Efficacy of dotinurad in patients with severe renal dysfunction.

BACKGROUND: Although hyperuricemia is associated with the progression of chronic kidney disease (CKD), a reduction in CKD progression by uric acid (UA)-lowering therapy has been controversial. Recently, dotinurad, a uricosuric drug with selective urate reabsorption inhibitory properties, has been developed. However, its efficacy in lowering serum UA levels and its effects on renal function in patients with severe renal dysfunction are unclear. Thus, this study aimed to determine the effects of dotinurad on renal function in patients with severe renal dysfunction. METHODS: Data from 53 outpatients with hyperuricemia who newly received dotinurad between December 2020 and October 2022 were retrospectively analyzed. The mean baseline estimated glomerular filtration rate (eGFR) was 38.7 ± 17.0 mL/min/1.73 m2. The patients were divided into three groups based on their baseline eGFR: eGFR < 30 (n = 17), 30 ≤ eGFR < 45 (n = 17), and eGFR ≥ 45 (n = 19). RESULTS: The mean follow-up period was 9.8 ± 4.5 (range, 3-21) months. Serum UA levels significantly decreased in all groups. Although eGFR did not significantly change in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45 (P = 0.918 and P = 0.535, respectively), it improved significantly in patients with eGFR < 30 (P = 0.032). The proportion of patients with improved eGFR was significantly higher in patients with eGFR < 30 (P = 0.038) than in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45. In the multivariate logistic regression analysis, baseline eGFR < 30 and achieving a serum UA level of ≤ 6.0 mg/dL were significantly associated with improved eGFR (P = 0.033 and P = 0.015, respectively). CONCLUSIONS: Dotinurad may have UA-lowering effects and the potential to improve kidney function in patients with severe renal dysfunction.

Electrophysiological and Histopathological Characteristics of Ventricular Tachycardia Associated With Primary Cardiac Tumors.

BACKGROUND: Ventricular tachycardia (VT) associated with primary cardiac tumors (PCTs) originating from the ventricles is rare, but lethal, in young patients. OBJECTIVES: This study aimed to clarify the mechanisms underlying primary cardiac tumor-related ventricular tachycardia (PCT-VT) and establish a therapeutic strategy for this form of VT. METHODS: Among 67 patients who underwent surgery for VT at our institute between 1981 and 2020, 4 patients aged 1 to 34 years, including 3 males, showed PCT-VT (fibroma, 2; lipoma, 1; and hamartoma, 1), which was investigated using a combination of intraoperative electroanatomical mapping and histopathological studies. RESULTS: All 4 patients developed electrical storms of sustained VTs refractory to multiple drugs and repetitive endocardial ablations. The VT mechanism was re-entry, and intraoperative electroanatomical mapping showed a centrifugal activation pattern originating from the border between the tumor and healthy myocardium, where fractionated potentials were detected during sinus rhythm. Histopathological studies of serial sections of specimens acquired from these areas revealed tumor infiltration into the surrounding myocardium with cell disorganization, exhibiting myocardial disarray. Several myocardia entrapped in the tumor edges contributed to the development and sustainment of re-entrant VT activation. In the 2 patients in whom complete resection was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing VT occurrence. CONCLUSIONS: The mechanism underlying PCT-VT involves re-entry localized at the tumor edges. Myocardial disarray associated with tumor infiltration is a substrate for this form of VT. Cryoablation along the border between the tumor and myocardium is a promising therapeutic option for unresectable PCT-VT.

Comparisons of Patients Living Alone versus Living with Others in Acute Coronary Syndrome.

