HLA-A*24 Increases the Risk of HTLV-1-Associated Myelopathy despite Reducing HTLV-1 Proviral Load.

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301-309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301-309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11-19 or Tax 301-309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1ß or in the expression of CD107a-a marker for the degranulation of cytotoxic molecules. However, Tax 301-309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11-19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

Development of a SARS-CoV-2 viral dynamic model for patients with COVID-19 based on the amount of viral RNA and viral titer.

The target-cell limited model, which is one of the mathematical modeling approaches providing a quantitative understanding of viral dynamics, has been applied to describe viral RNA profiles of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previous studies. However, these models have been developed mainly using patient data from the early phase of the pandemic. Furthermore, no reports focused on the profiles of the viral titer. In this study, the dynamics of both viral RNA and viral titer were characterized using data reflecting the current clinical situation in which the Omicron variant has become epidemic and vaccines for SARS-CoV-2 have become available. Consecutive data for 5212 viral RNA levels and 5216 viral titers were obtained from 720 patients with coronavirus disease 2019 (COVID-19) in a phase II/III study for ensitrelvir. Our model assumed that productively infected cells would produce only infectious viruses, which could be transformed into non-infectious viruses, and has been used to describe the dynamics of both viral RNA levels and viral titer. The time from infection to symptom onset (tinf) of unvaccinated patients was estimated to be 3.0 days, which was shorter than that of the vaccinated patients. The immune-related parameter as a power function for the vaccinated patients was 1.1 times stronger than that for the unvaccinated patients. Our model allows the prediction of the viral dynamics in patients with COVID-19 from the time of infection to symptom onset. Vaccination status was identified as a factor influencing tinf and the immune function.

Effect of Renal Impairment on Pharmacokinetics and Safety of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor.

INTRODUCTION: Ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2, shows efficacy and safety in participants with mild to moderate COVID-19. Since urinary recovery of ensitrelvir ranged from 12.9% to 21.8% across dose groups given 20-1000 mg in a single-ascending dose study, renal excretion contributes to the elimination of ensitrelvir. Therefore, the effect of renal impairment on the pharmacokinetics and safety of ensitrelvir needed to be evaluated. METHODS: This study (NCT05363215) was a phase 1, open-label, nonrandomized, parallel-group study. The effect of renal function on the pharmacokinetics of ensitrelvir was investigated. Ensitrelvir was administered as a single dose of 375 mg to participants with normal renal function and those with mild, moderate, and severe renal impairment. The participants with normal renal function were matched to each participant with moderate renal impairment with respect to sex, age, and body mass index. The unbound fractions in plasma after administration of ensitrelvir were also evaluated. For the safety assessment, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The plasma concentrations of participants with renal impairment were higher than those of participants with normal renal function. The ratios (90% confidence intervals) of the area under the plasma concentration-time curve from 0 to infinity (AUC0-inf) in participants with mild, moderate, and severe renal impairment compared to normal renal function were 1.4374 (1.1716-1.7636), 1.4885 (1.1883-1.8646), and 1.6021 (1.2782-2.0080), respectively. The plasma protein-unbound fraction was similar regardless of the plasma ensitrelvir concentration or renal function. Ensitrelvir was well tolerated in participants with mild to severe renal impairment and normal renal function. CONCLUSION: Ensitrelvir was well tolerated by participants with renal impairment. There was no clinically meaningful increase on exposure to ensitrelvir in participants with renal impairment, indicating that no dose adjustment would be required due to renal function.

Clinical features, future cardiac events, and prognostic factors following percutaneous coronary intervention in young female patients.

