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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. [ABSTRACT FROM AUTHOR]

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. Author summary: Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects 5–10 million people worldwide. HTLV-1 infection can cause serious diseases including hematologic malignancy, adult T-cell leukemia/lymphoma (ATL), and progressive neurologic disease known as HTLV-1-associated myelopathy/tropical spastic paraplegia (HAM/TSP). An increase in the mortality rate among HTLV-1-infected individuals has become an issue of concern in recent years. Differences in HTLV-1 infection rates and subgroup distribution are considered to be caused by the historical global movement of HTLV-1-infected individuals. Furthermore, recent global population movements have resulted in the redistribution of HTLV-1-infected individuals, which may lead to outbreaks of ATL and HAM/TSP in non-endemic areas. In this study, we investigated the molecular characteristics of HTLV-1 in East Asia and found that the transcontinental subgroup was more prevalent in Taiwan, whereas the Japanese subgroup was 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]