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INTRODUCTION We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI). METHODS Participants aged 65‐85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months. RESULTS Of 531 participants, 406 completed the trial. The between‐group difference in composite score changes was 0.047 (95% CI: −0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels. DISCUSSION The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required. Highlights This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions.

Mushroom-forming basidiomycetes produce a wide range of metabolites and have great value not only as food but also as an important global natural resource. Here, we demonstrate CRISPR/Cas9-based genome editing in the model species Coprinopsis cinerea . Using a high-throughput reporter assay with cryopreserved protoplasts, we identified a novel promoter, CcDED1 pro , with seven times stronger activity in this assay than the conventional promoter GPD2 . To develop highly efficient genome editing using CRISPR/Cas9 in C. cinerea , we used the CcDED1 pro to express Cas9 and a U6-snRNA promoter from C . cinerea to express gRNA . Finally, CRISPR/Cas9-mediated GFP mutagenesis was performed in a stable GFP expression line. Individual genome-edited lines were isolated, and loss of GFP function was detected in hyphae and fruiting body primordia. This novel method of high-throughput CRISPR/Cas9-based genome editing using cryopreserved protoplasts should be a powerful tool in the study of edible mushrooms.

Purpose This study aimed to identify the characteristics of acute acquired comitant esotropia (AACE) in young patients from a single institution; and clarify their relationship with the excess use of digital devices. Study design Retrospective, observational. Methods We extracted the clinical charts of patients aged between 5 and 35 years who presented at the Hamamatsu University Hospital with AACE symptoms from January 1, 2015 to December 31, 2018. The age of onset, angle of deviation, refractive errors, history of near work, including excess smartphone use, and treatment modality were retrieved. Patients were divided into three groups: CHILD (aged 5–12 years), JUNIOR (aged 13–17 years), and ADULT (aged 18–35 years) and statistically analyzed with Kruskal–Wallis test. Results Forty-one patients were retrieved, with a mean age at onset of 15.8 (5–28) years; eight in the CHILD group, 23 in the JUNIOR group, and 10 in the ADULT group. Refractive errors and age of patients were correlated, but were not significantly different among groups. The mean angle of deviation at distance was 28.0 ± 12.8 prism diopters (PD) and 28.6 ± 17.2 PD at near. The CHILD group showed the largest near-distant dissociation. History of excessive near work was found in all groups. Conclusion AACE was most commonly found in the JUNIOR group, especially those aged 15–16 years. AACE may encompass multiple diseases; using common diagnostic criteria and asking common questions regarding digital device usage is necessary to clarify the influence of digital device usage, and a multicenter prospective study is recommended.

Purpose To describe clinical presentations of acquired comitant esotropia and digital device use in children, adolescents, and young adults without neurological problems. Study design Multicenter prospective observational study. Methods Patients with acquired comitant esotropia, without intracranial diseases aged 5–35 years at the time of visit, who were seen at pre-registered facilities within 1 year of onset were enrolled. The duration from the onset of symptoms and the time of digital device usage approximately 1 month before onset and their lifestyles were surveyed. Visual acuity, cycloplegic refraction, and strabismus angles were measured. Data were analyzed in three age groups (Child: 5–12 years, Adolescent: 13–18 years, and Young adult: 19–35 years). Results Between November 2019 and December 2021, 218 patients were enrolled from 55 facilities, and 194 patients (including 62 children, 69 adolescents, and 63 young adults) were analyzed. The child group spent the least amount of time using digital devices (children: 159; adolescents: 210; young adults: 267 min/work day, p < 0.05; (mean time in the same order below) 229, 338, 314 min/holiday, p < 0.05) and had the largest strabismus angle (mean strabismus angle at near: 30, 22, 18 PD, p < 0.01; at far: 28, 26, 21 PD, p<0.05). Conclusion The clinical features of acquired comitant esotropia and hand-held digital device usage differed between children aged ≤ 12 years and older patients. This report gives the current clinical characteristics of young patients with acquired esotropia and digital device usage.