We aimed to examine the relationship of living arrangements (i.e., living alone or living with others) with background, clinical severity, preintervention culprit lesion plaque morphology, and clinical outcomes in patients with acute coronary syndrome (ACS). Among 1,683 consecutive patients with ACS, we retrospectively compared patients living alone ( n = 318) versus living with others ( n = 1,362). Optical coherence tomography (OCT) findings, which are high-resolution intracoronary imaging devices, were analyzed in patients with preintervention OCT and compared between patients living alone ( n = 174) versus those living with others ( n = 665). Older (median; 69 vs. 67 y, p = 0.046) and female (31 vs. 17%, p < 0.001) patients more frequently lived alone. Frequency of achieving a time interval of 6 hours or less from ACS onset to admission was lower in patients living alone (56 vs. 63%, p = 0.022). Clinical presentation was more severe in patients living alone (Killip II/III/IV; 27 vs. 22%, p = 0.029). Plaque morphology evaluated by OCT was similar between groups (plaque rapture; 48 vs. 48%, p = 0.171). Kaplan-Meier analyses revealed higher rates of cardiac mortality during 2-year follow-up period in patients living alone [13.9 vs. 8.5%, hazard ratio (HR) 1.604, 95% confidence interval (CI) 1.112-2.313, p = 0.010]. After traditional cardiovascular risk factors and clinical severity upon admission had been adjusted, living alone was an independent predictor of cardiac mortality in ACS patients (HR 1.582, 95% CI 1.056-2.371, p = 0.026). Living alone was independently associated with 2-year cardiacmortality in ACS patients after adjusting for background and presentation and might be unrelated to the development of atherosclerosis.

Excitatory amino acids, possible causative agents of nodding syndrome in eastern Africa.

BACKGROUND: Nodding syndrome (NS) is one type of epilepsy and a progressive disease characterized by nodding symptoms with children in sub-Saharan Africa. The burden for NS children is heavy, not only mentally but financially for themselves and their families, and yet, the cause and cure of NS remain unknown. The kainic acid-induced model in experimental animals is a well-known epilepsy model that is useful for studying human diseases. In this study, we examined similarities of clinical symptoms and histological brain changes between NS patients and kainic acid-treated rats. In addition, we argued for kainic acid agonist as one of the causes of NS. METHODS: Clinical signs in rats were studied after kainic acid administration, and histological lesions including the expression of tau protein and gliosis, were examined at 24 h, 8 days, and 28 days after dosing. RESULTS: Kainic acid-induced epileptic symptoms were observed in rats, including nodding accompanied by drooling and bilateral neuronal cell death in the hippocampus and piriform cortex regions. In the regions that exhibited neuronal cell death, an increase in tau protein expression and gliosis were found immunohistochemically. The symptoms and brain histology were similar in the NS and kainic acid-induced rat models. CONCLUSION: The results suggest that kainic acid agonist may be one of the causative substances for NS.

Early recurrence of attack after myocardial infarction with non-obstructive coronary arteries: a case report.

Background: Diagnostic strategies depend on non-standardized workup, and the causes of myocardial infarction with non-obstructive coronary arteries remain unclear for some patients. Intracoronary imaging is recommended for detecting the missed causes by coronary angiography. Myocardial infarction with non-obstructive coronary arteries is a heterogeneous entity; a meta-analysis of myocardial infarction with non-obstructive coronary artery studies demonstrated that all-cause mortality rate at 1 year is 4.7%, and its prognosis is not so favourable. Case summary: A 62-year-old man without remarkable medical history complained of acute chest pain at rest, which resolved at his arrival. Although echocardiography and electrocardiogram exhibited normal findings, the concentration of high-sensitive cardiac troponin T increased up to 0.384 from 0.04 ng/mL. Coronary angiography was performed, and mild stenosis of the proximal right coronary artery was detected. He was discharged without catheter intervention and medications as he reported no symptoms. He returned 8 days later because of inferoposterior ST-segment elevation myocardial infarction with ventricular fibrillation. Emergent coronary angiography showed that the mild stenosis of the proximal right coronary artery had progressed to total occlusion. Optical coherence tomography after thrombectomy revealed rupture of the thin-cap fibroatheroma and protruding thrombus. Discussion: Patients presenting with myocardial infarction with non-obstructive coronary arteries and plaque disruption and/or thrombus detected by optical coherence tomography do not show normal coronaries on coronary angiography. Aggressive investigation into plaque disruption using intracoronary imaging is recommended even if coronary angiography demonstrates mild stenosis to prevent a fatal attack for suspicious cases of myocardial infarction with non-obstructive coronary arteries.

