How Electrical Storms Recur Over Time in Patients With Implantable Cardioverter Defibrillators　- Subanalysis of the Nippon Storm Study.

BACKGROUND: Electrical storms (E-storms), defined as multiple fatal ventricular arrhythmias over a short period, negatively affect the prognosis of patients receiving an implantable cardioverter defibrillator or cardiac resynchronization therapy with a defibrillator (ICD/CRT-D). However, the prognostic impact of recurrent E-storms has not been well elucidated. METHODS AND RESULTS: We analyzed the association between E-storm recurrences and mortality using data from 1,274 participants in the Nippon Storm Study, a prospective observational study conducted at 48 ICD/CRT-D centers in Japan. Differences in E-storm recurrences by patient characteristics were evaluated using the mean cumulative function (MCF), which is the cumulative number of E-storm episodes per patient as a function of time. Patients with multiple E-storms had a 3.39-fold higher mortality risk than those without E-storms (95% confidence interval 1.82-6.28; P<0.01). However, there was no significant difference in mortality risk between patients with a single E-storm and those without E-storms. The MCF curve exhibited a slower ascent in patients who received primary prevention ICD/CRT-D than in those who received secondary prevention ICD/CRT-D. However, when analyzing only patients with E-storms, the MCF curves demonstrated comparable trajectories in both groups. CONCLUSIONS: E-storm recurrences may have a negative impact on prognosis. Once patients with primary prevention experience an E-storm episode, they face a similar risk of subsequent recurrent E-storms as patients with secondary prevention.

Effectiveness and feasibility of selective intra-arterial low dose of cisplatin infusion and concomitant radiotherapy for patients with advanced laryngeal cancer with impaired renal function: A retrospective cohort study.

BACKGROUND: Chemoradiation therapy with high-dose cisplatin is the standard regimen against advanced squamous cell carcinoma of the larynx (SCC-L). However, patients with renal dysfunction are ineligible for this regimen. We investigated the effectiveness and feasibility of selective intra-arterial low-dose cisplatin infusion and radiotherapy (modified [m]-RADPLAT) for patients with impaired renal function. METHODS: We retrospectively reviewed the data of 77 patients with SCC-L who received m-RADPLAT. RESULTS: Fourteen and 63 patients had creatinine clearance (CrCl) values of 30 ≤ CrCl < 60 mL/min and ≥60 mL/min, respectively. The m-RADPLAT regimen led to no significant changes in serum creatinine or CrCl values post-treatment. The 5-year local control, overall survival, and laryngectomy-free survival rates of the CrCl < 60 and ≥60 groups were 90.0% and 90.5%, 100% and 81.8%, and 100% and 79.0%, respectively. Grade 3 or higher toxicity rates were not significantly different between the groups. CONCLUSIONS: The m-RADPLAT regimen yielded favorable survival rates and clinical outcomes in patients with impaired renal function.

Impact of frailty in patients with non-valvular atrial fibrillation undergoing catheter ablation.

Background: The relationships between frailty and clinical outcomes in elderly Japanese patients with non-valvular atrial fibrillation (NVAF) after catheter ablation (CA) have not been established. We evaluated the frailty rate of patients undergoing CA for NVAF, examined whether CA for NVAF improves frailty, and analyzed the CA outcomes of patients with and without frailty. Methods: Elderly Japanese patients (≥65 years; mean age: 72.8 years) who participated in the real-world ablation therapy with anti-coagulants in management of atrial fibrillation registry and who responded to the frailty screening index survey were included (n = 213). Frailty and AF recurrence were assessed preoperatively and at 3 and 6 months after CA. Results: Twenty-six patients (12.8%) were frail, 109 (53.7%) were pre-frail, and 68 (33.5%) were robust. Cardiovascular (frailty: 0.5%/person-year; pre-frailty: 0.1%/person-year; robust: 0.1%/person-year) and cardiac (frailty: 0.5%/person-year; pre-frailty: 0.1%/person-year; robust: 0.1%/person-year) events, as well as major bleeding (frailty: 0.3%/person-year; pre-frailty: 0.1%/person-year; robust: 0.1%/person-year), were numerically more frequent in the frailty group. No deaths from cardiovascular or stroke/systemic thromboembolic events occurred. A large proportion of patients did not experience 3-month (frailty: 96.2%; pre-frailty: 96.3%; robust: 88.2%) or 6-month (frailty: 88.5%; pre-frailty: 91.7%; robust: 86.8%) AF recurrence after CA. Weight loss, walking speed, and fatigue improved in the frailty and pre-frailty groups after CA. Conclusion: Japanese patients aged ≥65 years with frailty or pre-frailty had improved frailty screening index components, such as weight loss, walking speed and fatigue, after CA. Therefore, elderly patients with frailty or pre-frailty may benefit from CA for NVAF.

