Kazuto Ito

Human metapneumovirus genotype A (HMPV-A) comprises genetically diverse lineages, but whether F-gene diversification is accompanied by changes in the conserved fusion (F) protein remains unclear. We analyzed 500 PARNAS-selected HMPV-A F gene sequences from 25 countries collected between 1982 and 2025 using time-scaled phylogenetics, Bayesian skyline analysis, evolutionary-rate and patristic-distance estimation, codon-based selection analysis, sequence-identity profiling, and structural epitope modeling. Three phylogenetically distinct clusters were identified. Cluster 1 diverged from the common ancestor of Clusters 2 and 3 around 1927. Cluster 3 comprised 435 representative sequences and showed the highest estimated evolutionary rate, greatest phylogenetic diversity, and the most pronounced recent demographic fluctuations. The overall evolutionary rate was 9.20 × 10⁻⁴ substitutions/site/year. Despite nucleotide-level diversification, whole-protein identity exceeded 97% in all clusters, 299 codons (approximately 55%) were consistently under negative selection, whereas positive-selection signals were limited and method-specific, with MEME identifying codons 188 and 271 and FUBAR identifying codon 528. Major neutralizing antibody-binding regions were largely conserved, and the six modeled representatives showed similar global F-protein backbone structures and predicted epitope-surface distributions, although A61S and K143T occurred within neutralizing antibody-binding sites and require experimental evaluation. These findings demonstrate lineage-specific F gene diversification under strong functional constraint and support the HMPV F protein as a broadly conserved intervention target.

Objective: To evaluate complementary roles of Prostate Health Index (phi) and multiparametric magnetic resonance imaging (mpMRI) in detection of any prostate cancer (PC) and clinically significant PC (csPC) and to investigate likelihood of risk stratification for recommending prostate biopsy in men with prostate‐specific antigen (PSA) ≤ 10 ng/mL. Methods: This exploratory post hoc analysis of the prospective multicenter PROPHET cohort included 108 Japanese men who underwent prebiopsy mpMRI. All MRI findings were retrospectively reviewed by one specialized radiologist and scored using Prostate Imaging Reporting and Data System (PI‐RADS) v2.1. csPC was defined as ISUP grade group (GG) of 2–5. Then, the likelihood of risk stratification for detecting any PC and csPC based on PI‐RADS categories and a significant [−2]proPSA‐related index assessed by receiver operating characteristic (ROC) analyses was retrospectively investigated. Results: PC was detected in 51 of 108 men (47.2%). The ROC analyses revealed the superiority of phi in detecting PC and csPC. Among men with phi ≤ 36.0 and PI‐RADS 1–3, csPC was detected in 2 of 36 men (5.6%), but no GG 3–5 cancers were observed. In contrast, in men with phi > 36.0, the risk of detecting PC/csPC was 42.9% (9/21)/23.8% (5/21), 42.9% (3/7)/42.9% (3/7), and 89.3% (25/28)/71.4% (20/28) in PI‐RADS 1–2, 3, and 4–5, respectively. Conclusions: phi and mpMRI have complementary roles for biopsy decision‐making in men with PSA ≤ 10 ng/mL. Men with phi ≤ 36.0 and PI‐RADS 1–3 may be candidates for biopsy avoidance, whereas phi > 36.0 may be a high‐risk group recommending prostate biopsy regardless of mpMRI findings. Registry and Registration No. of the Study/Trial: This study was registered with the UMIN Clinical Trials Registry (UMIN‐CTR), registration number UMIN000047187.

Background: [‐2]proPSA(p2PSA)‐related indices have demonstrated diagnostic value for detecting prostate cancer (PC) in males with modest increases in prostate‐specific antigen levels (PSA) of < 10 ng/mL. However, the “leak point” of p2PSA level in the blood circulation before developing screen‐detectable PC remains uncertain. Therefore, this study evaluated the ability of p2PSA‐related indices in the years before considering conventional biopsy indications. Methods: This case‐control study analyzed database and serum bank information from a population‐based screening cohort in Gunma Prefecture. The case group included 58 males diagnosed with PC due to increased PSA (4–10 ng/mL) followed serially for 5 years. The control group comprised 58 males without PC based on biopsy who were matched to the case group by adjusted PSA levels (± 2 ng/mL) and age (± 5 years) at the time of biopsy. p2PSA, free PSA, and PSA were measured from frozen serum samples from 0 to 5 years before biopsy. Results: p2PSA‐to‐free PSA ratio (%p2PSA) and prostate health index (phi) were significantly higher in the case group than in the control group from five, three, and 3 years before biopsy, respectively. The areas under the receiver operating characteristic curve for predicting PC were 0.437 for PSA, 0.637 for phi, 0.663 for %p2PSA, and 0.618 for free PSA‐to PSA ratio (%fPSA) at 3 years before biopsy. Conclusions: p2PSA‐related indices showed group‐level differences between future PC cases and matched controls before PSA exceeded conventional cut‐offs. These findings should be regarded as hypothesis‐generating and require validation in prospective studies before clinical application to risk‐stratified screening.

