Evaluating haemodynamic changes: vericiguat in patients with heart failure with reduced ejection fraction.

AIMS: Vericiguat has been used to treat patients with heart failure with reduced ejection fraction (HFrEF) who demonstrated worsening heart failure despite treatment with other guideline-directed medical therapies. The haemodynamic effects of vericiguat remain unclear. METHODS AND RESULTS: This study enrolled 12 patients (median age, 63 [quartiles 53.5, 70] years; 16.7%(N=2) women) with symptomatic HFrEF (New York Heart Association functional class II-IV) who demonstrated worsening heart failure despite treatment with the four foundational guideline-recommended therapies between March and December 2022, with follow-ups completed in June 2023. A balloon-tipped pulmonary artery thermodilution catheter was placed in the right internal jugular vein to perform right heart catheterisation (RHC) on day 1. Haemodynamic data were acquired before and after vericiguat intake (2.5 mg) on days 2 and 3. The data on days 2 and 3 were averaged. RHC was repeated on day 105 (37, 168). Oral intake of vericiguat 2.5 mg decreased mean pulmonary artery pressure (19.3 [14.3, 26.8] mmHg) and pulmonary artery wedge pressure (PAWP) (11 [7.5, 15] mmHg) before the intake to mean pulmonary artery pressure (17.5 [12.5, 24] mmHg) and PAWP (9.3 [6.8, 14] mmHg) at 30 min after (both P < 0.05). Reduction in PAWP was also found from 14.5 [9.5, 19.5] mmHg on day 1 to 9.5 [6.5, 12.5] mmHg on day 105 (37, 168) (P < 0.05), when vericiguat was titrated to 2.5 mg 25% (N = 3), 5 mg 50% (N = 6), and 10 mg 25% (N = 3). CONCLUSIONS: The consistent reduction in PAWP underscores the well-tolerated nature of vericiguat and its potential to enhance cardiac performance in patients with HFrEF.

Chronic Effects of Adaptive Servo-Ventilation Therapy on Mortality and the Urgent Rehospitalization Rate in Patients Experiencing Recurrent Admissions for Heart Failure　- A Multicenter Prospective Observational Study (SAVIOR-L).

BACKGROUND: This study investigated whether the chronic use of adaptive servo-ventilation (ASV) reduces all-cause mortality and the rate of urgent rehospitalization in patients with heart failure (HF).Methods and Results: This multicenter prospective observational study enrolled patients hospitalized for HF in Japan between 2019 and 2020 who were treated either with or without ASV therapy. Of 845 patients, 110 (13%) received chronic ASV at hospital discharge. The primary outcome was a composite of all-cause death and urgent rehospitalization for HF, and was observed in 272 patients over a 1-year follow-up. Following 1:3 sequential propensity score matching, 384 patients were included in the subsequent analysis. The median time to the primary outcome was significantly shorter in the ASV than in non-ASV group (19.7 vs. 34.4 weeks; P=0.013). In contrast, there was no significant difference in the all-cause mortality event-free rate between the 2 groups. CONCLUSIONS: Chronic use of ASV did not impact all-cause mortality in patients experiencing recurrent admissions for HF.

Nasal polyps show decreased mucociliary transport despite vigorous ciliary beating.

OBJECTIVE: Mucociliary transport function in the airway mucosa is essential for maintaining a clean mucosal surface. This function is impaired in upper and lower airway diseases. Nasal polyps are a noticeable pathological feature that develop in some of the patients with chronic rhinosinusitis. Like ordinary nasal mucosae, nasal polyps have a ciliated pseudostratified epithelium with vigorous ciliary beating. We measured ex vivo Mucociliary Transport Velocity (MCTV) and Ciliary Beat Frequency (CBF) and explored the expressions of Planar Cell Polarity (PCP) proteins in nasal polyps in comparison with turbinate mucosae. METHODS: Inferior turbinates and nasal polyps were surgically collected from patients with chronic rhinosinusitis. Ex vivo MCTV and CBF were measured using a high-speed digital imaging system. Expressions of PCP proteins were explored by fluorescence immunohistochemistry and quantitative RT-PCR. RESULTS: The MCTV of nasal polyps was significantly lower than that of the turbinates (7.43 ±â€¯2.01 vs. 14.56 ±â€¯2.09 µm/s; p = 0.0361), whereas CBF did not differ between the two tissues. The MCTV vector was pointed to the posteroinferior direction in all turbinates with an average inclination angle of 41.0 degrees. Immunohistochemical expressions of Dishevelled-1, Dishevelled-3, Frizzled3, Frizzled6, Prickle2 and Vangl2 were lower in the nasal polyps than in the turbinates. Confocal laser scanning microscopy showed that Frizzled3 was localized along the cell junction on the apical surface. The expression levels of mRNAs for Dishevelled-1, Dishevelled-3 and Frizzled3 in the nasal polyps were also decreased in comparison with the turbinates. CONCLUSION: These results indicate that muco ciliary transport in nasal polyps is impaired although vigorous ciliary beating is maintained, and that the impairment may be caused by a decrease in Dishevelled/Frizzled proteins and resultant PCP disarrangement. LEVEL OF EVIDENCE: Level 3.