Relationship between Swallowing Pressure and Saliva Residue on Endoscopic Evaluation in Pharyngeal Dysphagia.

OBJECTIVE: In pharyngeal dysphagia, poor pharyngeal contraction and upper esophageal sphincter (UES) dysfunction result in post-swallow saliva residue (SR). This study aimed to clarify the relationship between swallowing pressure and SR in the valleculae and piriform sinuses on flexible endoscopic evaluation of swallowing (FEES). METHODS: Pharyngeal dysphagia patients with Wallenberg syndrome were included. Amounts of post-swallow SR in the valleculae and piriform sinuses were classified into four grades using SR scores based on FEES. The Hyodo score was also calculated to evaluate swallowing function. High-resolution manometric data in the nasopharyngeal, oropharyngeal, hypopharyngeal, oro-hypopharyngeal, and UES zones on swallowing were obtained for comparison with SR and Hyodo scores. RESULTS: Of the 31 recruited, data from 26 patients who successfully underwent FEES and manometry were analyzed. Vallecular SR scores were strongly negatively correlated with a maximum pressure of the oropharynx (r = -0.52, p = 0.006), distal contractile integrals (DCI) of the oropharynx (r = -0.52, p = 0.007), and DCI of the oro-hypopharynx (r = -0.55, p = 0.004). Hyodo scores for parameters 1 and 4 (corresponding to salivary pooling and pharyngeal clearance, respectively) were strongly negatively correlated with a maximum hypopharyngeal pressure (r = -0.57, p = 0.002) and strongly positively correlated with peristaltic velocity (r = 0.53, p = 0.007), respectively. SR scores and Hyodo scores related to SR were not correlated with pressure data of the UES. CONCLUSION: Manometric analysis of our SR scoring method using FEES revealed that a higher amount of SR in the valleculae, but not in the piriform sinuses, is associated with weaker pharyngeal pressure in pharyngeal dysphagia, especially at the oropharyngeal level. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3519-3526, 2024.

Changes in estimated glomerular filtration rate before and after the first visit for atrial fibrillation.

BACKGROUND: Although the development of atrial fibrillation (AF) and the progression of chronic kidney disease are known to be interrelated, it remains unclear when and how renal function changes during the clinical course of AF. METHODS: This study retrospectively enrolled 131 patients who were able to collect data on estimated glomerular filtration rate (eGFR) at least five times during the 500 days before and 500 days after the first visit (baseline) of new-onset AF, respectively. To investigate the temporal relationship between the development of AF and the beginning of worsening renal function (WRF), a piecewise regression model was applied to the eGFR time series data. The time point at which the slopes of the two regression lines changed (inflection -point), the slope before and after the inflection-point (ß1 and ß2, respectively), and the difference in slope (Δß) were estimated. The presence of WRF was defined as having the inflection-point at which both Δß and ß2 were < - 0.0083 mL/min/1.73 m2/day (corresponding to 3.03 mL/min/1.73 m2/year), and the corresponding the inflection-point was defined as the beginning of WRF. RESULTS: WRF was detected in 54 (41.2%) patients. The beginning of WRF were distributed at various times, but most frequently (23 of 54 patients) within 100 days before and after baseline. The presence of WRF was not associated with age, heart failure, or baseline eGFR, but was associated with positive ß1 (odds ratio 30.5, 95% confidence interval 11.1-83.9, P < 0.01). CONCLUSION: In nearly half of AF patients with WRF, the beginning of WRF was observed within a few months before or after the first visit for AF. Patients with a positive eGFR slope before the onset of AF are more likely to develop WRF after the onset of AF, suggesting that potential kidney damage may be underlying.