Identification of Membrane-expressed CAPRIN-1 as a Novel and Universal Cancer Target, and Generation of a Therapeutic Anti-CAPRIN-1 Antibody TRK-950.

Specific targets for cancer treatment are highly desirable, but still remain to be discovered. While previous reports suggested that CAPRIN-1 localizes in the cytoplasm, here we now show that part of this molecule is strongly expressed on the cell membrane surface in most solid cancers, but not normal tissues. Notably, the membrane expression of CAPRIN-1 extended to the subset of highly tumorigenic cancer stem cells and epithelial-mesenchymal transition (EMT)-induced metastatic cancer cells. In addition, we revealed that cancer cells with particularly high CAPRIN-1 surface expression exhibited enhanced tumorigenicity. We generated a therapeutic humanized anti-CAPRIN-1 antibody (TRK-950), which strongly and specifically binds to various cancer cells and shows antitumor effects via engagement of immune cells. TRK-950 was further developed as a new cancer drug and a series of preclinical studies demonstrates its therapeutic potency in tumor-bearing mouse models and safety in a relevant cynomolgus monkey model. Together, our data demonstrate that CAPRIN-1 is a novel and universal target for cancer therapies. A phase I clinical study of TRK-950 has been completed (NCT02990481) and a phase Ib study (combination with approved drugs) is currently underway (NCT03872947) in the United States and France. In parallel, a phase I study in Japan is in progress as well (NCT05423262). Significance: Antibody-based cancer therapies have been demonstrated to be effective, but are only approved for a limited number of targets, because the majority of these markers is shared with healthy tissue, which may result in adverse effects. Here, we have successfully identified CAPRIN-1 as a novel truly cancer-specific target, universally expressed on membranes of various cancer cells including cancer stem cells. Clinical studies are underway for the anti-CAPRIN-1 therapeutic antibody TRK-950.

Practical guide for safe sedation.

This practical guide has been developed to ensure safe and effective sedation performed in adult patients outside of the operating room, for instance in intensive care units and dental treatment rooms and in the field of palliative care. Sedation levels are classified based on level of consciousness, airway reflex, spontaneous ventilation, and cardiovascular function. Deep sedation induces loss of consciousness and protective reflexes, and can cause respiratory depression and pulmonary aspiration. Invasive medical procedures necessitating deep sedation include cardiac ablation, endoscopic submucosal dissection, and internal radiation therapy. Appropriate analgesia is necessary for procedures that require deep sedation. The sedationist should evaluate the risks of the planned procedure, explain the sedation process to the patient, and obtain the patient's informed consent. Major parameters to be evaluated preoperatively are the patient's airway and general condition. Equipment, instruments, and drugs necessary for emergency situations should be defined and routinely maintained. To prevent aspiration, patients scheduled for moderate or deep sedation should fast preoperatively. In both inpatients and outpatients, biological monitoring should be continued until the discharge criteria are met. Anesthesiologists should be involved in management systems that ensure safe and effective sedation even if they do not personally perform all sedation procedures.

Last Entrainment Sequence: A Novel Diagnostic Technique for Atrial Tachycardia Mimicking Other Supraventricular Tachycardias.