An optimal method of hydrogel spacer insertion for stereotactic body radiation therapy of prostate cancer.

PURPOSE: This study aimed to explore an ideal method for hydrogel spacer insertion by analyzing the efficacy and safety of our originally developed apex expansion method. MATERIALS AND METHODS: Overall, 100 patients with low- and intermediate-risk localized prostate cancer treated with stereotactic body radiation therapy were included. A hydrogel spacer was inserted in 64 and 36 patients using the conventional and apex expansion methods, respectively. For dosimetry, we trisected the rectum into the upper rectum, middle rectum, and lower rectum on the sagittal section of magnetic resonance imaging. We compared the dose to each part of the rectum between the two methods using dose-volume histograms. Genitourinary and gastrointestinal toxicity assessments were conducted until 3 months of follow-up. RESULTS: The whole rectal dose in the apex expansion method group was lower than that in the conventional method group, which was significant in all dose regions (V5-V35). Similarly, in the apex expansion method group, the dose to the middle rectum was lower in the low- to high-dose region (V10-V35), and the dose to the lower rectum was lower in the middle- to high-dose region (V15-35). No Grade ≥ 3 toxicity or procedure-related complications were observed. Additionally, Grade 2 genitourinary and gastrointestinal toxicities during the treatment showed no significant differences between the two methods. CONCLUSION: The apex expansion method may be safe and effective in achieving a more efficient rectal dose reduction by expanding the anterior perirectal space in the prostatic apex area.

Intractable Ventricular Tachycardia Prior to an Overt Cardiac Tumor Mass of Metastatic Cardiac Rhabdomyosarcoma (Spindle-cell Type).

We herein report a 37-year-old man who experienced recurrence of metastatic cardiac rhabdomyosarcoma along with intractable ventricular tachycardia (VT) 7 years after resection of rhabdomyosarcoma in his right elbow. At 36 years old, he developed VT unresponsive to radiofrequency catheter ablation (RFCA). Initially, the cardiac tumor was not detected, but it gradually grew in size at the RFCA site. A surgical biopsy confirmed the diagnosis of metastatic cardiac rhabdomyosarcoma. Despite radiation therapy, cardiac tumor progression and VT instability could not be prevented. Ultimately, the patient died 27 months after the initial documentation of VT.

Glioblastoma initiation, migration, and cell types are regulated by core bHLH transcription factors ASCL1 and OLIG2.

Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex driver mutations and glioma stem cells (GSCs). The neurodevelopmental transcription factors ASCL1 and OLIG2 are co-expressed in GBMs, but their role in regulating the heterogeneity and hierarchy of GBM tumor cells is unclear. Here, we show that oncogenic driver mutations lead to dysregulation of ASCL1 and OLIG2, which function redundantly to initiate brain tumor formation in a mouse model of GBM. Subsequently, the dynamic levels and reciprocal binding of ASCL1 and OLIG2 to each other and to downstream target genes then determine the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in defining GSCs by upregulating a collection of ribosomal protein, mitochondrial, neural stem cell (NSC), and cancer metastasis genes - all essential for sustaining the high proliferation, migration, and therapeutic resistance of GSCs.

Identification of Plasma Proteins as Biomarkers for Mild Cognitive Impairment and Alzheimer's Disease Using Liquid Chromatography-Tandem Mass Spectrometry.

Blood proteins can be used for biomarkers to monitor the progression of cognitive decline, even in the early stages of disease. In this study, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based blood test to identify plasma proteins that can be used to detect mild cognitive impairment (MCI) and Alzheimer's disease (AD). Using this system, we quantified plasma proteins using isotope-labeled synthetic peptides. A total of 192 patients, including 63 with AD, 71 with MCI, and 58 non-demented controls (NDCs), were analyzed. Multinomial regression and receiver operating characteristic (ROC) analyses were performed to identify specific combinations of plasma protein panels that could differentiate among NDCs, those with MCI, and those with AD. We identified eight plasma protein biomarker candidates that can be used to distinguish between MCI and AD. These biomarkers were associated with coagulation pathways, innate immunity, lipid metabolism, and nutrition. The clinical potential to differentiate cognitive impairment from NDC was assessed using area under the curve values from ROC analysis, which yielded values of 0.83 for males and 0.71 for females. This LC-MS-based plasma protein panel allows the pathophysiology of AD to be followed through detection of cognitive decline and disease progression markers.