The risk of pocket infection or bloodstream infection following central venous port placement for the patients with Cetuximab therapy.

OBJECTIVE: Cetuximab is a molecular targeted drug that targets epithelial growth factor receptors. The skin toxicity of cetuximab arising from epithelial growth factor inhibition is well known. Some patients with cetuximab therapy decided to make central venous port during the long-term intravenous treatments. Therefore, the author hypothesized that cetuximab administration might increase the risk of central venous port-related infection due to damage to skin barrier function. The main aim of the present study was to investigate the relationship between cetuximab administration and central venous port-related infection. METHODS: A total of 83 patients had a central venous port placed from 2016 through 2021. We analyzed, retrospectively, the relationship between cetuximab therapy and the incidence of central venous port-related infection involving central line-associated bloodstream infection and pocket infection. Additionally, the risk factors of central venous port-related infection were examined in the population undergoing cetuximab therapy. RESULTS: In total populations (83 cases), central line-associated bloodstream infection happened in five patients (6%) and pocket infection happened in six patients (7%) after central venous port placement. In the cetuximab therapy group (45 cases), there were four patients with central line-associated bloodstream infection (9%) and six with pocket infection (13%). The pocket infection happened more frequently in the cetuximab group than the other group with significant differences. Additionally, in the cetuximab group, the patients who had an interval of less than seven days between central venous port placement and cetuximab dosing, or central venous port placement preceded by cetuximab dosing had more pocket infection with significant differences. CONCLUSION: Skin complications after the central venous port placement were related to cetuximab administration and the timing of cetuximab therapy.

Pathogenesis of Reinke's Edema of the Vocal Fold.

OBJECTIVES: The most frequent etiologic factor of Reinke's edema (RE) is considered to be smoking. However, the mechanism for the onset and development of the disease remains unclear. Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-dependent transcriptional activator which plays crucial roles in angiogenesis in hypoxic microenvironments. HIF-1α induces the expression of vascular endothelial growth factor (VEGF) which involves angiogenesis and enhances vascular permeability. This study investigated the roles of HIF-1α in the pathogenesis of RE. METHODS: Surgical specimens of RE from patients who underwent endolaryngeal microsurgery were used. Normal vocal folds were used as a control group. Expression of HIF-1α and VEGF was analyzed by immunohistochemistry. Three-dimensional fine structures of the vessels in RE were investigated using correlative light and electron microscopy (CLEM) technique. RESULTS: HIF-1α and VEGF were broadly expressed in the stromal, inflammatory, and endothelial cells in the lamina propria of the vocal fold of RE. The expression of HIF-1α and VEGF of RE were significantly higher than in the lamina propria of the normal vocal fold mucosa. CLEM showed vascularization and telangiectasia and there were many dilated capillaries with thin endothelium not covered with pericytes indicating the vessels were fragile. CONCLUSION: Transcription factor HIF-1α and induced VEGF likely play roles in the pathogenesis of RE. And increased vascular permeability with fragile vessels in angiogenesis is likely to be an etiology of RE. Transcription factor HIF-1α and induced VEGF are potential therapeutic targets for RE. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1785-1791, 2024.

Two-Year Outcomes of Primary Prophylactic Use of Defibrillators for Ischemic and Non-Ischemic Cardiomyopathy　- Propensity Score-Matched Analysis From the Nippon Storm Study.

BACKGROUND: In 2016, the DANISH study reported negative results regarding the efficacy of implantable cardioverter-defibrillators (ICDs) in patients with non-ischemic cardiomyopathy (NICM) and reduced left ventricular ejection fraction (LVEF). In this study we determined the efficacy of using ICDs for primary prophylaxis in patients with NICM.Methods and Results: We selected 1,274 patients with underlying cardiac disease who were enrolled in the Nippon Storm Study. We analyzed the data of 451 patients with LVEF ≤35% due to NICM or ischemic cardiomyopathy (ICM) who underwent ICD implantation for primary prophylaxis (men, 78%; age, 65±12 years; LVEF, 25±6.4%; cardiac resynchronization therapy, 73%; ICM, 33%). After propensity score matching, we compared the baseline covariates between groups: NICM (132 patients) and ICM (132 patients). The 2-year appropriate ICD therapy risks were 27.7% and 12.2% in the NICM and ICM groups, respectively (hazard ratio, 0.390 [95% confidence interval, 0.218-0.701]; P=0.002). CONCLUSIONS: This subanalysis of propensity score-matched patients from the Nippon Storm Study revealed that the risk of appropriate ICD therapy was significantly higher in patients with NICM than in those with ICM.