Purpose To investigate changes in strabismus angles in children and young adult patients with recent onset of constant acquired comitant esotropia (ACE) following instructions on hand-held digital devices (DD). Study design Prospective multicenter non-randomized interventional study. Methods This study included subjects aged 5–35 years who developed ACE within 1 year. Subjects were divided into two groups: (i) subjects who used DD for an average of ≥120 minutes/day for junior high-school students and older and ≥60 minutes/day for primary-school students and younger (DD+); and (ii) subjects who used DD for less than that (DD-) based on the questionnaire at the study’s start. During the initial visit, glasses were prescribed when necessary; verbal instructions on DD use including time reduction and viewing-distance elongation were provided. For each group, strabismus angles at the initial visit and at 3 months were compared. Cure was defined as esophoria within 8 prism diopters without symptoms. Results In total, 181 cases were investigated. At baseline, strabismus angles in DD+ and DD- groups were 23±14 PD and 25±15 PD at near and 25±13 PD and 27±14 PD at distance, respectively. At 3 months, they were 22±16 PD and 25±15 PD at near and 23±14 PD and 27±13 PD at distance, respectively. Only in the DD+ group, reduction in strabismus angle was observed, but this was not clinically significant. Ten and 1 subjects in DD+ and DD- groups were cured. Conclusion Although changes in strabismus angles were not large enough, DD use instructions were beneficial for some ACE subjects.

Purpose To evaluate changes in intraocular pressure (IOP) at different gaze positions before and after superior rectus muscle-lateral rectus muscle (SR-LR) loop myopexy in highly myopic strabismus (HMS). Study design Nonrandomized clinical, prospective, interventional trial. Methods Fourteen patients with HMS (18 eyes) who underwent SR-LR loop myopexy were divided into 3 groups: < 100 prism diopters (PD) (mild esotropia [ET] group), > 100 PD (large ET group), and > 100 PD, and simultaneous recession of the medial rectus (MR) muscle was performed (large ET + MR group). Intraocular pressure was measured preoperatively and postoperatively at the primary, abduction, and adduction positions in each group. Results Intraocular pressure did not change after surgery in the mild ET group. Intraocular pressure significantly decreased in the abduction position (from 20.0 ± 2.1 to 16.0 ± 1.9 mmHg, P  = 0.043) in the large ET group and in the abduction (from 22.2 ± 5.9 to 15.6 ± 4.3 mmHg, P  = 0.048) and primary positions (from 15.8 ± 5.0 to 10.2 ± 2.8 mmHg, P  = 0.043) in the large ET + MR group. The preoperative significant differences in IOP between the abduction and adduction positions in the large ET group (7.4 ± 3.4 mmHg) and the large ET + MR group (10.0 ± 5.5 mmHg) disappeared postoperatively (3.2 ± 2.8 mmHg and 3.6 ± 1.7 mmHg, respectively). The differences in IOP between abduction and adduction were similar in all the groups. Conclusion SR-LR loop myopexy decreased IOP in patients with HMS in the abduction and primary positions.

•In healthy Japanese infants/toddlers, V114 given subcutaneously was well tolerated.•The V114 safety profile was comparable to that of PCV13.•V114 elicited immune responses to all 15 serotypes in healthy infants/toddlers.•V114 was non-inferior for the 13 PCV13 serotypes after the three-dose infant series.•V114-elicited immune responses were higher than PCV13 for serotypes 22F and 33F. This phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in Japanese infants. V114 contains all 13 serotypes in PCV13 plus additional serotypes 22F and 33F. Healthy Japanese infants were randomized to receive three primary doses of V114 or PCV13 (dose 1 at 2–6 months of age; doses 2 and 3 ≥ 27 days after prior dose), plus a toddler dose at 12–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-dose 3, pre-dose 4, and 30 days post-dose 4. Primary objectives included non-inferiority of V114 to PCV13 for the 13 shared serotypes based on serotype-specific IgG response rates (IgG ≥ 0.35 μg/mL) and geometric mean concentration (GMC) ratios, and for serotypes 22F and 33F based on IgG response rates and compared with the lowest response of any serotype in the PCV13 group, at 30 days post-dose 3. Overall, 694 infants were randomized to V114 (n = 347) or PCV13 (n = 347). Proportions of participants with solicited and serious AEs were comparable between vaccination groups. V114 met non-inferiority criteria for all 13shared serotypes, based on difference in proportion of responders (lower bound of two-sided 95 % confidence interval [CI] > −10.0) and IgG GMC ratios (V114/PCV13, lower bound of two-sided 95 % CI > 0.5) at 30 days post-dose 3. The non-inferiority criterion based on IgG response rates was met for serotype 22F, but narrowly missed for serotype 33F (90.9 %, lower bound of two-sided 95 % CI −10.6). In Japanese infants, a four-dose series of V114 was generally well tolerated. Compared with PCV13, V114 provided non-inferior immune responses to the 13 shared serotypes and higher immune responses to serotype 22F and 33F post-primary series. Trial registration:ClinicalTrials.gov: NCT04384107; EudraCT 2019-003644-68.