BACKGROUND: Adenosine-sensitive re-entrant atrial tachycardia (AT) originating from near the atrioventricular (AV) node or AV annulus resembles other supraventricular tachycardias (SVTs), and the differential diagnosis is sometimes challenging. OBJECTIVES: This study sought to develop a novel technique to distinguish adenosine-sensitive re-entrant AT from AV nodal re-entrant tachycardia (AVNRT) and orthodromic reciprocating tachycardia (ORT). METHODS: The study retrospectively studied 117 re-entrant SVTs that were successfully entrained by atrial overdrive pacing (AOP) (27 adenosine-sensitive re-entrant ATs, 63 AVNRTs, 27 ORTs). If the second atrial electrogram after AOP (A2) at the earliest atrial activation site (EAAS) accelerated to the pacing cycle length, the EAAS was considered orthodromically activated. Then, we compared the sequence of A2 and the last entrained His bundle (H∗) and QRS complex (V∗). The study hypothesized that the last entrained impulse would activate the EAAS before it enters the AV node, His bundle, and ventricle during AT (A2-H∗-V∗) but would activate the EAAS after the His bundle activation during AVNRT and ORT (H∗-V∗-A2 or H∗-A2-V∗). RESULTS: Orthodromic EAAS activation was documented during AOP in 84 SVTs (72%) when performing AOP from sites proximal to the entrance of SVTs. A2-H∗-V∗ responses were observed in 21 of 25 ATs, but were never for AVNRTs or ORTs. All ORTs and fast-slow AVNRTs had H∗-V∗-A2 responses. Eleven of 21 slow-fast AVNRTs had H∗-A2-V∗ responses. The sensitivity, specificity, and positive and negative predictive values of the A2-H∗-V∗ response for diagnosing AT were 84%, 100%, 100%, and 94%, respectively. CONCLUSIONS: The last entrainment sequence was useful for differentiating ATs with diagnostic difficulties.

HotBalloon Pulmonary Vein Isolation Registry Study　- Real-World Efficacy and Safety of HotBalloon Ablation.

BACKGROUND: Radiofrequency hotballoon (RHB) is an ablation device used for atrial fibrillation (AF) treatment. The efficacy and safety of RHB-based pulmonary vein isolation (PVI) in real-world practice are unknown.Methods and Results: A multicenter, prospective registry study (UMIN000029567) enrolled AF patients who underwent RHB-PVI. The primary endpoint was the AF recurrence-free survival rate at 12 months after PVI. Of the 679 patients enrolled, 613 (90.3%; paroxysmal AF, n=370; persistent AF, n=136; long-standing AF, n=107) underwent initial RHB-PVI. Acute isolation using only the RHB was successful for 55.6% of patients and 83.5% of pulmonary veins (PVs). The acute isolation rate was higher for patients with paroxysmal AF and more experienced centers. Antiarrhythmic drugs were prescribed after 3 months for 47.5% of patients. The AF recurrence-free survival rate at 12 months was 83.7%. Procedure-related complications including atrio-esophageal fistula (n=1) and phrenic nerve injury (persistent; n=4, permanent; n=2) were observed in 19 (3.1%) patients. Five (1.7%) of the 302 patients who underwent pre-procedural and post-procedural multidetector computed tomography had severe PV stenosis. CONCLUSIONS: The size-adjustable RHB has been used for the treatment of various AF types. The arrhythmia recurrence-free rate at 12 months, with the use of antiarrhythmic drugs in approximately half of the patients, was acceptable, but the acute isolation rate using the RHB requires further improvement.

Indocyanine green conjugated phototheranostic nanoparticle for photodiagnosis and photodynamic therapy.

BACKGROUND: Phototheranostics represents a highly promising paradigm for cancer therapy, although selecting an appropriate optical imager and sensitizer for clinical use remains challenging. METHODS: Liposomally formulated phospholipid-conjugated indocyanine green, denoted as LP-iDOPE, was developed as phototheranostic nanoparticle and its cancer imaging-mediated photodynamic reaction, defined as the immune response induced by photodynamic and photothermal effects, was evaluated with a near-infrared (NIR)-light emitting diode (LED) light irradiator. RESULTS: Using in vivo NIR fluorescence imaging, we demonstrated that LP-iDOPE was selectively delivered to tumor sites with high accumulation and a long half-life. Following low-intensity NIR-LED light irradiation on the tumor region of LP-iDOPE accumulated, effector CD8+ T cells were activated at the secondary lymphoid organs, migrated, and subsequently released cytokines including interferon-γ and tumor necrosis factor-α, resulting in effective tumor regression. CONCLUSIONS: Our anti-cancer strategy based on tumor-specific LP-iDOPE accumulation and low-intensity NIR-LED light irradiation to the tumor regions, i.e., photodynamic reaction, represents a promising approach to noninvasive cancer therapy.

Efficacy of electrical isolation of the left atrial posterior wall depends on the existence of left atrial low-voltage zone in patients with persistent atrial fibrillation.

