento significativo da pressão da artéria pulmonar (PAP), da pressão de oclusão da artéria pulmonar (POAP) e do índice cardíaco em todos os grupos de doentes e da resistência vascular pulmonar (RVP) no grupo de doentes graves.A administração de oxigénio durante o exercício promoveu uma atenuação significativa no aumento da PAP e da POAP e inibiu completamente o aumento da RVP. A redução da POAP durante o exercício sob oxigénio correlacionou-se positivamente com o índice de air-trapping (diferença entre a capacidade vital â VC â e a capacidade vital forçada â FVC).Os autores sugerem que a administração de oxigénio durante o exercício é benéfica em doentes com DPOC com obstrução moderada a grave. Estes benefícios traduziram-se numa melhoria do desempenho no esforço e redução da hipertensão pulmonar durante o exercício, mesmo nos doentes que em repouso ou durante o exercício evidenciaram apenas uma hipoxemia ligeira. COMENTÃRIO: Este estudo foi o primeiro a demonstrar que a administração de oxigénio pode melhorar a tolerância ao esforço em doentes com DPOC sem hipoxemia significativa em repouso ou durante o exercício.São vários os mecanismos apontados para a melhoria da tolerância ao esforço como resultado da administração de oxigénio: o alívio da dispneia, a prevenção da dessaturação durante o exercício, a melhoria da hemodinâmica pulmonar, a redução da ventilação e, consequentemente, da hiperinsuflação pulmonar dinâmica, e a melhoria do transporte e entrega de oxigénio aos tecidos, promovendo o metabolismo oxidativo ao nível dos músculos respiratórios e dos músculos periféricos durante o exercício1â6.OâDonnell et al1,3 sugerem que o alívio da dispneia e a melhoria da tolerância ao exercício com a administração de oxigénio podem ser explicadas pela redução da ventilação e consequentemente pela redução da hiperinsuflação dinâmica, em particular nos doentes que são relativamente normoxémicos em repouso. Somfay et al7 demonstraram recentemente que o suplemento de oxigénio reduziu significativamente os scores de dispneia, a hiperinsuflação dinâmica (avaliada indirectamente pela medição dinâmica da capacidade inspiratória), a ventilação e a frequência respiratória durante o exercício em doentes não hipoxémicos com DPOC grave. A melhoria observada na capacidade para o exercício correlacionou-se com a redução da hiperinsuflação dinâmica. Esta ocorre em doentes com DPOC com obstrução grave das vias aéreas e hiperinsuflação pulmonar avaliada em repouso, tem um efeito mecânico deletério sobre os músculos respiratórios, contribui para a sensação de dispneia e limita a capacidade para o exercício2,8. Desta forma, é de esperar que os efeitos do oxigénio sejam mais evidentes em doentes com obstrução grave das vias aéreas.Quanto ao efeito do oxigénio na dinâmica vascular pulmonar, com redução do incremento da pressão da artéria pulmonar durante o exercício, pode ser explicado pela redução da vasoconstrição hipóxica. Por outro lado, a redução da pressão de oclusão da artéria pulmonar (POAP) com o oxigénio leva à redução da pressão da artéria pulmonar nos doentes com DPOC moderada a grave e a POAP correlaciona-se positivamente com o índice de air-trapping (VC-FVC), sugerindo que a redução da hiperinsuflação dinâmica devido à supressão da ventilação pelo oxigénio pode resultar na redução da POAP.Este estudo baseou-se nos efeitos âagudosâ da administração de oxigénio sobre a hemodinâmica pulmonar e a capacidade para o exercício. Mas torna-se importante avaliar os efeitos a longo prazo da oxigenoterapia. Zielinski et al9 estudou o efeito da OLD na hemodinâmica pulmonar num grupo de 95 doentes com DPOC ao longo de seis anos e verificou que a OLD administrada 14 a 15 horas por dia, resultou numa pequena redução da hipertensão pulmonar ao fim de dois anos, seguindo-se um retorno aos valores iniciais com estabilização subsequente até ao final do estudo. A estabilização da hipertensão pulmonar ocorreu apesar do agravamento progressivo da limitação do débito das vias aéreas e da acentuação da hipoxemia.Quanto ao efeito da oxigenoterapia a longo prazo sobre a capacidade para o exercício, em particular em programas de reabilitação, existem poucos estudos que documentem o seu efeito. Teoricamente o oxigénio permite treinar os indivíduos com cargas mais elevadas ou permitir maior duração do treino, o que irá melhorar a capacidade aeróbica e atingir níveis mais eficazes de treino. Este pressuposto tem implicado que grande parte dos programas de reabilitação com treino ao exercício em doentes com DPOC que dessaturam com o esforço, tem sido realizado sob oxigenoterapia. Dois estudos recentes (Garrod et al4 e Rooyakers JM et al10) demonstraram que o oxigénio suplementar não revelou benefícios significativos durante a reabilitação em doentes que dessaturavam com o esforço. No primeiro4 verificou-se uma redução significativa da dispneia no grupo que recebeu oxigénio, embora não se tenha verificado um aumento significativo da capacidade para o exercício. No segundo estudo 10, os doentes tinham indicação para suspender o exercício logo que a saturação de oxigénio atingisse os 90 %, pelo que não foi avaliada até que ponto os doentes dessaturavam com o exercício. Estes estudos envolveram um pequeno número de doentes, o que pode revelar-se insuficiente para detectar benefícios significativos, sendo necessários estudos mais alargados para responder a esta questão. Palavras-chave: DPOC, Hiperinsuflação dinâmica, Exercício, Oxigenoterapia, Pressão da artéria pulmonar, Hemodinâmica pulmonar, Prova de marcha, Key-words: COPD, Dynamic hyperinflation, Exercise, Oxygen therapy, Pulmonary artery pressure, Pulmonary hemodynamics, Walking test

Cholesteryl ester transfer protein (CETP) plays an important role in regulating the concentration and composition of high density lipoprotein (HDL) and low density lipoprotein (LDL). Although several genetic abnormalities causing CETP deficiency have been identified in the Japanese subjects with a marked hyperalphalipoproteinemia (HALP), there are many CETP-deficient subjects for whom the genetic abnormalities have not been clarified. In the present study, we analyzed the molecular basis of an HALP subject without CETP activity and mass, and found a novel mutation in the CETP gene. This novel mutation (G181X) was a G-to-T substitution at codon 181 of exon 6 which replaced a codon for glycine (GGA) with a premature stop codon (TGA). The G181X mutation created a new cutting site by restriction enzyme MaeIII. To estimate the frequency of G181X, we investigated unrelated 294 HALP (HDL-cholesterol > or = 2.59 mmol/L = 100 mg/dl) subjects by restriction fragment length polymorphism (RFLP) analysis with Mae III. One (0.34%) HALP subject was homozygous and four (1.36%) were heterozygous for this mutation. The allelic frequency of a G-to-T substitution at codon 181 of exon 6 was 0.0102 in HALP subjects. From the lipid analysis of the proband and the homozygote, it was clarified that the G181X mutation had dominant effects on HDL and LDL metabolism, similar to a G-to-A substitution at the 5' splice donor site of the intron 14 (1451 + 1G–>A). In conclusion, the G181X mutation is one of causes of HALP in the Japanese HALP subjects, having dominant effects on lipid metabolism.

Cholesteryl ester transfer protein (CETP) deficiency is the most common cause of hyperalphalipoproteinemia in Japan. However, the genetic basis of this disorder has not been fully characterized. We have studied a 49-year-old Japanese male presenting with total cholesterol, HDL-cholesterol, and apolipoprotein A-I levels of 300, 236, and 233 mg/dl, respectively, and total absence of CETP activity and mass in plasma. Sequence analysis of the patient's CETP gene revealed that the splice donor consensus GT was substituted by GG in intron 10 (intron 10 splice defect) and by AT in intron 14 (intron 14 splice defect). Restriction digestion of PCR-amplified DNA using NdeI and MaeIII established that the patient was a compound heterozygote for both gene defects. Sequencing of cDNA amplified by RT-PCR from the patient's monocyte-derived macrophage RNA demonstrated abnormal splicing with deletion of exon 10 as well as alternative splicing at a native AG site located 31 nucleotides 5' of the normal splice acceptor in intron 13. Thus, the intron 10 splice defect results in exon 10 skipping and the insertion of a 31 bp fragment between exon 13 and exon 14, which contains an in frame stop codon. The presence of abnormally spliced mRNA was further confirmed by amplification of patient cDNA using CETP specific primers. Abnormal splicing of exon 14 as a result of the intron 14 splice defect was not detected, indicating potential unstable CETP mRNA derived from that mutation. These findings demonstrate that a novel splice site mutation in intron 10 of the CETP gene results in the skipping of exon 10, as well as disruption of downstream splicing at intron 13 identifying a novel mechanism leading to CETP deficiency.