Glycolytic Metabolism of the Tissue Stem Cells in the Maculae Flavae of the Human Vocal Fold.

OBJECTIVES: Metabolic programs in the stem cells are essential for maintaining homeostasis and protecting against stem cell aging. There is growing evidence that the tissue stem cells reside in the anterior and posterior maculae flavae of the human vocal fold mucosa. Our previous studies observed that the glycolysis of the cell in the human maculae flavae seems to rely more on anaerobic glycolysis for energy supply in comparison with oxidative phosphorylation. However, previous studies showed only the metabolic enzymes of glycolysis and functional morphology of the mitochondria, therefore, it has not yet been determined whether anaerobic glycolysis actually took place. The purpose of this study is to investigate the glycolytic metabolites of the cells in the maculae flavae of the human vocal fold in vitro. METHODS: Four normal human vocal folds were used. After extraction of the anterior maculae flavae, cells in the maculae flavae were cultured and proliferated. Glucose transporter-1 was assessed using immunocytochemistry and metabolites of glycolysis (lactate and NADPH) were measured. RESULTS: The cells in the maculae flavae expressed glucose transporter-1 in the cytoplasm and the cell membranes. In addition, the cultured cells produced lactate (metabolites of anaerobic glycolysis) and NADPH (metabolites of the pentose phosphate pathway). CONCLUSIONS: The cells in the maculae flavae of the human vocal folds were found to undergo anaerobic glycolysis via the pentose phosphate pathway. This suggests that the cells in the maculae flavae of the human vocal fold have a metabolism that favors the maintenance of stemness and undifferentiated states.

A Case of Syphilis Suspected Preoperatively as a Case of Tongue Cancer.

Syphilis is a sexually transmitted disease caused by Treponema pallidum (TP). We report a case of syphilis that was initially suspected as tongue cancer. An 86-year-old man consulted a neighborhood clinic with an approximately one-month history of pain in the right tongue. The result of scraping cytology of the tongue performed at the clinic was classified as class V, squamous cell carcinoma, and the patient was referred to our hospital. Physical examination revealed a mass on the right side of the tongue and a firm cervical mass. Biopsy revealed no evidence of malignancy; however, the imaging findings led to the suspicion of tongue cancer and lymph node metastasis. The results of blood examination revealed that the patient had syphilis, but since the patient showed few other symptoms, we decided to treat the infection after the planned surgery. We performed right partial glossectomy and neck dissection; however, the postoperative histopathology revealed no evidence of malignancy but nonspecific inflammatory changes with TP spirochetes. The incidence of syphilis has increased dramatically around the world, including Japan, during the last 20 years, and it no longer remains a rare disease. Therefore, syphilis should be included in the differential diagnosis of oral or cervical masses.

A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice.

Facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies, is caused by an abnormal expression of the DUX4 gene in skeletal muscles, resulting in muscle weakness. In this study, we investigated MT-DUX4-ASO, a novel gapmer antisense oligonucleotide (ASO). MT-DUX4-ASO decreased the expression of DUX4 and its target genes in FSHD patient-derived myoblasts. For the first time, we demonstrated that a systemically administered ASO, even without a ligand for drug delivery, could significantly improve muscle injury and motor function in the ACTA1-MCM/FLExDUX4 (DUX4-TG) mouse model of FSHD. Tamoxifen (TMX) injection transiently induces skeletal-muscle-specific DUX4 expression in DUX4-TG mice, while the skeletal muscles of TMX-untreated DUX4-TG mice have leaky DUX4 expression in a small subset of myofibers similar to those of FSHD patients. Subcutaneous 10 mg/kg of MT-DUX4-ASO at two-week intervals significantly suppressed muscular DUX4 target gene expression, histological muscle injury, and blood muscle injury marker elevation in TMX-untreated DUX4-TG mice. Notably, MT-DUX4-ASO at 10 mg/kg every other week significantly prevented the TMX-induced declines in treadmill test running speed and muscle force in DUX4-TG mice. Thus, the systemically administered unconjugated MT-DUX4-ASO suppressed disease progression in DUX4-TG mice, extending the potential of unconjugated ASOs as a promising FSHD treatment strategy.