BACKGROUND: Modification of the low-voltage zone in the left atrium (LA-LVZ) in addition to pulmonary vein isolation (PVI) has not shown sufficient improvement in arrhythmia-free survival in patients with persistent atrial fibrillation (PerAF). Further, the effect of electrical posterior wall isolation (PWI) is controversial. We investigated the impact of existence of LA-LVZ on the outcome of patients undergoing additional PWI for PerAF. METHODS: A total of 347 patients with PerAF who underwent primary catheter ablation with LA-LVZ based strategy were retrospectively analyzed. Voltage mapping in the left atrium (LA) was performed during sinus rhythm. Additional LVZ ablation was performed in patients with LA-LVZ. The operators decided whether additional PWIs were to be performed. RESULTS: Of 347 patients, 108 had LA-LVZ. In the LVZ group, patients with additional PWI (N = 70) had higher rates of freedom from tachyarrhythmia recurrence than those without (77.1% vs. 42.1%, p < 0.001). Furthermore, even when patients were limited to those with LA-LVZ in areas other than the posterior wall (N = 85), PWI had higher success rates (80.9% vs. 42.1%, p < 0.001). In contrast, in patients without LVZ (N = 239), there was no significant difference in the rate of successful outcome between those with and without PWI (81.3% vs. 88.1%, p = 0.112). On the other hand, the patients with PWI had greater atrial tachycardia (AT) recurrence rate than those without PWI (10.0% vs. 2.5%, p = 0.003). CONCLUSIONS: PWI, in addition to PVI and LVZ modification, may improve single procedural outcomes in patients with PerAF who have LVZ, regardless of the distribution in the LA. A combination of voltage-guided ablation and PWI may be a simple, tailored, and effective ablation strategy.

Device for retrieval of vena cava filter with combination of a multi-loop snare and Amplatz catheter.

A 25-year-old woman diagnosed as having a non-massive pulmonary embolism and deep vein thrombosis from the right superficial femoral to the right common iliac vein was treated by deployment of a DENALI® Vena Cava Filter. Filter retrieval was attempted 6 months later using a BARD snare retrieval kit. However, the conventional technique was unsuccessful because of a tilt and attachment of the filter head to the vessel wall. Hence, we passed an EN Snare Endovascular Snare System through an Amplatz Left 1 guiding catheter to successfully penetrate the attached portion of the filter hook and vessel wall. This combination provided controlled direction and a strong backup force that helped capture and retrieve the filter. This technique could be an alternative method to retrieve inferior vena cava filter with severe tilt and tight attachment to the vena cava wall when the conventional technique is unsuccessful.

Distal type of nodo-ventricular pathway: Unique electrophysiological characteristics mimicking fasciculo-ventricular pathway.

Fasciculo-ventricular and nodo-ventricular pathways (FVP and NVP) are rare preexcitation variants. Normally, NVP is electrophysiologically different from FVP. We describe a unique type of NVP emerging from the distal part of the slow pathway, designated as "distal type" NVP. The distal type NVP resembled FVP but was proven by unexpected elimination of the NVP during the slow pathway ablation. Also, NVP was distinguishable from FVP by a careful comparison of the HV intervals during conduction over the fast and slow pathways. Demonstration of this novel type NVP provides insights into how the insertion site of NVP affects its electrophysiologic behaviors.

Helicopter emergency medical service for patients with acute coronary syndrome: selection validity and impact on clinical outcomes.