This study investigated the impact of relative dose intensity (RDI) on the effectiveness and safety of immuno-oncology plus tyrosine kinase inhibitor (IO-TKI) therapy in Japanese patients with renal cell carcinoma (RCC). A total of 145 patients receiving first-line treatment were analyzed: 55 received IO-TKI therapy and 90 received immuno-oncology combination (IO-IO) therapy. Patients in the IO-TKI group were divided based on an RDI threshold of 80% into high- and low-RDI groups. Median progression-free survival (mPFS) was significantly longer in the IO-TKI group compared to the IO-IO group (P < 0.05), while no significant difference in median overall survival (mOS) was observed (P = 0.53). Interestingly, the mOS tended to be shorter in the IO-TKI high-RDI group than in the IO-TKI low-RDI (P = 0.05) and IO-IO groups (P = 0.13). Moreover, treatment discontinuation due to adverse effects occurred earlier in the IO-TKI high-RDI group (P < 0.05). An association was found between RDI ≥ 80% in IO-TKI therapy, discontinuation due to adverse events, and poor prognosis. Careful dose adjustment of TKIs may be necessary to optimize outcomes in Japanese patients with RCC receiving IO-TKI combination therapy.

Hypertension (HT) is the most attributable and modifiable risk factor for spontaneous intracerebral hemorrhage (SICH). However, epidemiological data on blood pressure (BP) control before SICH and its relationship to patient lifestyles are lacking. This study prospectively enrolled patients with acute SICH from six stroke centers in Tochigi, Japan. BP control and patient lifestyles were investigated using a questionnaire conducted on patients and their families. A total of 365 patients were analyzed, 270 (74.0%) of whom had HT and 198 (54.2%) untreated HT. The prevalence of untreated HT was much higher in younger patients and decreased with age (79.0%, 71.8%, 62.2%, 44.8%, and 31.0% in those aged <50, 50–59, 60–69, 70–79, and ≥80 years, respectively). Patients with untreated HT were significantly less likely have a family doctor and attended fewer annual health checkups than did those with treated or no HT. Untreated HT with awareness was much higher in younger and middle-age men than in women, whereas untreated HT without awareness was much higher in younger women than in men. Among patients who received antihypertensives, the prevalence of well-controlled HT was also very low, especially in younger patients (20.0% and 23.5% in those aged <50, and 50–59 years, respectively). In-hospital mortality was much higher in younger patients (age <70 years) with untreated than with treated or no HT. Untreated and uncontrolled HT were highly detected and seemed to be important targets for the primary prevention of Japanese SICH. Different strategies to improve BP control are warranted for each generation and sex.

Significance Androgen is essential for the masculinization of external genitalia such as the organ size and the male-type urethra in mammals. However, the genes downstream of androgen, which are responsible for these masculinization processes, have not been identified. Here, we show v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( Mafb ) as an essential masculinization gene for embryonic urethral formation. Mafb expression is prominent in developing male external genitalia, driving masculinization of embryonic urethral formation in an androgen-dependent manner. External genitalia of Mafb KO males exhibit urethral defects, giving insight into human hypospadias. The current findings indicate that Mafb is a crucial mediator of urethral masculinization and is a possible new candidate gene for hypospadias derived from embryonic abnormalities. Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor ( Ar ) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.