Use of Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death in Asia.

The effectiveness of primary prevention implantable cardioverter-defibrillators (ICDs) is well established. However, there are several unsolved problems related to ICD use for primary prevention in Asia, including ICD underuse, population differences in underlying heart disease, and the rate of appropriate ICD therapy compared with Western countries. Although the prevalence of ischemic cardiomyopathy in Asia is lower than in Europe and the United States, the mortality rate of Asian patients with ischemic heart disease has been increasing recently. As for the use of ICDs for primary prevention, there have been no randomized clinical trials, and limited data are available in Asia. This review focuses on the unmet needs related to ICD use for primary prevention in Asia.

Prognostic values of systemic inflammation and nutrition-based prognostic indices in oropharyngeal carcinoma.

Objective: Pretreatment systemic inflammation and nutrition-based prognostic indices (SINBPI) have demonstrated significance. This study investigated the prognostic value of pretreatment SINBPI for patients with oropharyngeal cancer and identified unfavorable prognostic markers. Methods: We retrospectively reviewed the data of 124 patients with oropharyngeal squamous cell carcinoma (OPSCC) who received definitive treatment between January 2010 and December 2018. The prognostic utility of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index, and high-sensitivity modified Glasgow prognostic score (HS-mGPS) was assessed for disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) using univariate and multivariate analyses. Results: Multivariate analyses revealed that human papillomavirus (HPV) status and HS-mGPS were significantly associated with DFS, DSS, and OS. Patients with a HS-mGPS of 2 had a significantly higher rate of treatment-related deaths than those with a HS-mGPS of 0 or 1. The combination of the HS-mGPS and PLR had more accurate predictive ability in DFS and OS compared with the HS-mGPS alone, and the combination of the HS-mGPS and LMR had more accurate predictive ability in DSS and OS. Conclusion: Our results indicated that the HS-mGPS was a useful prognostic marker for patients with OPSCC, and combined markers consisting of the HS-mGPS and PLR or LMR may provide more accurate prognostic predictions.Level of Evidence: 3.

A pitfall of cognitive bias during the pandemic: Two cases of Plasmodium falciparum malaria coinfected or misdiagnosed with COVID-19.

We report two the cases of patients with imported Plasmodium falciparum malaria during the COVID-19 pandemic. One was coinfected with COVID-19 and the other was misdiagnosed with COVID-19; either way, the diagnosis of malaria was delayed. These cases suggest that physicians should beware of cognitive biases during pandemics and carefully evaluate febrile patients. Malaria should be considered in any febrile patient returning from a malaria-endemic area.

Synthesis and properties of a novel modified nucleic acid, 2'-N-methanesulfonyl-2'-amino-locked nucleic acid.

2'-Amino-locked nucleic acid has a functionalizable nitrogen atom at the 2'-position of its furanose ring that can provide desired properties to a nucleic acid as a scaffold. In this study, we synthesized a novel nucleic acid, 2'-N-methanesulfonyl-2'-amino-locked nucleic acid (ALNA[Ms]) and conducted comparative studies on the physical and pharmacological properties of the ALNA[Ms] and on conventional nucleic acids, such as 2'-methylamino-LNA (ALNA[Me]), which is a classical 2'-amino-LNA derivative, and also on 2',4'-BNA/LNA (LNA). ALNA[Ms] oligomers exhibited binding affinities for the complementary RNA strand that are similar to those of conventional nucleic acids. Four types of ALNA[Ms] nucleosides exhibited no genotoxicity in bacterial reverse mutation assays. The knockdown abilities of Malat1 RNA using the Matat1 antisense oligonucleotide (ASO) containing ALNA[Ms] were higher than those of ALNA[Me] and were closer to those of LNA. Furthermore, the ASO containing ALNA[Ms] showed different tissue tropism from that containing LNA. ALNA[Ms] exhibited biological activities that were distinct from conventional constrained nucleic acids, suggesting the possibility that ALNA[Ms] can serve as novel modified nucleic acids in oligonucleotide therapeutics.