BACKGROUND: The proportion of young females among the patients who undergo percutaneous coronary intervention (PCI) is relatively small, and information on their clinical characteristics is limited. This study investigated the clinical characteristics and prognostic factors for future cardiac events in young females who underwent PCI. METHODS: This multicenter observational study included 187 consecutive female patients aged < 60 years who underwent PCI in seven hospitals. The primary composite endpoint was the incidence of cardiac death, nonfatal myocardial infarction, and target vessel revascularization. RESULTS: The mean patient age was 52.1 ± 6.1 years and 89 (47.6%) had diabetes, and renal dysfunction (an estimated glomerular filtration rate < 60 mL/min/1.73 m2) was observed in 38 (20.3%). During a median follow-up of 3.3 years, the primary endpoint occurred in 28 patients. The Cox proportional hazards models showed that renal dysfunction was an independent predictor for the primary endpoint (hazard ratio 3.04, 95% confidence interval 1.25-7.40, p = 0.01), as well as multivessel disease (hazard ratio 2.79, 95% confidence interval 1.12-6.93, p = 0.03). Patients with renal dysfunction had a significantly higher risk for the primary endpoint than those without renal dysfunction. CONCLUSIONS: Renal dysfunction was strongly associated with future cardiac events in young females who underwent PCI.

Geographic characteristics of HTLV-1 molecular subgroups and genetic substitutions in East Asia: Insights from complete genome sequencing of HTLV-1 strains isolated in Taiwan and Japan.

BACKGROUND: Although Japan is a major endemic area for human T-lymphotropic virus type 1 (HTLV-1) and the virus has been well-studied in this region, there is limited research on HTLV-1 in surrounding regions. In this study, we determined the complete genome sequences of HTLV-1 strains isolated from Taiwan and Japan and investigated the geographic characteristics of molecular subgroups and substitution mutations to understand the spread of HTLV-1 and its correlation with human migration. METHODOLOGY/PRINCIPAL FINDINGS: The complete genome sequences of 26 HTLV-1 isolates from Taiwan were determined using next-generation sequencing and were compared with those of 211 isolates from Japan in terms of subgroup and genetic mutations. In total, 15/26 (58%) isolates from Taiwan belonged to the transcontinental subgroup and 11/26 (42%) isolates belonged to the Japanese subgroup. The transcontinental subgroup was significantly more prevalent among Taiwanese isolates than Japanese isolates (58% vs 18%, P < 0.0001). The mutation rate for the complete HTLV-1 sequence was as low as 0.2%. On examining individual base substitutions, the G-to-A mutation was predominant. Bayesian phylogenetic tree analysis estimated the time to the most recent common ancestor for the transcontinental and Japanese subgroups to be 28447 years. The transcontinental subgroups from Taiwan and Japan appeared to form clusters according to their respective regions. CONCLUSIONS/SIGNIFICANCE: The transcontinental subgroup of HTLV-1 is predominant in Taiwan, while the Japanese subgroup is common in Japan. The difference in subgroup distribution may be attributed to the initial spread of the transcontinental subgroup in East Asia, followed by the influx of the Japanese subgroup.

Performance evaluation of Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test for different diagnostic situations.

IMPORTANCE: The World Health Organization estimated that 5-10 million people are infected with human T-cell leukemia virus type 1 (HTLV-1). This number is likely to be underestimated because reliable endemic data are available for only approximately 1.5 billion people worldwide. The point-of-care test is a powerful tool for the easy and quick detection of infections without the requirement for expensive instruments and laboratory equipment. Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test that was evaluated in this study, might significantly advance our understanding of the global epidemiology of HTLV-1 infection.

A Phase 1 Study of Ensitrelvir Fumaric Acid Tablets Evaluating the Safety, Pharmacokinetics and Food Effect in Healthy Adult Populations.