Age-related changes in alpha 1-, alpha 2-, and beta-catecholamine receptors on membrane of rat epididymal fat cells were investigated. Both young (6 weeks old, weight about 190 g) and aged (20 weeks old, weight about 490 g) Sprague-Dawley male rats were used. For the alpha 1-adrenoceptor binding experiment, we developed a novel analytical method using the hydrophilic alpha 1-receptor selective antagonist, [3H]bunazosin. The binding of [3H]bunazosin to its binding sites was rapid, reversible, saturable, and stereospecific. Scatchard binding analysis showed a single class of binding site. The sites were characterized as alpha 1-adrenoceptors by inhibition experiments using various agonists and antagonists. The number of maximum binding sites (Bmax) of alpha 1-receptor binding was 37.0 +/- 6.5 (young) versus 24.0 +/- 3.2 (aged) fmol/mg protein (P less than 0.01). [3H]Rauwolscine and [3H]CGP-12177 were used for alpha 2- and beta-receptor binding, respectively. In alpha 2-receptor detection using [3H]rauwolscine as a ligand, Bmax increased markedly from 19.8 +/- 4.9 to 86.2 +/- 19.5 fmol/mg protein (P less than 0.01). In contrast, Bmax for beta-receptor decreased from 69.7 +/- 9.7 to 45.4 +/- 13.9 fmol/mg protein with increasing rat age (P less than 0.05). Kd showed no change in each of the binding experiments between young and aged rats. The cell volume increased from 0.07 +/- 0.02 to 0.15 +/- 0.06 nl. It is implied that anti-lipolytic activity strengthened on the whole mainly with the marked increase of alpha 2-receptor number and decrease of beta-receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of chloroquine or 4,4'-bis(diethylaminoethoxy)alpha, beta-diethyldiphenylethane (DH) to rats in oral doses of 100 mg/kg for 7 days causes phospholipid and cholesteryl ester accumulation in liver. To further characterize this drug-induced lipidosis, we have isolated and characterized the lipids of subcellular fractions from control rats and rats treated with chloroquine, DH, and Triton WR-1339. The phospholipid content of liver is increased 1.5-fold by chloroquine or DH treatment but is unaffected by Triton WR-1339. Acid phosphatase is increased by treatment with these three agents. Chloroquine and DH cause a shift of acid phosphatase from the light mitochondrial fraction (L) to the heavy mitochondrial fraction (M). Multilamellar bodies, an ultrastructural hallmark of chloroquine and DH-induced lipidosis, were isolated in a highly-purified form from the M fraction of chloroquine- or DH-treated rats. They are highly enriched in acid phosphatase indicating their lysosomal origin. In addition, they contain large amounts of phospholipid, cholesterol, and cholesteryl ester and are the sole site of bis(monoacylglycero)phosphate and the enzyme which catalyzes its synthesis from phosphatidylglycerol. Analysis of the phospholipid content of the respective control and drug-treated liver fractions shows that the entire excess phospholipid content of chloroquine- or DH-treated liver can be accounted for by the drug-induced multilamellar bodies. Triton WR-1339-induced lysosomes, which were isolated for comparison, also contain bis(monoacyglycero)phosphate and bis(monoacyglycero)phosphate synthetase. However, they differ from the drug-induced lysosomes in that their sphingomyelin content is much higher and their total phospholipid and phosphatidylinositol content much lower. The multilamellar bodies are the principal intracellular site of accumulation of chloroquine and DH, respectively. Increased delivery of phospholipid to lysosomes and decreased lysosomal catabolism of phospholipid are the factors which are thought to cause this experimental lipidosis. High levels of phosphatidylinositol in the multilamellar body may be in part responsible for the increased content of bis(monoacyglycero)phosphate since it has been identified as an acyl donor in bis(monoacylglycero)phosphate synthesis.

Aims: The human epididymis protein 4 (HE4), a novel fibrosis marker, is expressed only in activated fibroblasts and is thought to reflect ongoing left ventricular (LV) fibrosis. LV fibrosis is a feature of severe aortic stenosis (AS) and is related to the post-operative outcome of patients with AS. We investigated the relationship between serum levels of HE4 and the post-operative prognosis of patients with severe AS., Methods and Results: We measured the serum HE4 levels of 55 participants (80.8 ± 8.0 years old, male n = 26, 46%) with severe AS prior to surgical aortic valve replacement (n = 31, 56%) or transcatheter aortic valve implantation (n = 24, 44%) at Kumamoto University Hospital in 2018. We followed them for cardiovascular (CV) death or hospitalization for heart failure (HF) for 3 years. Serum HE4 levels were positively correlated with computed tomography-extracellular volume (CT-ECV) values (r = 0.53, P = 0.004). Kaplan-Meier curves demonstrated a significantly higher probability of hospitalization for HF or CV-related death in the patients with high HE4 (greater than the median HE4 value) compared with the patients with low HE4 (lower than the median HE4 value) (log-rank P = 0.003). Multivariate analysis showed HE4 (log(HE4)) to be an independent prognostic factor [hazard ratio (HR): 7.50; 95% confidence interval (CI): 1.81-31.1; P = 0.005]. Receiver operating characteristic (ROC) curve analysis suggested that HE4 is a marker of increased risk of CV-related death or hospitalization for HF at 3 years after surgery, with an area under the curve (AUC) of 0.76 (95% CI: 0.62-0.90; P = 0.003)., Conclusions: We found that HE4 is a potentially useful biomarker for predicting future CV events in patients scheduled for AS surgery. Measuring serum HE4 values could help consider AS surgery., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The importance of prehospital (PH) electrocardiograms (ECG) recorded by emergency medical services (EMS) for diagnosing coronary artery spasm-induced acute coronary syndrome (CS-ACS) remains unclear., Methods and Results: We enrolled 340 consecutive patients with ACS who were transported by EMS within 12 h of symptom onset. According to Japanese Circulation Society guidelines, CS-ACS (n=48) was diagnosed with or without a pharmacological provocation test (n=34 and n=14, respectively). Obstructive coronary artery-induced ACS (OC-ACS; n=292) was defined as ACS with a culprit lesion showing 99% stenosis or >75% stenosis with plaque rupture or thrombosis observed via angiographic and intravascular imaging. Ischemic ECG findings included ST-segment deviation (elevation or depression) and negative T and U waves. In CS-ACS, the prevalence of ST-segment deviation decreased significantly from PH-ECG to emergency room (ER) ECG (77.0% vs. 35.4%; P<0.001), as did the prevalence of overall ECG abnormalities (81.2% vs. 45.8%; P<0.001). Conversely, in OC-ACS, there was a similar prevalence on PH-ECG and ER-ECG of ST-segment deviations (94.8% vs. 92.8%, respectively; P=0.057) and abnormal ECG findings (96.9% vs. 95.2%, respectively; P=0.058). Patients with abnormal PH-ECG findings that disappeared upon arrival at hospital without ER-ECG or troponin abnormalities were more frequent in the CS-ACS than OC-ACS group (20.8% vs. 1.0%; P<0.001)., Conclusions: PH-ECG is valuable for detecting abnormal ECG findings that disappear upon arrival at hospital in CS-ACS patients.

