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The frequency of falls increases with age. In Japan, the population is aging rapidly, and fall prevention measures are an urgent issue. However, assessing fall risk during the coronavirus disease pandemic was complicated by the social distancing measures implemented to prevent the disease, while traditional assessments that involve actual measurements are complicated. This prospective cohort study predicted the risk of falls in community-dwelling older adults using an assessment method that does not require actual measurements. A survey was conducted among 434 community-dwelling older adults to obtain data regarding baseline attributes (age, sex, living with family, use of long-term care insurance, and multimorbidity), Frailty Screening Index (FSI) score, and Questionnaire for Medical Checkup of Old-Old (QMCOO) score. The participants were categorized into fall ( n = 78) and non-fall ( n = 356) groups. The binomial logistic regression analysis showed that it is better to focus on the QMCOO sub-item score, which focuses on multiple factors. The items significantly associated with falls were Q5 (odds ratio [OR] 1.95), Q8 (OR 2.33), and Q10 (OR 3.68). Our results were similar to common risk factors for falls in normal times. During the pandemic, being able to gauge the risk factors for falls without actually measuring them was important.

[Purpose] We aimed to explore the factors that predict falls in community-dwelling older people over 6 months during their voluntary self-isolation for the coronavirus disease (SARS-CoV-2). [Participants and Methods] In this longitudinal study, we surveyed older people aged ≥65 years living in Takasaki City, Gunma Prefecture, using a questionnaire. We investigated the relationship between the frailty screening index and fall rate. [Results] A total of 588 older adults (response rate, 35.7%) filled and returned the questionnaire during the study period. Of these, 391 participants who had not applied for long-term care insurance and had completed the data on the response items were included in the study. Based on their responses in the survey questionnaire, 35 (8.95%) participants were grouped into the fall group and 356 into the non-fall group. Subsequently, the "no" response to "Can you recall what happened 5 minutes ago?" and "yes" response to "Have you felt tired for no reason (in the past 2 weeks)?" were identified as the significant factors associated with falls. [Conclusion] It is important to pay attention to the subjective evaluation of patients' cognitive decline and fatigue to prevent falls owing to the implementation of SARS-CoV-2 countermeasures., Competing Interests: The authors declare no conflicts of interest., (2023©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway., (© 2023. The Author(s).)

Background: The aim of this study was to determine the number of new subjective cognitive decline (SCD) complaints and associated factors in community-dwelling older adults during the COVID-19 pandemic in Japan., Method: A prospective cohort study was conducted in two periods: May to June 2020, and November 2020 to January 2021. We mailed a questionnaire to 1953 older adults in the first survey, and received 700 responses in the second. We analysed 534 participants without SCD in the first survey. We collected data on sociodemographic characteristics and administered the Questionnaire for Medical Checkup of Old-Old (QMCOO) to assess respondents' health condition. SCD was operationally defined using the QMCOO as reports of (1) forgetfulness, and (2) difficulty in naming dates. The subjects were divided into two groups by their condition at the second survey: an SCD (new SCD complaints) and a no-SCD (no new SCD complaints) group., Results: A total of 85 (15.9%) participants had new SCD complaints. The Mann-Whitney U-test and chi-squared test showed that the SCD group had significantly more risk factors of SCD: walking speed (P = 0.001), smoking (P = 0.001), and existence of person with whom the patient could consult when disordered (P = 0.002). Multiple logistic regression analysis revealed that walking speed (odds ratio (OR) = 2.115, 95% confidence interval (CI): 1.259-3.553) and the presence of person to consult (OR = 3.619, 95% CI: 1.553-8.433) were significant related factors of new SCD complaints., Conclusion: Maintenance of physical condition and social support were associated with new SCD complaints during the COVID-19 pandemic., (© 2022 Japanese Psychogeriatric Society.)

Purpose: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants., Methods: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies., Results: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities., Conclusion: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Aim: The purpose of this study was to categorize and clarify transitions in the health status of older adults living in the community during the coronavirus disease (coronavirus disease 2019: COVID-19) pandemic., Methods: The participants were older adults (≥65 years of age) who lived in Takasaki City, Gunma Prefecture. The survey items included basic information and subjective health perception (questionnaire for medical checkup of old-old). Latent class analyses were conducted for the first (baseline) and second surveys (6 months). The scores for each item were compared to identify the characteristics of each class at baseline and at 6 months. In addition, transitions in class affiliation from baseline to 6 months were summarized., Results: A total of 434 of 1,953 participants (mean age: 79.1 years, 98 males and 336 females) completed the survey (22.2%). In both time periods, the responses were categorized into four classes: 1) good, 2) poor physical, oral and cognitive function, 3) poor social status and lifestyle, and 4) poor in all except social status and lifestyle. During 6 months of follow-up, a transition from the generally good class to the poor physical, oral and cognitive functions class was observed in many cases., Conclusions: The health status of the older adults living in the community was classified into four classes, and changes in health status occurred even within a short period of time during the COVID-19 pandemic.