Inhaled nitric oxide testing in predicting prognosis in pulmonary hypertension due to left-sided heart diseases.

AIMS: The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. METHODS AND RESULTS: This was a single-centre, retrospective study with a median follow-up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. CONCLUSIONS: Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.

Prevention of fetal brain injury in category II tracings.

INTRODUCTION: With category II fetal heart rate tracings, the preferred timing of interventions to prevent fetal hypoxic brain damage while limiting operative interventions remains unclear. We aimed to estimate fetal extracellular base deficit (BDecf ) during labor with category II tracings to quantify the timing of potential interventions to prevent severe fetal metabolic acidemia. MATERIAL AND METHODS: A longitudinal study was conducted using the database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy, including infants with severe cerebral palsy born at ≥34 weeks' gestation between 2009 and 2014. Cases included those presumed to have an intrapartum onset of hypoxic-ischemic insult based on the fetal heart rate pattern evolution from reassuring to an abnormal pattern during delivery, in association with category II tracings marked by recurrent decelerations and an umbilical arterial BDecf ≥ 12 mEq/L. BDecf changes during labor were estimated based on stages of labor and the frequency/severity of fetal heart rate decelerations using the algorithm of Ross and Gala. The times from the onset of recurrent decelerations to BDecf 8 and 12 mEq/L (Decels-to-BD8, Decels-to-BD12) and to delivery were determined. Cases were divided into two groups (rapid and slow progression) based upon the rate of progression of acidosis from onset of decelerations to BDecf 12 mEq/L, determined by a finite-mixture model. RESULTS: The median Decels-to-BD8 (28 vs. 144 min, p < 0.01) and Decels-to-BD12 (46 vs. 177 min, p < 0.01) times were significantly shorter in the rapid vs slow progression. In rapid progression cases, physicians' decisions to deliver the fetus occurred at ~BDecf 8 mEq/L, whereas the "decisions" did not occur until BDecf reached 12 mEq/L in slow progression cases. CONCLUSIONS: Fetal BDecf reached 12 mEq/L within 1 h of recurrent fetal heart rate decelerations in the rapid progression group and within 3 h in the slow progression group. These findings suggest that cases with category II tracings marked by recurrent decelerations (i.e., slow progression) may benefit from operative intervention if persisting for longer than 2 h. In contrast, cases with sudden bradycardia (i.e., rapid progression) represent a challenge to prevent severe acidosis and hypoxic brain injury due to the limited time opportunity for emergent delivery.

A teenage boy with acute myocarditis and reversible microvascular angina: A case report.

A 17-year-old male was diagnosed with acute myocarditis based on the presence of CD3-positive T-lymphocytes in myocardial biopsy, normal coronary angiography, and focal increase in late gadolinium enhancement, T2 intensity and native T1 value. On day 2, the patient suffered from recurrence of chest pain with new ST segment elevations on electrocardiogram. A transient metabolic alteration (inversed lactate level of the coronary sinus relative to that of the coronary artery) accompanied by chest pain and electrocardiographic changes without epicardial coronary spasm in acetylcholine provocation test led to the diagnosis of microvascular angina, which is characterized by a transient myocardial ischemia secondary to a dysfunction of the resistance coronary vessels (<500 µm) that, because of their small size, are not visualized at coronary angiography. Benidipine, a dihydropyridine calcium channel antagonist, was started for chest pain due to microvascular angina. On 6 months after admission, when the findings of cardiac magnetic resonance were recovered, intracoronary infusion of acetylcholine did not induce chest pain, electrocardiographic changes, epicardial coronary spasm, and adverse changes of lactate levels of the coronary artery and sinus. The patient had no chest symptoms 2 years after discontinuation of benidipine. Learning objective: The present case of microvascular angina, which was complicated with acute myocarditis on acute phase and recovered in chronic phase, indicates an association of myocardial inflammation with reversible coronary microvascular dysfunction.

O-GalNAc glycosylation determines intracellular trafficking of APP and Aß production.