Helicopter emergency medical service (HEMS) has the potential to improve prognosis for acute coronary syndrome (ACS). However, adequacy and effectiveness of HEMS have not been fully evaluated. A total of 862 ACS patients transferred by emergency medical services were divided into two groups: patients transferred by HEMS (n = 171) or by ground ambulance (GA; n = 691). Among them, angiography images for 718 patients (149 in HEMS and 569 in GA group) and optical coherence tomography (OCT) images for 374 patients (75 in HEMS and 299 in GA groups) were analyzed. Additional analysis to compare 2-year cardiac mortality between groups was conducted following propensity score matching to adjust for inter-group differences. ST-segment elevation myocardial infarction (81% vs. 66%, p < 0.001) and cardiogenic shock (Killip IV; 20% vs. 10%, p < 0.001) at admission were more prevalent in HEMS than GA group. Time from admission to balloon angioplasty was shorter in HEMS group (median 54 min vs. 69 min, p < 0.001). Antegrade coronary flow was worse in HEMS group (TIMI flow grade 0 or 1; 68% vs. 51%, p < 0.001). Plaque rupture was more frequently detected by OCT in HEMS group (68% vs. 49%, p = 0.029). Following propensity score matching, the incidence of cardiac death was significantly lower in HEMS group (6.3% vs. 14.9%, p = 0.019). In conclusion, severe ACS patients requiring early reperfusion were appropriately triaged and transferred more rapidly by HEMS. Lower mortality in HEMS group after propensity score matching suggests that HEMS may improve cardiac mortality in ACS patients.

Use of the Japanese Version of the Montreal Cognitive Assessment to Estimate Cognitive Decline in Patients Aged 75 Years or Older with and without Type 2 Diabetes Mellitus.

BACKGROUND: The number of people diagnosed with dementia worldwide is set to increase significantly. Patients with dementia often have comorbidities, particularly diabetes, and patients with type 2 diabetes mellitus (T2DM) have a high risk of cognitive decline. This study investigated whether older people with T2DM have disease-specific cognitive deficits. METHODS: The Montreal Cognitive Assessment is a well-known tool for examining mild cognitive impairment, and the modified Japanese version (MoCA-J) has been confirmed as effective. Using the MoCA-J, we assessed the cognitive function of Japanese adults aged ≥75 years with and without T2DM and analyzed the results. RESULTS: Thirty-three patients with T2DM and 23 non-DM patients completed the examination, and MoCA-J total scores differed between these groups (T2DM mean, 21.4 ± 3.5; non-DM mean, 23.5 ± 3.6). Only 9% of patients with T2DM and 39% of those with non-DM had scores ≥26, which is the cutoff point for mild cognitive impairment, although all patients were capable of self-care. Additionally, delayed recall scores were significantly lower for the older patients with T2DM had for the non-DM group. CONCLUSIONS: Patients aged ≥75 years with T2DM might have worse cognition than those without T2DM; the inability to perform delayed recall in T2DM patients suggests a decline in cognitive function. Therefore, patients aged ≥75 years with T2DM should receive explanations of their care that are individualized in relation to their cognitive status.

Characteristics of patients with atrial flutter and spontaneous 1:1 atrioventricular conduction with and without anti-arrhythmic drug treatment.

Atrial flutter (AFL) is a large reentrant circuit located in the right atrium. Anti-arrhythmic drugs (AADs) can provoke AFL with 1:1 atrioventricular conduction (AVC) to cause hemodynamic collapse. We elucidated the characteristics of patients with AFL exhibiting spontaneous 1:1 AVC. Fifteen patients (1:1 AFL group; 11 males, 52.4 ± 13.7 years old) who documented AFL with 1:1 AVC were enrolled and compared to 153 patients without 1:1 AVC (Control group; 137 males, 68.9 ± 11.2 years old). AFL cycle length during maximum AVC was significantly longer in the 1:1 AFL group than in the control group (274.7 ± 37.0 vs. 216.2 ± 25.6 ms, p < 0.001). Among 1:1 AVC group, 9 patients had AADs, and AFL cycle length was significantly longer during 1:1 AVC as compared with 2:1 AVC documented the other day (284.4 ± 41.3 vs. 233.3 ± 26.0 ms, p < 0.001), suggesting enhancement effect of the AADs during 1:1 AVC. Remaining 6 patients who did not take AADs, 2 patients showed enlargement of the tricuspid annulus and 3 patients developed 1:1 AVC during exercise. Multivariate analysis revealed that younger age and the use of AADs was independent risk factors for the development of 1:1 AFL group. Prolonged AFL cycle length associated with the class Ia/Ic AAD use, slower heart rate during sinus rhythm and younger age were important risk factors for the development of 1:1 AVC during AFL.