Capillary electrophoresis coupled with tandem mass spectrometry (CE-MS/MS) offers advantages in peak capacity and sensitivity for metabolic profiling owing to the electroosmotic flow-based separation. However, the utilization of data-independent MS/MS acquisition (DIA) is restricted due to the absence of an optimal procedure for analytical chemistry and its related informatics framework. We assessed the mass spectral quality using two DIA techniques, namely, all-ion fragmentation (AIF) and variable DIA (vDIA), to isolate 60-800 Da precursor ions with respect to annotation rates. Our findings indicate that vDIA, coupled with the updated MS-DIAL chromatogram deconvolution algorithm, yields higher spectral matching scores and annotation rates compared to AIF. Additionally, we evaluated a linear migration time (MT) correction method using internal standards to accurately align chromatographic peaks in a data set. Postcorrection, the data set exhibited less than 0.1 min MT drifts, a difference mostly equivalent to that of conventional reverse-phase liquid chromatography techniques. Moreover, we conducted MT prediction for metabolites recorded in mass spectral libraries and metabolite structure databases containing a total of 469,870 compounds, achieving an accuracy of less than 1.5 min root mean squares. Our platform provides a peak annotation platform utilizing MT information, accurate precursor m / z , and the MS/MS spectrum recommended by the metabolomics standards initiative. Applying this procedure, we investigated metabolic alterations in lipopolysaccharide (LPS)-induced macrophages, characterizing 170 metabolites. Furthermore, we assigned metabolite information to unannotated peaks using an in silico structure elucidation tool, MS-FINDER. The results were integrated into the nodes in the molecular spectrum network based on the MS/MS similarity score. Consequently, we identified significantly altered metabolites in the LPS-administration group, where glycinamide ribonucleotide, not present in any spectral libraries, was newly characterized. Additionally, we retrieved metabolites of false-negative hits during the initial spectral annotation procedure. Overall, our study underscores the potential of CE-MS/MS with DIA and computational mass spectrometry techniques for metabolic profiling.

Aims: High platelet-derived thrombogenicity during the acute phase of ST-segment elevation myocardial infarction (STEMI) is associated with poor outcomes; however, the associated factors remain unclear. This study aimed to examine whether acute inflammatory response after STEMI affects platelet-derived thrombogenicity., Methods: This retrospective observational single-center study included 150 patients with STEMI who were assessed for platelet-derived thrombogenicity during the acute phase. Platelet-derived thrombogenicity was assessed using the area under the flow-pressure curve for platelet chip (PL-AUC), which was measured using the total thrombus-formation analysis system (T-TAS). The peak leukocyte count was evaluated as an acute inflammatory response after STEMI. The patients were divided into two groups: the highest quartile of the peak leukocyte count and the other three quartiles combined., Results: Patients with a high peak leukocyte count (＞15,222/mm 3 ; n=37) had a higher PL-AUC upon admission (420 [386-457] vs. 385 [292-428], p=0.0018), higher PL-AUC during primary percutaneous coronary intervention (PPCI) (155 [76-229] vs. 96 [29-170], p=0.0065), a higher peak creatine kinase level (4200±2486 vs. 2373±1997, p＜0.0001), and higher PL-AUC 2 weeks after STEMI (119 [61-197] vs. 88 [46-122], p=0.048) than those with a low peak leukocyte count (≤ 15,222/mm 3 ; n=113). The peak leukocyte count after STEMI positively correlated with PL-AUC during primary PPCI (r=0.37, p＜0.0001). A multivariable regression analysis showed the peak leukocyte count to be an independent factor for PL-AUC during PPCI (β=0.26, p=0.0065)., Conclusions: An elevated leukocyte count is associated with high T-TAS-based platelet-derived thrombogenicity during the acute phase of STEMI.

Background: The prognosis of patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer has improved significantly since the advent of EGFR tyrosine kinase inhibitors (EGFR-TKIs). We aimed to investigate the relationship between patient characteristics, EGFR genotype, therapeutic agents, and the prognosis of the patients with EGFR mutation-positive lung cancer., Methods: This retrospective cohort study analyzed 198 Japanese patients with unresectable EGFR mutation-positive lung cancer who were treated with EGFR-TKIs at Toho University Sakura Medical Center from April 2006 to December 2021. Factors associated with overall survival (OS) were analyzed using Cox proportional hazards analysis., Results: Patients who received osimertinib had a significantly longer OS than did those not receiving it (median OS, 36.2 versus 20.7 months; p < 0.001).There were significant differences in OS between patients with EGFR mutation who received osimertinib as first-line treatment, T790M-positive patients who received osimertinib as second- or later-line treatment, and those who did not receive it (median OS, 28.2 versus 40.2 versus 20.7 months; p = 0.003). However, in T790M-negative patients, no significant difference in OS was noted between those who did and did not receive osimertinib as post-treatment (median OS, 28.0 versus 40.0 months; p = 0.619). Multivariate Cox proportional hazards analysis showed that osimertinib treatment was associated with longer OS (hazard ratio, 0.480; 95% confidence interval, 0.326-0.707; p < 0.001)., Conclusion: The patients who were T790M-positive in the first-line treatment with first or second-generation EGFR-TKIs and were given osimertinib as the second or later line treatment had a better prognosis than the patients who were T790M-negative in the first-line treatment with first or second-generation EGFR-TKIs and could not receive osimertinib., (© 2024. The Author(s).)

Background: The benefit of prehospital 12‑lead electrocardiogram (PH-ECG) performed by emergency medical service personnel at the site of first medical contact (FMC) in patients with ST-segment elevation myocardial infarction (STEMI) with cardiogenic shock (CS-STEMI) remains unclear. This study aimed to investigate the effect of PH-ECG on door-to-device time in patients with CS-STEMI., Methods: This study enrolled CS-STEMI (Killip class IV) patients who were transferred directly to hospitals by ambulance (n = 517) from the Kanagawa Acute Cardiovascular Registry database. Patients were divided into PH-ECG (+) (n = 270) and PH-ECG (-) (n = 247) groups. Patients who experienced out-of-hospital cardiac arrest, who did not undergo emergent coronary intervention, or whose data were missing were excluded. Patient characteristics, FMC-to-door time, door-to-device time, and in-hospital mortality were compared between the groups., Results: The patient backgrounds of the PH-ECG (+) and PH-ECG (-) groups were comparable. The peak creatinine kinase level was greater in the PH-ECG (+) group than in the PH-ECG (-) group [2756 (1292-6009) IU/ml vs. 2270 (957-5258) IU/ml, p = 0.048]. The FMC-to-door time was similar between the two groups [25 (20-33) min vs. 27 (20-35) min, p = 0.530], while the door-to-device time was significantly shorter in the PH-ECG group [74 (52-103) min vs. 83 (62-111) min, p = 0.007]. In-hospital mortality did not differ between the two groups (18 % vs. 21 %, p = 0.405). Multivariable logistic regression analyses revealed that PH-ECG (+) was independently associated with a door-to-device time < 60 min [odds ratio (95 % confidence intervals): 1.88 (1.24-2.83), p = 0.003]., Conclusions: PH-ECG was significantly associated with shorter door-to-device times in patients with CS-STEMI. Further studies with larger populations and more defined protocols are required to evaluate the utility of PH-ECG in patients with CS-STEMI., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

No medications have been reported to inhibit the progression of aortic valve stenosis (AS). The present study aimed to investigate whether evolocumab use is related to the slow progression of AS evaluated by serial echocardiography. This was a retrospective observational study from 2017 to 2022 at Yokohama City University Medical Center. Patients aged ≥ 18 with moderate AS were included. Exclusion criteria were (1) mild AS; (2) severe AS defined by maximum aortic valve (AV) velocity ≥ 4.0 m/s; and/or (3) no data of annual follow-up echocardiography. The primary endpoint was the association between evolocumab use and annual changes in the maximum AV-velocity or peak AV-pressure gradient (PG). A total of 57 patients were enrolled: 9 patients treated with evolocumab (evolocumab group), and the other 48 patients assigned to a control group. During a median follow-up of 33 months, the cumulative incidence of AS events (a composite of all-cause death, AV intervention, or unplanned hospitalization for heart failure) was 11% in the evolocumab group and 58% in the control group (P = 0.012). Annual change of maximum AV-velocity or peak AV-PG from the baseline to the next year was 0.02 (- 0.18 to 0.22) m/s per year or 0.60 (- 4.20 to 6.44) mmHg per year in the evolocumab group, whereas it was 0.29 (0.04-0.59) m/s per year or 7.61 (1.46-16.48) mmHg per year in the control group (both P < 0.05). Evolocumab use was associated with slow progression of AS and a low incidence of AS events in patients with moderate AS., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

A 50-year-old man with a triglyceride (TG) level of 11,397 mg/dL was admitted to our hospital. He consumed a high-fat and high-carbohydrate diet as well as more than 100 g of alcohol per day. He had type 2 diabetes and obesity and had previously suffered from severe acute pancreatitis twice. A genetic analysis revealed compound heterozygous mutations in APOA5 (c.56C>G and c.553G>T). In addition to low-fat meals and alcohol cessation, administration of pemafibrate lowered his triglyceride levels to <150 mg/dL.