A primary pathology of Alzheimer's disease (AD) is amyloid ß (Aß) deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal Aß precursor protein (APP). Although vascular amyloid deposits' origins remain unclear, endothelial APP expression in APP knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APP's importance. Furthermore, two types of endothelial APP-highly O-glycosylated APP and hypo-O-glycosylated APP-have been biochemically identified, but only the former is cleaved for Aß production, indicating the critical relationship between APP O-glycosylation and processing. Here, we analyzed APP glycosylation and its intracellular trafficking in neurons and endothelial cells. Although protein glycosylation is generally believed to precede cell surface trafficking, which was true for neuronal APP, we unexpectedly observed that hypo-O-glycosylated APP is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires additional O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced Aß production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.

CD98 regulates the phosphorylation of HER2 and a bispecific anti-HER2/CD98 antibody inhibits the growth signal of human breast cancer cells.

Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be caused by cancer heterogeneity and persistent HER phosphorylation, often reduces overall therapeutic effects. We herein showed that a newly discovered molecular complex between CD98 and HER2 affected HER function and cancer cell growth. The immunoprecipitation of the HER2 or HER3 protein from lysates of SKBR3 breast cancer (BrCa) cells revealed the HER2-CD98 or HER3-CD98 complex. The knockdown of CD98 by small interfering RNAs inhibited the phosphorylation of HER2 in SKBR3 cells. A bispecific antibody (BsAb) that recognized the HER2 and CD98 proteins was constructed from a humanized anti-HER2 (SER4) IgG and an anti-CD98 (HBJ127) single chain variable fragment, and this BsAb significantly inhibited the cell growth of SKBR3 cells. Prior to the inhibition of AKT phosphorylation, BsAb inhibited the phosphorylation of HER2, however, significant inhibition of HER2 phosphorylation was not observed in anti-HER2 pertuzumab, trastuzumab, SER4 or anti-CD98 HBJ127 in SKBR3 cells. The dual targeting of HER2 and CD98 has potential as a new therapeutic strategy for BrCa.

Cystic fibrosis with multiple pulmonary arteriovenous malformations: A case report.

Cystic fibrosis is an autosomal recessive genetic disorder that damages the exocrine function of the body, resulting in alterations of multiple organs. In the respiratory system, it is known to cause bronchiectasis, recurrent bronchitis, and pneumonia; however, to the best of our knowledge, there are no reported cases of pulmonary arteriovenous malformations associated with this disease. Herein, we report a case of cystic fibrosis with multiple pulmonary arteriovenous malformations. A 16-year-old girl, who has been monitored since childhood for pancreatitis of unknown cause, experienced respiratory symptoms and hypoxemia (PaO2 = 57 mmHg). At 13 years of age, chest computed tomography revealed bronchiectasis, bronchial wall thickening, and tree-in-bud sign. Genetic testing was performed, and the patient was diagnosed with cystic fibrosis. However, the computed tomography scan also showed incidental nodular lesions in the left superior and both the inferior pulmonary lobes, suggesting multiple arteriovenous malformations. Dynamic computed tomography was performed which, confirmed the presence of 3 pulmonary arteriovenous malformations. Coil embolization was performed on all lesions, and the hypoxemia was corrected. Marked hypoxemia in a patient with cystic fibrosis may not be explained only by the presence of bronchiectasis and/or bronchial wall thickening; in such cases, it may be necessary to examine possible additional findings on computed tomography images, such as arteriovenous malformations.

Validation of eligibility criteria for the Japan Obstetric Compensation System for Cerebral Palsy in preterm infants: A case-control cohort study.

AIM: To verify validity of the criteria used for the Japan Obstetric Compensation System for Cerebral Palsy (JOCS-CP) in preterm infants, the association between the criteria and the development of CP was studied using a neonatal database. Our hypothesis was that the criteria would not be sufficient due to the recent advances made in perinatal care. METHODS: Preterm infants born between 2003 and 2019 and registered in the Neonatal Research Network of Japan database with a birth weight of 1500 g or less or a gestational age of less than 32 weeks were analyzed. The database included the clinical information of registered infants during their stay in NICUs and outcomes at 3 years of age. RESULTS: The database included 73 615 infants. After excluding those with an unknown outcome at discharge, 73 464 infants were analyzed for short-term outcomes, including mortality and morbidities. The incidence of CP at 3 years of age was analyzed in 36 151 infants. Furthermore, 16 467 infants born between 28 and 31 weeks of gestation were examined in terms of the validity of the current eligibility criteria. The mortality and incidences of severe intraventricular hemorrhage and periventricular leukomalacia significantly decreased during the study period (Cochrane-Armitage test, p < 0.01). Furthermore, the eligibility criteria were not sufficiently nor strongly associated with indicators for detecting perinatal hypoxia-ischemia resulting in CP. CONCLUSION: The existing eligibility criteria of the JOCS-CP used for preterm infants born between 28 and 31 weeks were no longer suitable because of the advances in perinatal care in Japan.