Objectives: To evaluate the diagnostic performance of the Prostate Health Index (phi) in detecting clinically significant prostate cancer (csPC) among men within the PSA gray zone (2.01–10.00 ng/mL), compared with total PSA and the free‐to‐total PSA ratio (F/T ratio), using a population‐based screening database in Kanazawa city, Japan. Methods: Between 2019 and 2023 (excluding 2022), 14 840 men participated in a biennial population‐based prostate cancer screening program in Kanazawa city, Japan. Among them, 2776 men with PSA levels of 2.01–10.00 ng/mL were identified, and 571 men who underwent prostate biopsy were included in the final analysis. The diagnostic accuracy for detecting csPC was compared among PSA, the F/T ratio, and phi using receiver operating characteristic (ROC) and decision curve analyses (DCA). Results: The area under the ROC curve (AUC) for detecting csPC was 0.691 for PSA, 0.673 for F/T ratio, and 0.761 for phi. The AUC for phi was significantly higher than that for F/T ratio ( p < 0.05). The DCA demonstrated that phi provided the greatest net benefit across threshold probabilities between 0.2 and 0.6, indicating improved clinical utility for csPC detection in the gray zone. Conclusions: In population‐based screening, adding phi to PSA and F/T ratio improved discrimination for csPC and may reduce unnecessary referrals and improve screening efficiency among men in the PSA gray zone.

Objective: In this study, we compared the prostate health index (PHI) and the Prostate Imaging Reporting and Data System (PI‐RADS) before prostate biopsy and evaluated the utility of combining them in the diagnosis of prostate cancer (PC).Methods: Between November 2021 and March 2023, 105 patients admitted to Gunma University Hospital for prostate biopsy after undergoing both MRI and PHI measurements were enrolled in this study. We investigated the diagnostic impacts of [−2]proPSA related indexes on clinically significant PC (csPC) and the complementary effects of PHI and PI‐RADS.Results: The median of PHI was 59.9, and 72 patients (69%) were diagnosed with PC. The receiver operating characteristic (ROC) curve for patients diagnosed with PC indicated an area under the curve (AUC) of 0.816 for PHI and 0.753 for PI‐RADS. For PHI, when the sensitivity was 90% and 95%, the specificity was 51.5% and 45.5%, respectively. Both are higher than those of the conventional PSA‐related indices. In addition, the ROC curve in patients with a diagnosis of csPC (n = 67) indicated an AUC of 0.793 for PHI and 0.746 for PI‐RADS. Furthermore, if biopsy was restricted to patients with PI‐RADS ≥ 4 or PHI ≥ 38.1, 21% of unnecessary biopsies could be avoided, with only one (1.5%) patient with csPC being missed.Conclusions: PHI is more available for detecting csPC than PSA and PSA F/T. Moreover, there is a possibility that unnecessary prostate biopsies can be avoided by combining PHI and PI‐RADS.

BackgroundIdentifying the likelihood of life-threatening recurrence after radical cystectomy by reliable and user-friendly predictive models remains an unmet need in the clinical management of invasive bladder cancer.MethodsA total of 204 consecutive patients undergoing open radical cystectomy (ORC) for bladder cancer were retrospectively enrolled between May 2005 and August 2020. Clinicopathological and peri-ORC therapeutic data were extracted from clinical records. We explored predictive factors that significantly affected the primary endpoint of overall survival (OS) and secondary endpoints of cancer-specific survival (CSS) and recurrence-free survival (RFS).ResultsDuring a median follow-up of 3.9 years, 42 (20.6%) and 10 (4.9%) patients died due to bladder cancer and other causes, respectively. Five-year RFS, CSS, and OS were 66.5%, 77.6%, and 75.4%, respectively. Pathological T and N categories and lymphovascular invasion (LVI) significantly affected RFS by Cox regression analysis. Accordingly, clinical T and pathological N categories and LVI significantly affected CSS. Clinical T and pathological N categories, LVI, age, and ORC tumor grade significantly affected OS. Based on the assessment score for each independent risk factor, we developed the Gunma University Oncology Study Group (GUOSG) score, which predicts RFS, CSS, and OS. The GUOSG score classified four groups for RFS, three for CSS, and five for OS, with statistically significant distribution for nearly all comparisons.ConclusionsThe GUOSG model is helpful to show individualized prognosis and functions as a risk-stratified historical cohort for assessing the lifelong efficacy of new salvage treatment regimens.