Clinical features of atlantoaxial involvement in patients with rheumatoid arthritis using 18F-fluorodeoxyglucose-positron emission tomography with computed tomography.

INTRODUCTION/OBJECTIVES: Cervical spine involvement is one of the most serious complications in rheumatoid arthritis (RA). The study aim was to assess the clinical significance of atlantoaxial (AA) joint involvement detected by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) with computed tomography (CT) in patients with RA. METHOD: A prospective cross-sectional study was conducted to evaluate AA joint involvement detected by FDG-PET/CT in consecutive RA patients from December 2017 to February 2022. We investigated the relationship between AA joint involvement and clinical data, including disease activity and patients' cervical symptoms. RESULTS: Among 48 patients enrolled, abnormal FDG uptake at AA joint was detected in 13 (27%). Rheumatoid factor titre, initial disease activity score 28-erythrocyte sedimentation rate and total standardized uptake value were significantly higher in the 13 patients than in the others (P = 0.004, P < 0.001 and P = 0.001, respectively). All patients with abnormal FDG uptake at AA joint had some cervical symptoms regardless of cervical spine X-ray abnormalities. Neck pain on movement and at rest were more frequent in the 13 patients than in the others (P = 0.001 and P = 0.004, respectively). The most sensitive symptom associated with AA joint involvement was neck pain on movement (sensitivity, 69%), and the most specific symptom was neck pain at rest (specificity, 100%). CONCLUSIONS: AA joint involvement was commonly observed by FDG-PET/CT in patients with active RA, independent of radiographic findings. Specific cervical symptoms can be important surrogate markers for detection of potential AA synovitis associated with active RA. Key Points • AA joint involvement was frequently seen in RA with high disease activity independent of radiographic findings. • Neck pain was a hallmark of AA joint involvement reflecting disease activity, and resting pain was highly specific.

Antitachycardia pacing success in implantable cardioverter-defibrillators by patient, device, and programming characteristics.

BACKGROUND: Antitachycardia pacing (ATP) is an established implantable cardioverter-defibrillator (ICD) therapy that terminates ventricular tachycardias (VTs) without painful ICD shocks. However, factors influencing ATP success are not well understood. OBJECTIVE: The purpose of this study was to examine ATP success rates by patient, device, and programming characteristics. METHODS: This retrospective analysis of the PainFree SmartShock Technology study included spontaneous ATP-treated monomorphic VT episodes. ATP success rates were calculated for various factors. Also, the relationship of ATP programming on shock burden and syncope were investigated. RESULTS: Of the 2770 enrolled patients (2200 [79%] male; mean age 65 years), 1699 (61%) received an ICD and 1071 (39%) a cardiac resynchronization therapy - defibrillator. ATP had >80% rate of success for terminating VTs overall, with similar rates observed between ICD and cardiac resynchronization therapy - defibrillator devices (82.2% vs 80.3%, respectively; P = .81) as well as between primary and secondary prevention patients with ICDs (77.2% vs 83.9% respectively; P = .25). Arrhythmias with a median cycle length of ≥320 ms had a significantly higher ATP success rate (88.0%; 95% confidence interval 84.8%-90.6%). The cumulative percentage of ATP success increased from 71% at 1 ATP sequence delivered to 87% at ≥8 sequences delivered. Programming more ATP sequences was associated with lower shock burden (P = .0005). There was no evidence that more sequences were associated with higher rates of syncope (P = .16). CONCLUSION: Delivering more ATP sequences resulted in a higher overall success of terminating VTs, while programming more ATP was associated with decreased shock burden and no evidence of increased syncope or acceleration. This suggests that more ATP sequences should be programmed when possible, but confirmation in prospective studies will be necessary.