BACKGROUND: A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use. OBJECTIVES: The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state. METHODS: A phase 1, multicenter, double-blinded, randomized, placebo-controlled study was conducted to evaluate the safety and pharmacokinetics of once-daily ensitrelvir tablets at loading/maintenance doses of 375/125 mg or 750/250 mg for 5 days in healthy Japanese females, Japanese elderly (only 375/125 mg), and White male and female participants. An open-label, two-group, two-period crossover study was also conducted to estimate the effect of food on the pharmacokinetics of ensitrelvir at single dose of 375 mg. The nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded in safety assessments in both studies. RESULTS: The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were similar within these populations. The geometric mean half-life of ensitrelvir following multiple-dose administration was 48.7-58.9 h across all cohorts. The Cmax and AUC increased in a dose-proportional manner in Japanese female participants, and increased in a less than dose-proportional manner in White participants. Furthermore, there was no clear relationship between the dose and geometric mean half-life of ensitrelvir. The plasma concentration at 24 h (C24) after an initial dose of 375/125 mg exceeded the target plasma concentration (6.09 µg/mL) in all populations. Regarding the effect of food on the pharmacokinetics of ensitrelvir, although time to Cmax in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (Cmax and AUC) of ensitrelvir between the fasted and fed states. Most treatment-emergent adverse events were mild in nature and had resolved. CONCLUSION: Ensitrelvir (375/125 mg and 750/250 mg tablet formulation) was well tolerated, without any major safety concerns. The pharmacokinetics of ensitrelvir between all populations in the study were similar and C24 exceeded the target plasma concentration at 375/125 mg. These results suggest that ensitrelvir can be effectively administered with no necessity for dose adjustment for age, sex, and race without food restriction. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202, registered on 16 July 2021.

Pharmacokinetics, safety, and tolerability of single and multiple doses of zuranolone in Japanese and White healthy subjects: A phase 1 clinical trial.

AIM: This phase 1 study assessed the pharmacokinetics, safety, and tolerability of zuranolone in Japanese and White healthy adults, and Japanese healthy elderly subjects. METHODS: This single-center study consisted of three parts. In Part A (randomized, double-blind), the safety, tolerability, and pharmacokinetics of single dose and 7-day consecutive multiple doses of zuranolone 10, 20, and 30 mg and placebo were assessed in 36 Japanese adults, 24 White adults, and 12 Japanese elderly (aged 65-75 years) subjects. In Part B (randomized, open-label, crossover), the effect of food intake on the pharmacokinetics and safety of single-dose zuranolone 30 mg was evaluated in 12 Japanese adults. In Part C (randomized, double-blind, crossover), the effects of single-dose zuranolone 10 and 30 mg and placebo on electroencephalography parameters were evaluated in eight Japanese adults. RESULTS: Single and multiple doses of zuranolone were safe and well tolerated in all subjects. Linear pharmacokinetics were observed in the studied dose range. Time to steady-state plasma concentration was within 72 h for Japanese and White adults. Pharmacokinetic profiles were comparable between Japanese and White adults and between Japanese adults and Japanese elderly subjects. Plasma exposures of zuranolone were greater in the fed versus fasted state. Single-dose zuranolone 30 mg increased low-beta electroencephalography power. CONCLUSION: In healthy Japanese subjects, zuranolone was well tolerated; pharmacokinetic profile was unaffected by ethnicity or age; plasma exposures were greater in the fed state. The increased low-beta electroencephalography power with the 30-mg dose is consistent with γ-aminobutyric acid receptor type A activation by zuranolone.

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder.

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9-17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD. CLINICALTRIALS.GOV IDENTIFIER: NCT03395353.

HTLV-1-associated myelopathy/tropical spastic paraplegia with sporadic late-onset nemaline myopathy: a case report.

BACKGROUND: Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date. CASE PRESENTATION: A 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment. CONCLUSION: This is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.

Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

BACKGROUND: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. OBJECTIVES: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. METHODS: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day - 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day - 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. CONCLUSION: The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202.

Identification and tracking of HTLV-1-infected T cell clones in virus-associated neurologic disease.

Human T lymphotropic virus type 1-assoicated (HTLV-1-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the persistent proliferation of HTLV-1-infected T cells. Here, we performed a T cell receptor (TCR) repertoire analysis focused on HTLV-1-infected cells to identify and track the infected T cell clones that are preserved in patients with HAM/TSP and migrate to the CNS. TCRß repertoire analysis revealed higher clonal expansion in HTLV-1-infected cells compared with noninfected cells from patients with HAM/TSP and asymptomatic carriers (ACs). TCR clonality in HTLV-1-infected cells was similar in patients with HAM/TSP and ACs. Longitudinal analysis showed that the TCR repertoire signature in HTLV-1-infected cells remained stable, and highly expanded infected clones were preserved within each patient with HAM/TSP over years. Expanded HTLV-1-infected clones revealed different distributions between cerebrospinal fluid (CSF) and peripheral blood and were enriched in the CSF of patients with HAM/TSP. Cluster analysis showed similarity in TCRß sequences in HTLV-1-infected cells, suggesting that they proliferate after common antigen stimulation. Our results indicate that exploring TCR repertoires of HTLV-1-infected cells can elucidate individual clonal dynamics and identify potential pathogenic clones expanded in the CNS.