At the beginning of 2020, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to epidemics worldwide. Obesity and visceral fat accumulation have been reported to be independent risk factors for severe COVID-19. Several reports have focused on the levels of adipocytokines/adipokines, including adiponectin (APN), which is exclusively secreted from adipocytes, although the importance of these factors in acute disease conditions remains unclear. Therefore, we investigated the relationship between serum adiponectin levels and COVID-19 severity. Patients with COVID-19 who were admitted to Sumitomo Hospital (Osaka, Japan) from May through October 2021 were included. A total of 107 patients were enrolled in this study. We obtained the anthropometric and clinical laboratory data of the patients at the time of admission and examined the associations between various parameters and COVID-19 severity. The mean period from onset to admission was 6.5 ± 2.8 days. We divided the patients into "non-severe" (mild, moderate-I and moderate-II) (n = 80) and "severe" (n = 27) groups. The "severe" patients were significantly older than "non-severe" patients. Additionally, no significant differences were observed in BMI, sex, or the period from onset to admission. The serum adiponectin levels of "severe" patients at the time of admission were significantly greater than those of "non-severe" patients even after adjusting for age, sex, and BMI. These results suggest that the serum APN levels at the time of admission can predict COVID-19 severity. However, further investigations on the changes in APN levels in acute diseases are needed.

We report an extremely rare case of an extraluminal interstitial pregnancy. A 36-year-old nulliparous woman visited our hospital during the fifth week of gestation. Although no intrauterine gestational sac (GS) was identified, transabdominal ultrasonography revealed a GS-like cyst was detected in the right uterine horn. She underwent laparoscopic surgery for a suspected interstitial ectopic pregnancy. After laparoscopic cornuotomy, dye leakage was observed from the fimbria rather than the incision site. Finally, the patient was diagnosed with a right extraluminal interstitial pregnancy. Hysterosalpingography performed at three postoperative months revealed bilateral tubal passage. She conceived 7 months after surgery, with safe delivery by elective cesarean section at 38 weeks., (© 2024 Japan Society of Obstetrics and Gynecology.)

It has not yet been established whether angiotensin II receptor blockers (ARB), statins, and multiple drugs affect the severity of COVID-19. Therefore, we herein performed an observational study on the effects of 1st- and 2nd-generation ARB, statins, and multiple drugs, on COVID-19 in patients admitted to 15 Japanese medical facilities. The results obtained showed that ARB, statins, and multiple drugs were not associated with the primary outcome (odds ratio: 1.040, 95% confidence interval: 0.688-0.571; 0.696, 0.439-1.103; 1.056, 0.941-1.185, respectively), each component of the primary outcome (in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and admission to the intensive care unit), or the secondary outcomes (oxygen administration, disturbed consciousness, and hypotension, defined as systolic blood pressure ≤90 mmHg). ARB were divided into 1st- and 2nd-generations based on their approval for use (before 2000 and after 2001), with the former consisting of losartan, candesartan, and valsartan, and the latter of telmisartan, olmesartan, irbesartan, and azilsartan. The difference of ARB generation was not associated with the primary outcome (odds ratio with 2nd-generation ARB relative to 1st-generation ARB: 1.257, 95% confidence interval: 0.613-2.574). The odd ratio for a hypotension as one of the secondary outcomes with 2nd-generation ARB was 1.754 (95% confidence interval: 1.745-1.763) relative to 1st-generation ARB. These results suggest that patients taking 2nd-generation ARB may be at a higher risk of hypotension than those taking 1st-generation ARB and also that careful observations are needed. Further studies are continuously needed to support decisions to adjust medications for co-morbidities., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Aims: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is often accompanied by atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT), which are difficult to control because beta-blockers and antiarrhythmic drugs can worsen heart failure (HF). This study aimed to investigate the outcomes of catheter ablation (CA) for AF/AFL/AT in patients with ATTRwt-CM and propose a treatment strategy for CA., Methods and Results: A cohort study was conducted on 233 patients diagnosed with ATTRwt-CM, including 54 who underwent CA for AF/AFL/AT. The background of each arrhythmia and the details of the CA and its outcomes were investigated. The recurrence-free rate of AF/AFL/AT overall in ATTRwt-CM patients with multiple CA was 70.1% at 1-year, 57.6% at 2-year, and 44.0% at 5-year follow-up, but CA significantly reduced all-cause mortality [hazard ratio (HR): 0.342, 95% confidence interval (CI): 0.133-0.876, P = 0.025], cardiovascular mortality (HR: 0.378, 95% CI: 0.146-0.981, P = 0.045), and HF hospitalization (HR: 0.488, 95% CI: 0.269-0.889, P = 0.019) compared with those without CA. There was no recurrence of the cavotricuspid isthmus (CTI)-dependent AFL, non-CTI-dependent simple AFL terminated by one linear ablation, and focal AT originating from the atrioventricular (AV) annulus or crista terminalis eventually. Twelve of 13 patients with paroxysmal AF and 27 of 29 patients with persistent AF did not have recurrence as AF. However, all three patients with non-CTI-dependent complex AFL not terminated by a single linear ablation and 10 of 13 cases with focal AT or multiple focal ATs originating beyond the AV annulus or crista terminalis recurred even after multiple CA., Conclusion: The outcomes of CA for ATTRwt-CM were acceptable, except for multiple focal AT and complex AFL. Catheter ablation may be aggressively considered as a treatment strategy with the expectation of improving mortality and hospitalization for HF., Competing Interests: Conflict of interest: H.K. has received grants from Medtronic Japan, Nihon Kohden, Abbott Medical Japan, Fukuda Denshi, Boston Scientific Japan, Japan Lifeline, Nipro, and Biotronik Japan. K.T. has received honoraria from Bayer Yakuhin, Daiichi Sankyo, Kowa, MSD, Sanofi, and Takeda Pharmaceutical and grants from Astellas Pharma, Abbott Vascular Japan, Bayer Yakuhin, Boehringer Ingelheim Japan, Boston Scientific Japan, Bristol-Myers, Chugai Pharmaceutical, Daiichi Sankyo, Goodman, Japan Lifeline, Medtronic Japan, Mitsubishi Tanabe Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical, Sanofi, Takeda Pharmaceutical, and Terumo. All remaining authors have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Changes in stride regularity and joint motion during gait appear to be related to improved gait speed in hospitalized patients with stroke. We aimed to clarify the changes in stride regularity and joint motion during gait through longitudinal observations. Furthermore, we aimed to clarify the relationship between changes in gait speed, stride regularity, and joint motion during gait. Seventeen inpatients with stroke were assessed for physical and gait functions at baseline, when they reached functional ambulation category 3, and before discharge. Physical function was assessed using the Fugl-Meyer assessment for the lower extremities and the Berg Balance Scale. Gait function was assessed on the basis of gait speed, joint motion, stride regularity, and step symmetry using inertial sensors. The correlations between the ratio of change in gait speed and each indicator from baseline to discharge were analyzed. Both physical and gait functions improved significantly during the hospital stay. The ratio of change in gait speed was significantly and positively correlated with the ratio of change in vertical stride regularity (r = 0.662), vertical step symmetry (rs = 0.627), hip flexion (rs = 0.652), knee flexion (affected side) (r = 0.611), and ankle plantarflexion (unaffected side) (rs = 0.547). Vertical stride regularity, hip flexion, and knee flexion (affected side) were significant factors in determining the ratio of changes in gait speed. Our results suggest that stride regularity, hip flexion, and knee flexion could explain the entire gait cycle and that of the affected side. These parameters can be used as indices to improve gait speed., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Although the prevalence rate of valvular heart disease (VHD) is high in patients with systemic lupus erythematosus (SLE), the predictive factors of concomitant VHD have not been fully evaluated., Methods and Results: Among 288 patients with SLE who underwent transthoracic echocardiography at Kumamoto University Hospital from 2016 to 2021, 241 patients with sufficient echocardiographic data were retrospectively analysed. Among them, 22 (9 %) had VHD (10 had mitral regurgitation, 3 had aortic regurgitation, 6 had tricuspid regurgitation, 1 had mitral regurgitation and tricuspid regurgitation, and 2 had a prosthetic cardiac valve). After excluding the two patients with a prosthetic cardiac valve, we divided the remaining patients into two groups: the VHD group and non-VHD group. Multivariate logistic regression analysis revealed that age and the platelet count were significantly and independently associated with having VHD (age: odds ratio, 1.06; 95 % confidence interval, 1.02-1.10; p < 0.01) (platelet count: odds ratio, 0.99; 95 % confidence interval, 0.98-1.00; p < 0.05). After excluding 95 patients aged < 40 years, receiver operating characteristic analysis revealed that the area under the curve of the platelet count for prediction of VHD was 0.73 with an optimal cut-off value of 166.5 × 10 3 /µL (sensitivity: 76.6 %, specificity: 60.0 %). Among patients with a low platelet count (<166.5 × 10 3 /µL), the rate of having VHD was 29 % (12/41 patients). However, among those with a high platelet count (≥166.5 × 10 3 /µL), this rate was only 8 % (8/103 patients)., Conclusion: The platelet count is useful to predict concomitant VHD in middle-aged and older patients with SLE., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes., Methods and Results: In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P =0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P <0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes., Conclusions: Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.