Adult-onset Leigh Syndrome with a m.9176T>C Mutation Manifested As Reversible Cerebral Vasoconstriction Syndrome.

A 26-year-old woman developed a sudden headache, ptosis, and diplopia. Magnetic resonance imaging and angiography demonstrated a symmetrical lesion from the midbrain to the brainstem, involving the solitary nucleus and multifocal cerebral artery narrowing. Reversible cerebral vasoconstriction syndrome (RCVS) was suspected, and the patient improved after vasodilatation. Leigh syndrome was suspected due to the elevated serum pyruvate level, so mitochondrial DNA was analyzed, and an m.9176T>C mutation was detected. The final diagnosis was adult-onset Leigh syndrome manifesting as RCVS. An uncontrolled baroreflex due to a solitary nuclear lesion or endothelial dysfunction may have contributed to her unique presentation.

TRPA1/M8 agonists upregulate ciliary beating through the pannexin-1 channel in the human nasal mucosa.

BACKGROUND: Nasal breathing is important for maintaining physiological respiration. However, airflow in the nasal cavity has an inherent cooling effect and may suppress ciliary beating, an essential frontline defense in the airway. Nasal airflow is thought to be perceived by thermoreceptors for cool temperatures. We herein investigated the effect of the activation of thermosensitive transient receptor potentials (TRPs) for cool/cold temperatures on ciliary beating to search for a compensatory mechanism. METHODS: Inferior turbinates were collected from patients with chronic hypertrophic rhinitis. Ex vivo ciliary beat frequency (CBF) and ATP release were measured using a high-speed digital video camera and by luciferin-luciferase assay, respectively. Intracellular Ca2+ ([Ca2+]i) imaging of isolated ciliated cells was performed using Fluo-8. The nasal mucosae were also subjected to fluorescence immunohistochemistry and real-time RT-PCR for TRPA1/TRPM8. RESULTS: CBF was significantly increased by adding either cinnamaldehyde (TRPA1 agonist) or l-menthol (TRPM8 agonist). This increase was inhibited by pannexin-1 blockers, carbenoxolone and probenecid. Cinnamaldehyde and l-menthol also increased the ATP release from the nasal mucosa and [Ca2+]i of isolated ciliated cells. Immunohistochemistry detected TRPA1 and TRPM8 on the epithelial surface including the cilia and in the submucosal nasal glands. Existence of these receptors were confirmed at the transcriptional level by real-time RT-PCR. CONCLUSIONS: These results indicate the stimulatory effect of the activation of TRPA1/TRPM8 on ciliary beating in the nasal mucosa, which would be advantageous to maintain airway mucosal defense against the fall of temperature under normal nasal breathing. This stimulatory effect is likely to be mediated by pannexin-1.

Duration of antimicrobial therapy after video-assisted thoracoscopic surgery for thoracic empyema and complicated parapneumonic effusion: A single-center study.

BACKGROUND: There are no evidence-based reports on the proper duration of antimicrobial therapy following video-assisted thoracoscopic surgery debridement (VATS-D) in thoracic empyema (TE) or complicated parapneumonic effusion (PPE). This study aimed to investigate the optimal duration of antimicrobial therapy after VATS-D. METHODS: Between January 2011 and December 2019, 33 patients corresponding to American College of Chest Physicians (ACCP) category 3 or 4 undergoing VATS-D were included. The times until the body temperature (BT) was confirmed to be less than 37.5 °C and 37.0 °C, white blood cell count (WBC) less than 10,000/µl, segmented neutrophils (seg) less than 80%, and C-reactive protein (CRP) level less than 25% of the preoperative value were retrospectively analyzed. RESULTS: The median time from the onset of TE/PPE to surgery was 13 days. The median durations of preoperative and postoperative antibiotic use were five and seven days, respectively. Major complications occurred in four cases (three and one cases of respiratory failure and cerebral infarction, respectively). The median postoperative hospital stay was 14 days. Recurrence or progression to chronic empyema was seen in four cases. The median numbers of days until the conditions were met were three days for BT < 37.5 °C, six days for BT < 37.0 °C, four days for WBC<10,000, seven days for seg<80% and seven days for CRP<25%. CONCLUSIONS: The proper duration of antimicrobial therapy after VATS-D for TE/PPE is approximately three to seven days. Urgent VATS-D may shorten the total antibiotic usage.