Iliopsoas Muscle Weakness as a Key Diagnostic Marker in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).

Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease that arises from HTLV-1 infection. Pathologically, the condition is characterized by diffuse myelitis, which is most evident in the thoracic spinal cord. Clinical manifestations of the infectious disease, HAM/TSP, are empirically known to include weakness of the proximal muscles of the lower extremities and atrophy of the paraspinal muscles, which is characteristic of the distribution of disturbed muscles usually seen in muscular diseases, except that the upper extremities are almost normal. This unique clinical presentation is useful information for physicians and physical therapists involved in diagnosing and rehabilitating patients with HAM/TSP, as well as critical information for understanding the pathogenesis of HAM/TSP. However, the precise pattern of muscle involvement in this condition has yet to be reported. The purpose of this study was to identify the muscles affected by HAM/TSP in order to understand the pathogenesis of HAM/TSP as well as to aid in the diagnosis and rehabilitation of HAM/TSP. A retrospective review of medical records was conducted on 101 consecutively admitted patients with HAM/TSP at Kagoshima University Hospital. Among 101 patients with HAM/TSP, all but three had muscle weakness in the lower extremities. Specifically, the hamstrings and iliopsoas muscle were the most frequently affected in over 90% of the patients. Manual muscle testing (MMT) revealed that the iliopsoas was the weakest of the muscles assessed, a consistent feature from the early to advanced stages of the disease. Our findings demonstrate a unique distribution of muscle weakness in HAM/TSP, with the proximal muscles of the lower extremities, particularly the iliopsoas muscle, being the most frequently and severely affected.

Evaluation of Drug-Drug Interactions of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor, With Transporter Substrates Based on In Vitro and Clinical Studies.

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.

Anti-ganglionic acetylcholine receptor antibodies in functional neurological symptom disorder/conversion disorder.

Objective: Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD). Methods: Clinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021. Results: Of the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed. Conclusions: An autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

Efficacy of l-Arginine treatment in patients with HTLV-1-associated neurological disease.

OBJECTIVE: HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP. METHODS: This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability. RESULTS: The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time -3.5%, 95% CI -10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (-9.4%, 95% CI -16.6% to -2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (-9.1%, 95% CI -15.5% to -2.7%; P < 0.01), and in neopterin concentration in CSF (-2.1 pmol/mL, 95% CI -3.8 to -0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly. INTERPRETATION: l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP. TRIAL REGISTRATION NUMBER: UMIN000023854.

The ridge line of left pulmonary vein isolation from left atrial appendage can subsequently increase the completion rate of the mitral isthmus block line.

BACKGROUND AND OBJECTIVES: Mitral isthmus (MI) ablation for mitral flutter is technically difficult, and incomplete block line is not uncommon. The objective of this study is to investigate the effect of the ridge line of left pulmonary vein isolation (LPVI) from left atrial appendage (LAA) on completion rate of mitral isthmus (MI) block line and recurrence rate of atrial tachycardia (AT) or atrial flutter (AFL) after the first MI ablation. METHODS: We identified 611 patients who underwent first MI ablation for mitral flutter during the study period. Finally, 559 patients were enrolled and divided into two groups according to the method of ridge line ablation of LPVI (LAA group, n = 467, conventional group, n = 92). Outcome measures were the completion of MI block line by first MI ablation, the recurrence of AT/AFL, and repeat MI ablation after the first MI ablation. RESULTS: The first MI block line completion rate was significantly higher in the LAA group than the conventional group (95% vs. 85%, p < 0.001). The recurrence rate of AT/AFL after 3 months from first MI ablation was significantly lower in the LAA group. The requirement of additional MI ablation tended to be lower in the LAA group. CONCLUSIONS: Our novel approach of ablating LPV-LAA ridge from the LAA side during PVI can increase the success rate of MI block line completion, and reduce the recurrence rate of AT/AFL and the need for additional MI block line ablation. Graphical abstract Ablation of the left pulmonary vein-left atrial appendage ridge from the left atrial appendage side during PVI increased the success rate of mitral isthmus block line completion.

Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults.

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced Cmax and delayed Tmax of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.

High Prevalence of HTLV-1 Carriers Among the Elderly Population in Kagoshima, a Highly Endemic Area in Japan.

Japan is one of the world's highly endemic areas for human T cell leukemia virus type 1 (HTLV-1), and it is known that the infection rate of HTLV-1 increases with age. The infection rate among the elderly has been estimated based on data from blood donors under the age of 65, and the actual number and rate of infection among the elderly are unknown. Data of 26,090 preoperative HTLV-1 screening tests conducted at Kagoshima University Hospital from 2001 to 2020, including 2726 HTLV-1-positive patients, were used for calculating the decadal infection rates for the year of birth. Estimated infection rates by birth year and demographic tables were used to estimate the current number of infected people in Kagoshima. The estimated total numbers of people infected with HTLV-1 in Kagoshima prefecture were 139,436 in 2005 and 80,975 in 2019. The infection rate increased with age for both men and women, reaching 17.3% for women born before the 1920s. Next, we tried to clarify whether the increase in infection rates with age was due to post-school age infections. The age of birth with the greatest increase in infection rate after 10 years was women born in the 1970s, and the increase in infection rate was only 0.98%, which is not a statistically significant increase. The number of infected people in Kagoshima was >80,000 in 2019. No data were available in this study to point to the involvement of horizontal transmission after school age in the high infection rate among the elderly. The high infection rate among the elderly is thought to have been high even when they were infants.

Comparison of the empirical linear ablation and low voltage area-guided ablation in addition to pulmonary vein isolation in patients with persistent atrial fibrillation: a propensity score-matched analysis.

BACKGROUND: The efficacy of pulmonary vein isolation (PVI) alone is not guaranteed for persistent atrial fibrillation (PeAF), and it is unclear which type of ablation approach should be applied in addition to PVI. This study aimed to compare outcomes and prognosis between empirical linear ablation and low-voltage area (LVA) ablation after PVI for PeAF. METHODS: We enrolled 128 patients with PeAF who were assigned to the linear ablation group (n = 64) and the LVA ablation group (n = 64) using a propensity score-matched model. After PVI and cardioversion, the patients underwent either empirical linear ablation or LVA ablation during sinus rhythm. All patients in the linear ablation group underwent both roof line and mitral valve isthmus (MVI) ablations. An electrical-guided ablation targeting LVA (< 0.5 mV) was performed in the LVA group. When there was no LVA in the LVA group, only PVI was applied. We compared the procedural outcomes and recurrence after ablation between the two groups. RESULTS: The baseline characteristics were well-balanced between the two groups. Fifty patients had LVA (22 and 28 patients in the linear and LVA groups). The roof and MVI lines were completed in 100% and 96.9% of the patients. During the mean follow-up of 279.5 ± 161.3 days, the LVA group had significantly lower recurrence than the linear group (15 patients [23%] vs. 29 patients [45%], p = 0.014). Thirty-five patients were prescribed antiarrhythmic drugs during the follow-up period (linear group, n = 17; LVA group, n = 18); amiodarone and bepridil were administered to most of the patients (15 and 17 patients, respectively). The difference in the prognosis was relevant among the patients with LVA, while this trend was not observed in those without LVA. The LVA ablation group demonstrated significantly lower radiofrequency energy and shorter procedural time compared to the linear ablation group. The recurrence of atrial flutter was more likely to occur in the linear group than in the LVA group (14 [22%] vs. 6 [9.4%], p = 0.052). CONCLUSION: The electrophysiological-guided LVA ablation is more effective than empirical linear ablation in PeAF patients with LVA. Unnecessary empirical linear ablation might have a risk of iatrogenic gap and atrial flutter recurrence.