Background: A delayed and recurrent complete atrioventricular block (CAVB) is a life-threatening complication of transcatheter aortic valve replacement (TAVR). Post-TAVR evaluation may be important in predicting delayed and recurrent CAVB requiring permanent pacemaker implantation (PPI). The impact of new-onset right bundle-branch block (RBBB) after TAVR on PPI remains unknown., Methods and Results: In total, 407 patients with aortic stenosis who underwent TAVR were included in this analysis. Intraprocedural CAVB was defined as CAVB that occurred during TAVR. A 12-lead ECG was evaluated at baseline, immediately after TAVR, on postoperative days 1 and 5, and according to the need to identify new-onset bundle-branch block (BBB) and CAVB after TAVR. Forty patients (9.8%) required PPI, 17 patients (4.2%) had persistent intraprocedural CAVB, and 23 (5.7%) had delayed or recurrent CAVB after TAVR. The rates of no new-onset BBB, new-onset left BBB, and new-onset RBBB were 65.1%, 26.8%, and 4.7%, respectively. Compared with patients without new-onset BBB and those with new-onset left BBB, the rate of PPI was higher in patients with new-onset RBBB (3.4% versus 5.6% versus 44.4%, P <0.0001). On post-TAVR evaluation in patients without persistent intraprocedural CAVB, the multivariate logistic regression analysis showed that new-onset RBBB was a statistically significant predictor of PPI compared with no new-onset BBB (odds ratio [OR], 18.0 [95% CI, 5.94-54.4]) in addition to the use of a self-expanding valve (OR, 2.97 [95% CI, 1.09-8.10])., Conclusions: Patients with new-onset RBBB after TAVR are at high risk for PPI.

Aims: This study aims to evaluate the distribution of extracellular volume fraction detected via computed tomography, clinical characteristics of high extracellular volume fraction detected via computed tomography, and the rate of incidental detection of cardiac amyloidosis in patients undergoing cardiac computed tomography for coronary artery evaluation., Methods and Results: This study included 874 consecutive patients (mean age, 74.4 ± 7.1 years; men, 65%), comprising men aged ≥60 years and women aged ≥70 years, who had undergone cardiac computed tomography between January 2020 and September 2022. The mean extracellular volume fraction detected via computed tomography was 29.7 ± 5.2%, and 108 patients (12.4%) had an extracellular volume fraction detected via computed tomography of ≥35%. Older age (75.9 ± 8.2 years vs. 74.2 ± 6.9 years; P = 0.042), male sex (75.9% vs. 63.0%; P = 0.007), impaired left ventricular ejection fraction, increased high-sensitivity cardiac troponin T and B-type natriuretic peptide levels, and increased left ventricular thickness showed significant associations with an extracellular volume fraction detected via computed tomography of ≥35%. Cardiac amyloidosis was diagnosed incidentally in 15 patients based on an increase in extracellular volume fraction detected via computed tomography. The prevalence of cardiac amyloidosis was 1.7% (15/874) and 14.3% (15/105) in the entire study population and in patients with an extracellular volume fraction detected via computed tomography of ≥35%, respectively. An increase in the extracellular volume fraction detected via computed tomography was suggestive of cardiac amyloidosis., Conclusion: Elevated extracellular volume fraction detected via computed tomography, associated with elevated cardiac biomarker levels and myocardial structural changes, may lead to the incidental diagnosis of cardiac amyloidosis., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10 -8 and 4.3 × 10 -7 ). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD., (© 2024. The Author(s).)

Aim: Low-density lipoprotein cholesterol (LDL-C) level reduction is highly effective in preventing the occurrence of a cardiovascular event. Contrariwise, an inverse association exists between LDL-C levels and prognosis in some patients with cardiovascular diseases-the so-called "cholesterol paradox." This study aimed to investigate whether the LDL-C level on admission affects the long-term prognosis in patients who develop acute coronary syndrome (ACS) and to examine factors associated with poor prognosis in patients with low LDL-C levels., Methods: We enrolled 410 statin-naïve patients with ACS, whom we divided into low- and high-LDL-C groups based on an admission LDL-C cut-off (obtained from the Youden index) of 122 mg/dL. Endothelial function was assessed using the reactive hyperemia index 1 week after statin initiation. The primary composite endpoint included all-cause death, as well as myocardial infarction and ischemic stroke occurrences., Results: During a median follow-up period of 6.1 years, 76 patients experienced the primary endpoint. Multivariate Cox regression analysis revealed that patients in the low LDL-C group had a 2.3-fold higher risk of experiencing the primary endpoint than those in the high LDL-C group (hazard ratio, 2.34; 95% confidence interval, 1.29-4.27; p=0.005). In the low LDL-C group, slow gait speed (frailty), elevated chronic-phase high-sensitivity C-reactive protein levels (chronic inflammation), and endothelial dysfunction were significantly associated with the primary endpoint., Conclusions: Patients with low LDL-C levels at admission due to ACS had a significantly worse long-term prognosis than those with high LDL-C levels; frailty, chronic inflammation, and endothelial dysfunction were poor prognostic factors.

Background: The antifibrotic drugs, nintedanib and pirfenidone, inhibit the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF). Nintedanib also inhibits the onset of acute exacerbation and reduces the risk of all-cause mortality. However, their effectiveness in real-world practice remains unclear. Our study aimed to investigate the changes in forced vital capacity, survival period, causes of death, and risk factors for mortality in patients with IPF receiving antifibrotic drugs., Methods: This retrospective study enrolled Japanese patients who visited Toho University Sakura Medical Center who were diagnosed with IPF and received antifibrotic drugs., Results: We included 102 patients [mean age ± standard deviation (SD): 71.8 ± 7.5 years], of whom 76 were males. The decline in forced vital capacity (mean ± SD) during the antifibrotic therapy period was - 154 ± 259 mL/year, which was significantly lower than before the antifibrotic therapy period (- 484 ± 589 mL/year; n = 80, p = 0.003). Altogether, 52 deaths were confirmed, and the median survival time from antifibrotic therapy initiation was 38.0 months (95% confidence interval: 25.9-50.1 months). Acute exacerbation accounted for 9.6% of all deaths (95% confidence interval: 1.6-17.6). The decline in forced vital capacity during antifibrotic therapy was a risk factor for mortality., Conclusions: In actual clinical practice in Japan, antifibrotic drugs suppressed the gradual decline in forced vital capacity, which is a risk factor for mortality. However, the median survival period remained poor at 38 months., (© 2023. The Author(s).)