The identification of pathogens associated with respiratory symptoms other than the novel coronavirus disease 2019 (COVID-19) can be challenging. However, the diagnosis of pathogens is crucial for assessing the clinical outcome of patients. We comprehensively profiled pathogens causing non-COVID-19 respiratory symptoms during the 7th prevalent period in Gunma, Japan, using deep sequencing combined with a next-generation sequencer (NGS) and advanced bioinformatics technologies. The study included nasopharyngeal swabs from 40 patients who tested negative for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) using immuno-chromatography and/or quantitative reverse transcription polymerase chain reaction (qRT-PCR) methods. Comprehensive pathogen sequencing was conducted through deep sequencing using NGS. Additionally, short reads obtained from NGS were analyzed for comprehensive pathogen estimation using MePIC (Metagenomic Pathogen Identification Pipeline for Clinical Specimens) and/or VirusTap. The results revealed the presence of various pathogens, including respiratory viruses and bacteria, in the present subjects. Notably, human adenovirus (HAdV) was the most frequently detected virus in 16 of the 40 cases (40.0%), followed by coryneforms, which were the most frequently detected bacteria in 21 of the 40 cases (52.5%). Seasonal human coronaviruses (NL63 type, 229E type, HKU1 type, and OC43 type), human bocaviruses, and human herpesviruses (human herpesvirus types 1–7) were not detected. Moreover, multiple pathogens were detected in 50% of the subjects. These results suggest that various respiratory pathogens may be associated with non-COVID-19 patients during the 7th prevalent period in Gunma Prefecture, Japan. Consequently, for an accurate diagnosis of pathogens causing respiratory infections, detailed pathogen analyses may be necessary. Furthermore, it is possible that various pathogens, excluding SARS-CoV-2, may be linked to fever and/or respiratory infections even during the COVID-19 pandemic.

To understand the evolution of GII.P6-GII.6 and GII.P7-GII.6 strains, the prevalent human norovirus genotypes, we analysed both the RdRp region and VP1 gene in globally collected strains using authentic bioinformatics technologies. A common ancestor of the P6- and P7-type RdRp region emerged approximately 50 years ago and a common ancestor of the P6- and P7-type VP1 gene emerged approximately 110 years ago. Subsequently, the RdRp region and VP1 gene evolved. Moreover, the evolutionary rates were significantly faster for the P6-type RdRp region and VP1 gene than for the P7-type RdRp region and VP1 genes. Large genetic divergence was observed in the P7-type RdRp region and VP1 gene compared with the P6-type RdRp region and VP1 gene. The phylodynamics of the RdRp region and VP1 gene fluctuated after the year 2000. Positive selection sites in VP1 proteins were located in the antigenicity-related protruding 2 domain, and these sites overlapped with conformational epitopes. These results suggest that the GII.6 VP1 gene and VP1 proteins evolved uniquely due to recombination between the P6- and P7-type RdRp regions in the HuNoV GII.P6-GII.6 and GII.P7-GII.6 virus strains.

To understand the evolution of the human norovirus GII.P6-GII.6 and GII.P7-GII.6 strains, we analyzed both the RdRp region and VP1 gene in globally collected strains using authentic bioinformatics technologies. A common ancestor of the P6- and P7-type RdRp region emerged approximately 50 years ago and a common ancestor of the P6- and P7-type VP1 gene emerged approximately 110 years ago. Subsequently, the RdRp region and VP1 gene evolved. Moreover, the evolutionary rates were significantly faster for the P6-type RdRp region and VP1 gene than the P7-type RdRp region and VP1 genes. Large genetic divergence was observed in the P7-type RdRp region and VP1 gene compared with the P6-type RdRp region and VP1 gene. The phylodynamics of the RdRp region and VP1 gene fluctuated after the year 2000. Positive selection sites in VP1 proteins were located in the antigenicity-related protruding 2 domain, and these sites overlapped with conformational epitopes. These results suggest that the GII.6 VP1 gene and VP1 proteins evolved uniquely due to recombination between the P6- and P7-type RdRp regions in the HuNoV GII.P6-GII.6 and GII.P7-GII.6 virus strains.

The continence self-management programme fee (CSPF) for hospitalized patients was revised in 2020 to include those receiving consistent care on an out-patient basis. We extracted candidate patients for CSPF on an out-patient basis (out-patient candidates hereafter) from those for whom-CSPF had been calculated during hospitalization at our hospital, and defined those who had undergone a medical examination related to continence care as out-patient calculation candidates. Of the 956 patients for whom CSPF had been calculated during hospitalization, 482 patients (50%) were out-patient candidates ; 275 (54%) and 169 (33%) of whom were seen in the urology and neurosurgery departments, respectively. Of the 482 out-patient candidates, 238 (49%) were out-patient calculation candidates ; 197 (83%) and 14 (6%) of whom were seen in the urology and neurosurgery departments, respectively. Forty-two and 41 of the calculation candidates were cases of benign prostatic hyperplasia and bladder cancer, respectively. The CSPF was actually processed 93 times for 78 of the 482 out-patient candidates (16%). There were various obstacles in the current system of calculating the fees to realize consistent care from hospitalization to out-patient care.