Background: Neither the efficacy nor safety of elobixibat has been investigated in the treatment of chronic constipation in patients with heart failure (HF). Methods and Results: In this prospective, single-center, single-arm study elobixibat (10 mg/day) was administered for 12 weeks to 18 HF patients with chronic constipation defined according to the Rome IV criteria. Spontaneous bowel movement (SBM), stool consistency as measured by the Bristol Stool Form Scale, and degree of straining during defecation were recorded. In addition, biomarkers, blood pressure (BP) measured by ambulatory monitoring, and adverse events were assessed. Although there was no significant difference, the frequency of SBM increased by 2.0/week from baseline to Week 12. Both the degree of straining during defecation and low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased at Week 12 (straining, -0.79 [95% confidence interval (CI), -1.40 to -0.17]; LDL-C, -10.4 mg/dL [95% CI, -17.9 to -2.9]). Although not significant, the difference in BP before and after defecation tended to decrease from baseline by approximately 10 mmHg at Week 12. Serious adverse events were not observed. Conclusions: Elobixibat reduced the degree of straining during defecation, and improved the lipid profile in HF patients with chronic constipation., Competing Interests: K.T. reports remuneration for lectures from Abbott Medical Co., Ltd., Amgen K.K., AstraZeneca K.K., Bayer Yakuhin Ltd., Daiichi Sankyo Co., Ltd., Medtronic Japan Co., Ltd., Kowa Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Janssen Pharmaceutical K.K.; trust research/joint research funds from CSL Behring K.K., JIMRO Co., Ltd., Alexion Pharmaceuticals Inc., AnGes Inc., PPD-Shin Nippon Biomedical Laboratories K.K., Sugi Bee Garden (International) Co., Ltd., Daiichi Sankyo Co., Ltd., Bayer Yakuhin Ltd., Pfizer Japan Inc., Bristol-Myers K.K., Mochida Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd.; scholarship funds from AMI Co., Ltd., Abbott Medical Co., Ltd., Boehringer Ingelheim Japan, Daiichi Sankyo Co., Ltd., ITI Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; and affiliations with endowed departments from Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., Nipro Corporation, Terumo Co., Ltd., Abbott Medical Co., Ltd., Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., and Medtronic Japan Co., Ltd. K.T. is a member of Circulation Reports’ Editorial Team. Y.M. reports affiliation with a donated course funded by Nishinihon Hospital. The other authors have no conflicts of interest to disclose. All authors have approved the final version of the manuscript., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: Mechanical compression of cardiac conduction system by transcatheter heart valves leads to complete atrioventricular block (CAVB) after transcatheter aortic valve replacement (TAVR). Bulging of ventricular septum in the left ventricular outflow tract (LVOT) may be associated with greater compression of conduction system, leading to irreversible CAVB., Objective: This study aimed to investigate the association of ventricular septal bulging with TAVR-related CAVB and permanent pacemaker implantation (PPI)., Methods: Among 294 consecutive patients with severe aortic stenosis who underwent TAVR between July 2017 and February 2023, 271 were included in the analysis. As a quantitative evaluation of bulging of the ventricular septum, the ratio of LVOT area to aortic annulus area (L/A ratio) was measured at the systolic phase of computed tomography images., Results: TAVR-related CAVB occurred in 64 patients (23.6%). Twenty-eight patients (10.3%) required PPI. The optimal thresholds of L/A ratio for predicting TAVR-related CAVB and PPI were 1.0181 and 0.985, respectively. Patients with less than the cut-off values had higher rate of TAVR-related CAVB and PPI than those above (28.3% vs 13.1%, p = 0.0063; 14.7% vs 4.4%, p = 0.0077, respectively). A multivariate analysis showed that L/A ratio < 1.0181 was an independent predictor of TAVR-related CAVB (odds ratio [OR] 2.65, p = 0.011), in addition to prior right bundle branch block (OR 3.76, p = 0.0005), use of a self-expanding valve (OR 1.99, p = 0.030), and short membranous septum length (OR 0.96, p = 0.037). Only L/A ratio < 0.985 was independently associated with PPI (OR 3.70, p = 0.011)., Conclusion: Low L/A ratio is a predictor of TAVR-related CAVB and PPI., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background : We retrospectively investigated the effects of the severity and classification of sleep-disordered breathing (SDB) on left ventricular (LV) function in patients with ST-segment elevation myocardial infarction (STEMI). Methods : A total of 115 patients with STEMIs underwent a sleep study using a multichannel frontopolar electroencephalography recording device (Sleep Profiler) one week after STEMI onset. We evaluated LV global longitudinal strain (LV-GLS) using two-dimensional echocardiography at one week and seven months. Patients were classified as no SDB (AHI < 5 events/h), obstructive SDB (over 50% of apnea events are obstructive), and central SDB (over 50% of apnea events are central). Due to the device's limitations in distinguishing obstructive from central hypopnea, SDB classification was based on apnea index percentages. Results : The obstructive apnea index (OAI) was significantly associated with LV-GLS at one week (r = 0.24, p = 0.027) and seven months (r = 0.21, p = 0.020). No such correlations were found for the central apnea index and SDB classification. Multivariable regression analysis showed that the OAI was independently associated with LV-GLS at one week (β = 0.24, p = 0.002) and seven months (β = 0.20, p = 0.008). Conclusions : OAI is associated with persistent LV dysfunction assessed by LV-GLS in STEMI.

Competing Interests: SS is an associate editor of the Western Pacific Surveillance and Response journal. She was not involved in the editorial decision to publish this article. The other authors have no conflicts of interest to declare.

Untargeted lipidomics using liquid chromatography (LC) coupled with tandem mass spectrometry (MS) is essential for large cohort studies. Using a fast LC gradient of less than 10 min for the rapid screening of lipids decreases the annotation rate, because of the lower coverage of the MS/MS spectra caused by the narrow peak width. A systematic procedure is proposed in this study to achieve a high annotation rate in fast LC-based untargeted lipidomics by integrating data-dependent acquisition (DDA) and sequential window acquisition of all-theoretical mass spectrometry data-independent acquisition (SWATH-DIA) techniques using the updated MS-DIAL program. This strategy uses variable SWATH-DIA methods for quality control (QC) samples, which are a mixture of biological samples that were analyzed multiple times to correct the MS signal drift. In contrast, biological samples are analyzed using DDA to facilitate the structural elucidation of lipids using the pure spectrum to the maximum extent. The workflow is demonstrated using an 8.6 min LC gradient, where the QC samples are analyzed using five different SWATH-DIA methods. The use of both DDA and SWATH-DIA achieves a 1.7-fold annotation coverage from publicly available benchmark data obtained using a fast LC-DDA-MS technique and offers 95.3% lipid coverage, as compared to the benchmark data set from a 25 min LC gradient. This study demonstrates that harmonized improvements in analytical conditions and informatics tools provide a comprehensive lipidome in fast LC-based untargeted lipidomics, not only for large-scale studies but also for small-scale experiments, contributing to both clinical applications and basic biology.

Numerous COVID-19 diagnostic imaging Artificial Intelligence (AI) studies exist. However, none of their models were of potential clinical use, primarily owing to methodological defects and the lack of implementation considerations for inference. In this study, all development processes of the deep-learning models are performed based on strict criteria of the "KAIZEN checklist", which is proposed based on previous AI development guidelines to overcome the deficiencies mentioned above. We develop and evaluate two binary-classification deep-learning models to triage COVID-19: a slice model examining a Computed Tomography (CT) slice to find COVID-19 lesions; a series model examining a series of CT images to find an infected patient. We collected 2,400,200 CT slices from twelve emergency centers in Japan. Area Under Curve (AUC) and accuracy were calculated for classification performance. The inference time of the system that includes these two models were measured. For validation data, the slice and series models recognized COVID-19 with AUCs and accuracies of 0.989 and 0.982, 95.9% and 93.0% respectively. For test data, the models' AUCs and accuracies were 0.958 and 0.953, 90.0% and 91.4% respectively. The average inference time per case was 2.83 s. Our deep-learning system realizes accuracy and inference speed high enough for practical use. The systems have already been implemented in four hospitals and eight are under progression. We released an application software and implementation code for free in a highly usable state to allow its use in Japan and globally., (© 2024. The Author(s).)

A 63-year-old man with adult T-cell leukemia-lymphoma underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. On day 17 after transplantation, chest computed tomography (CT) showed nodules in the lower lobes of both lungs, and invasive pulmonary aspergillosis (IPA) was suspected. Treatment with liposomal amphotericin B was started, and improvement of infectious lesions was confirmed with CT on day 28. The antifungal agent was changed to voriconazole on day 52 because of progressive renal dysfunction. Disorders of consciousness and paralysis of the left upper and lower extremities developed on day 61. Brain CT showed subcortical hemorrhage in the right parietal and occipital lobes, and the patient died on day 62. An autopsy revealed filamentous fungi, suspected to be Aspergillus, in the pulmonary nodules and a ruptured cerebral aneurysm. Although IPA occurs in 10% of transplant recipients, vigilant monitoring for mycotic cerebral aneurysms is required to prevent hematogenous dissemination of Aspergillus, which is associated with a high mortality rate.

Objective: In the present retrospective study, we evaluated potentially predictive factors and determined receiver operating characteristic (ROC) curve cut-off values for effective detection of patients at higher risk of re-hospitalization due to postoperative infection after total laparoscopic hysterectomy., Materials and Methods: We included 168 patients who had undergone laparoscopic hysterectomy. Data were collected from medical records. Patients were classified into non-infection (n = 161) and infection (n = 7) groups based on whether they developed fever after hospital discharge. We evaluated factors conventionally known to affect postoperative infection in general, and values of white blood cell (WBC) and C-reactive protein (CRP) determined on postoperative days 1 and 3-5., Results: There were significant differences in WBC 3-5 days postoperatively (WBC POD3-5) (p = 0.049), CRP 3-5 days postoperatively (CRP POD3-5) (p = 0.018) and CRP POD3-5 × WBC 1 day postoperatively (WBC POD1) (p = 0.002). Area under the ROC curves for CRP POD3-5 and CRP POD3-5 × WBC POD1 were 0.81 and 0.84, and cutoffs were 4.46 mg/dL and 46885.5, respectively., Conclusion: If CRP POD3-5 or CRP POD3-5 × WBC POD1 is high, the physician should be alert to postoperative infection, and the patient should be under careful management and supervision.

This study presents an approach for fabricating Wolter type-I mirrors for x-ray telescopes using a nickel electroforming replication process with quartz glass mandrels. The proposed method addresses the challenges encountered in conventional fabrication techniques, which involve using electroless nickel-coated aluminum mandrels that are susceptible to corrosion and thermal deformation. Quartz glass mandrels offer excellent chemical, thermal, and mechanical stability, enabling the efficient production of high-performance mirrors. Wolter type-I mirrors for telescopes possess a large aperture that collects x-ray photons from the universe. However, previous nickel electroforming replication processes using quartz glass mandrels have challenges in fabricating large mirrors, particularly due to bubble pit formation during nickel shell development. In this study, we introduced an efficient pitting inhibition technique via vacuum degassing. This technique facilitates the precise replication of pit-free Wolter type-I mirrors for telescopes using quartz glass mandrels. We demonstrated the fabrication process on a Wolter type-I mirror proposed for FOXSI-4 [(FOXSI) Focusing Optics X-ray Solar Imager], resulting in three mirrors obtained from the same mandrel without repolishing or repairing. The figure error of the mirror was within 1 µm over most areas in both longitudinal and circumferential directions. The ray-tracing simulation indicated that the performance of the mirror was ∼12 arcsec in half-power diameter, comparable to the performance achieved by previous high-resolution x-ray missions., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Background: Subclinical leaflet thrombosis occasionally occurs after transcatheter aortic valve implantation (TAVI), but its exact etiology and relationship with thrombogenicity remain unknown. Methods and Results: This study enrolled 35 patients who underwent TAVI. Thrombogenicity was evaluated using a total thrombus-formation analysis system (T-TAS) to compute the thrombus-formation area under the curve (PL 18 -AUC 10 and AR 10 -AUC 30 ). Periprocedural thrombogenic parameters including T-TAS were investigated at pre-TAVI, 2 days, 7 days, and 3 months post-TAVI. Hypoattenuated leaflet thickening (HALT) and maximum leaflet thickness (MLT) were evaluated using contrast-enhanced computed tomography 7 days and 3 months post-TAVI. The associations between thrombogenicity and HALT or MLT were assessed. T-TAS parameters consistently decreased at 2 and 7 days post-TAVI, followed by improvement at 3 months. HALT was detected in 20% and 17% of patients at 7 days and 3 months, respectively, post-TAVI. The median MLT value was 1.60 mm at 7 days and 3 months post-TAVI. A significant positive correlation was observed between the decrease in the AR 10 -AUC 30 and MLT at 7 days post-TAVI. Univariate linear regression analysis revealed a decrease in the AR 10 -AUC 30 and an increase in the D-dimer level as a significant predictor of MLT deterioration. Conclusions: The findings suggested that a transient decrease in thrombogenicity following TAVI predicts leaflet thrombosis, implying that monitoring thrombogenicity may be useful for predicting progression of leaflet thrombosis., Competing Interests: K.K., K.T. are members of Circulation Reports’ Editorial Team. K.K. received Grants-in-Aid for Scientific Research (20K08451) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, received remuneration for lectures from Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Novartis Pharma AG., Otsuka Pharmaceutical Co., Ltd., Bristol-Myers K.K., and Kowa Pharmaceutical Co. Ltd., received trust research/joint research funds from Bayer Yakuhin, Ltd., and Daiichi Sankyo Co., Ltd., and received scholarship funds from Abbott Medical Co., Ltd. K.T. received significant research grants from Bayer Yakuhin, Ltd., Bristol-Myers K.K., EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., CSL Behring K.K., JIMRO Co., Ltd., Alexion Pharmaceuticals, Inc., AnGes, Inc., PPD-Shin Nippon Biomedical Laboratories K.K., SUGI BEE GARDEN (International) Co., Ltd., Pfizer Japan Inc., scholarship funds from AMI Co., Ltd., Boehringer Ingelheim Japan, Daiichi Sankyo Co., Ltd., ONO Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Abbott Medical Co., Ltd., and ITI Co., Ltd. and honoraria from Amgen K.K., Abbott Medical Co., Ltd., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Medtronic Japan Co., Ltd., Kowa Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Janssen Pharmaceutical K.K., and belongs to endowed departments donated by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., NIPRO Corporation, Terumo Co, Ltd., Abbott Medical Co., Ltd., Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., and Medtronic Japan Co., Ltd., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)

Background Contradictions between management modalities of type A acute aortic dissection (TAAAD) and ST-elevation-myocardial infarction (STEMI) may result in clinical catastrophe. Therefore, we aimed to explore which 2-dimensional echocardiography (2DE) findings are optimal for differentiating TAAAD from STEMI. Methods and Results This study included 340 patients with STEMI and 340 patients with TAAAD who underwent 2DE in the emergency department between 2012 and 2021. The proximal ascending aorta (PAA) diameter and other echocardiographic parameters were analyzed. PAA diameters were measured at 4 levels in the parasternal view: Valsalva, the sinotubular junction (STJ), the PAA at 1 cm above the STJ, and the PAA at 2 cm above the STJ. Receiver-operating characteristic curve analysis showed that Valsalva, STJ, PAA at 1 cm above the STJ, and PAA at 2 cm above the STJ were significant predictors of TAAAD (areas under the curve: 0.777, 0.924, 0.965, and 0.975, respectively; P <0.001) with the respective cutoff values of 39.4, 38.5, 39.8, and 41.2 mm. Multivariable analysis suggested that all 2DE parameters were significant predictors of TAAAD. Among the 2DE parameters examined, the incorporation of PAA at 2 cm above the STJ to clinical indicators exhibited the most significant diagnostic capability (C-statistics, 0.97; net reclassification improvement, 1.81; integrated discrimination improvement, 0.61). When only TAAAD with coronary malperfusion and STEMI were analyzed, the diagnostic utility of PAA at 1 cm above the STJ was evident (C-statistics, 0.99; net reclassification improvement, 1.79; integrated discrimination improvement, 0.67), with PAA at 2 cm above the STJ ranking second in diagnostic significance (C-statistics, 0.99; net reclassification improvement, 1.12; integrated discrimination improvement, 0.66). Conclusions PAA measurements were the most beneficial for diagnosing TAAAD in all 2DE findings and TAAAD from STEMI.

Belantamab mafodotin, a B-cell maturation antigen-targeting antibody-drug conjugate (ADC), was investigated in Japanese patients with relapsed/refractory multiple myeloma in Part 1 of the phase I DREAMM-11 study. Patients who had received ≥ 2 prior lines of therapy including a proteasome inhibitor and immunomodulatory agent were eligible. Eight patients received belantamab mafodotin monotherapy at 2.5 mg/kg (n = 4) or 3.4 mg/kg (n = 4) by intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. Primary objectives were tolerability and safety, and secondary objectives included pharmacokinetics (PK) and efficacy. The most common Grade ≥ 3 adverse event was thrombocytopenia/platelet count decreased (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]), and no dose-limiting toxicities were observed. Ocular events, including keratopathy findings, were observed in most patients (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]) and were managed with dose modifications. All resolved within the study period. Overall response rates were 50% (2/4) in the 2.5 mg/kg cohort and 25% (1/4) in the 3.4 mg/kg cohort. Although PK profiles in Japanese patients varied, individual exposures overlapped with previous results in Western populations. Belantamab mafodotin monotherapy was generally well-tolerated and demonstrated clinical activity at both doses., (© 2023. The Author(s).)

Background: The indications for fertility preservation (FP) have expanded. A few patients who underwent gonadotoxic treatment did not have the opportunity to receive FP, leading to concerns that these patients may develop premature ovarian insufficiency. However, the usefulness of FP in women with reduced ovarian reserve has also been questioned. Progestin-primed ovarian stimulation can improve the controlled ovarian stimulation (COS) protocol, but there is limited data on the efficacy of FP with progestin-primed ovarian stimulation., Methods: We conducted a prospective study of 43 women with cancer or autoimmune diseases before and after gonadotoxic treatment at the reproductive unit of Keio University Hospital, counselled between 1 January 2018 and 31 December 2021. After counselling, informed consent was obtained for FP from 43 patients, with those who underwent gonadotoxic treatment of the primary disease being prioritised. Gonadotropin-releasing hormone analogue or progestin was used to suppress luteinising hormone in COS before or after gonadotoxic treatment. The number of cryopreserved mature oocytes was the primary outcome., Results: Forty-three patients and 67 assisted reproductive technology cycles were included in the analysis. The median age at entry was 32 [inter quartile range (IQR), 29-37] years. All patients in the post-gonadotoxic treatment group had their oocytes frozen. Gonadotoxic treatment resulted in fewer oocytes [median 3 (IQR 1-4); pre-gonadotoxic treatment group: five patients, 13 cycles] vs. median 9 (IQR 5-14; pre-gonadotoxic treatment group: 38 patients, 54 cycles; P < 0.001). Although anti-Müllerian hormone levels were lower in the post-gonadotoxic treatment group (n = 5, 13 cycles, median 0.29 (IQR 0.15-1.04) pg/mL) than in the pre-gonadotoxic treatment group (n = 38, 54 cycles, median 1.89 (IQR 1.15-4.08) pg/mL) (P = 0.004), oocyte maturation rates were higher in the post-gonadotoxic treatment group [median 100 (IQR 77.5-100) %] than in the pre-gonadotoxic group [median 90.3 (IQR 75.0-100) %; P = 0.039]. Five patients in the pre-gonadotoxic treatment group had their cryopreserved embryos thawed, of which three had live births., Conclusions: Oocytes obtained for FP from women with cancer or autoimmune disease for FP are of satisfactory quality, regardless of whether they are obtained post-gonadotoxic treatment or COS protocols., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Rationale: Although IgG4-related disease (IgG4-RD) can affect various organs, its association with a cardiac mass is exceptionally rare. Here, we report a case of a woman with IgG4-RD and a cardiac mass and discuss 10 similar cases reported previously., Patient Concerns: A 65-year-old woman was referred to our hospital for chest discomfort and back pain., Diagnoses: In accordance with the 2019 ACR/EULAR diagnostic criteria for IgG4-RD, she was diagnosed with IgG4-RD based on dense lymphocytic infiltration on histopathology, IgG/IgG4-positive cell ratio <40%, >10/hpf IgG4-positive cells on immunostaining, and paraspinal zone soft tissue lesions in the chest., Interventions: An external pacemaker was implanted for the complete atrioventricular block on the electrocardiogram. After the diagnosis of IgG4-RD, she was treated with glucocorticoids and rituximab., Outcomes: She remains under observation without disease recurrence., Lessons: IgG4-RD are usually treated with glucocorticoids; however, in cases of a cardiac mass, life-threatening complications may occur and surgery is often needed. Combination therapy with glucocorticoids and rituximab may be effective even in patients with IgG4-RD and cardiac mass, which may avoid the need of invasive treatments, such as surgery., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This study aimed to investigate the effect of glycemic variability (GV), determined using a continuous glucose monitoring system (CGMS), on left ventricular reverse remodeling (LVRR) after ST-segment elevation myocardial infarction (STEMI)., Methods: A total of 201 consecutive patients with STEMI who underwent reperfusion therapy within 12 h of onset were enrolled. GV was measured using a CGMS and determined as the mean amplitude of glycemic excursion (MAGE). Left ventricular volumetric parameters were measured using cardiac magnetic resonance imaging (CMRI). LVRR was defined as an absolute decrease in the LV end-systolic volume index of > 10% from 1 week to 7 months after admission. Associations were also examined between GV and LVRR and between LVRR and the incidence of major adverse cardiovascular events (MACE; cardiovascular death, acute coronary syndrome recurrence, non-fatal stroke, and heart failure hospitalization)., Results: The prevalence of LVRR was 28% (n = 57). The MAGE was independent predictor of LVRR (odds ratio [OR] 0.98, p = 0.002). Twenty patients experienced MACE during the follow-up period (median, 65 months). The incidence of MACE was lower in patients with LVRR than in those without (2% vs. 13%, p = 0.016)., Conclusion: Low GV, determined using a CGMS, was significantly associated with LVRR, which might lead to a good prognosis. Further studies are needed to validate the importance of GV in LVRR in patients with STEMI., (© 2023. BioMed Central Ltd., part of Springer Nature.)

This cross-sectional study examined the immediate effects of four types of real-time feedback during overground gait performed using inertial measurement units on gait kinematics in healthy young participants. Twelve healthy young participants (mean age: 27.1 years) performed 60-s gait trials with each of the following real-time feedback: walking spontaneously (no feedback trial); increasing the ankle plantar-flexion angle during the late stance (ankle trial); increasing the leg extension angle, defined the location of the ankle joint relative to the hip joint in the sagittal plane, during late stance (leg trial); and increasing the knee flexion angle during the swing phase (knee trial). Tilt angles and accelerations of the pelvis and lower limb segments were measured using seven inertial measurement units pre- and postfeedback trials. The differences in gait parameters pre- and postfeedback according to the types of feedback were compared using one-factor repeated-measures analysis of variance, Friedman test, and post hoc test. Real-time feedback in the ankle trial increased gait speed, step length, and ankle plantar-flexion angle compared to the no feedback trial (p ≤ .001). Meanwhile, real-time feedback in the leg trial increased step length and hip extension angle compared to the no feedback trial (p ≤ .001) and showed a tendency to increase gait speed and leg extension angle. Real-time feedback using inertial measurement units increased gait speed immediately with specific changes in gait kinematics in healthy participants. This study might imply the possibility of clinical application for overground gait training, and further studies are needed to clarify the effectiveness for older people.