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD., Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature., Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism., Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the association between consistent subjective cognitive decline and fall occurrence six months later., Method: A cohort study was conducted at two time points in community-dwelling older adults. The first survey was conducted from May to July 2020 and the second from November 2020 to January 2021. Older adults without missing data who had not fallen during the past year were analyzed. The questionnaire included sociodemographic data, a questionnaire for medical checkup of older adults, and a frailty screening index. We divided the participants into three groups according to the occurrence of subjective cognitive decline (SCD): 1) no SCD (did not complain of SCD at both time points), 2) unstable SCD (complained of SCD once), and 3) consecutive SCD (consistently complained of SCD). Multiple logistic regression analysis was used to examine the association between fall occurrence and SCD. Fall occurrences were obtained from the second survey., Results: In total, 322 participants were included in the analysis. The numbers of patients with no SCD, unstable SCD, and consecutive SCD were 226 (70.2%), 61 (19.0%), and 35 (10.9%), respectively. In the second survey, the number of falls was 26 (8.1%). Multiple logistic regression analysis showed that consecutive SCD was associated with fall occurrence, even after adjusting for age, sex, comorbidity, cohabitants, and frailty status (OR:3.143, 95% CI:1.076-9.388); however, unstable SCD was not (OR:2.348, 95% CI:0.816-6.468)., Conclusion: Consistent complaints of SCD were associated with the occurrence of falls. We highlighted the importance of evaluating SCD over time when considering falls., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects., Methods: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated., Results: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments., Conclusion: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Pigmentary mosaicism of the Ito type, also known as hypomelanosis of Ito, is a neurocutaneous syndrome considered to be predominantly caused by somatic chromosomal mosaicism. However, a few monogenic causes of pigmentary mosaicism have been recently reported. Eleven unrelated individuals with pigmentary mosaicism (mostly hypopigmented skin) were recruited for this study. Skin punch biopsies of the probands and trio-based blood samples (from probands and both biological parents) were collected, and genomic DNA was extracted and analyzed by exome sequencing. In all patients, plausible monogenic causes were detected with somatic and germline variants identified in five and six patients, respectively. Among the somatic variants, four patients had MTOR variant (36%) and another had an RHOA variant. De novo germline variants in USP9X, TFE3, and KCNQ5 were detected in two, one, and one patients, respectively. A maternally inherited PHF6 variant was detected in one patient with hyperpigmented skin. Compound heterozygous GTF3C5 variants were highlighted as strong candidates in the remaining patient. Exome sequencing, using patients' blood and skin samples is highly recommended as the first choice for detecting causative genetic variants of pigmentary mosaicism., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We aimed to verify the frailty status and the factors associated with the change in frailty status during the COVID-19 pandemic. A three-wave cohort study was conducted every six months, from May to July 2020, November 2020 to January 2021, and again from May to July 2021. The frailty status was assessed using the frailty screening index. Multivariate generalized linear mixed-effects models were used to determine whether changes in frailty status were associated with health conditions and lifestyle. The 404 survey forms were analyzed. Decline in chewing function (beta = 0.552) and leg muscle strength weakness (beta = 0.515) were significantly associated with the change in frailty status over six months, and leg muscle strength weakness (beta = 0.512) was significantly associated over 12 months. Risk factors associated with worsening health should be assessed for appropriate support. It is especially important to assess subjective leg muscle weakness in older adults., Competing Interests: Declaration of competing interest The authors have no declarations of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Assessment-oriented group action (AGA) could be used to empower community-dwelling older adults to maintain their health by groups. AGA can be implemented with the support of a health professional to provide feedback to older adults on physical and cognitive function., Objective: To evaluate the effects of AGA., Methods: For this feasibility study, we enrolled 23 and 20 participants in the intervention and control groups, respectively. Thοse in the intervention group received feedback of their assessments and devised exercise plans with professional support. The participants performed their exercises over 12 weeks; the follow-up examination was conducted at 40 weeks. The control group only received feedback. The change in health-related consciousness and behavior was evaluated. Muscle strength and mass were measured and the timed up and go test, and the Brief-balance evaluation system test (BESTest) were performed., Results: There were no significant differences in consciousness or behavior between the groups. The score was higher in the intervention than in the control group at 40 weeks in Section-I of the Brief-BESTest, indicating that the muscle strength contributed to balance function., Conclusion: AGA did not show positive changes in consciousness or behaviors but demonstrated significant improvements and lasting effects in balance function.

Objectives: The WISH-type S-form hip brace (WISH brace) has significantly improved hip function and functional mobility in patients with hip osteoarthritis (OA). However, most patients later undergo surgery. The main purpose of this study was to evaluate how long the orthosis can be effectively used by patients with hip OA, and to reveal the associated prognostic factors., Methods: This prospective study examined the survival curve of the equipment by using surgery as an endpoint and investigated how the duration of use affects patients. Harris Hip Score, muscle strength, and the Timed Up and Go test (TUG) were evaluated as prognostic factors., Results: By drawing the survival curves of 26 patients, approximately one third were expected to be still using the brace after 7 years. A rapid decrease in use was observed at around 1 year. A significant difference between patients with and without bracing at 1 year was found for the TUG result with the unaffected leg inside (ULI) at the start of bracing. A cut-off value of 9.5 s for the TUG with ULI significantly differentiated patients with and without bracing at 1 year, suggesting a possible predictor of brace survivorship in the early phase., Conclusions: The TUG with ULI with a cut-off value of 9.5 s, or at most 10 s, may be a possible predictor of persistence of brace use in the early phase., Competing Interests: CONFLICTS OF INTEREST: The authors report no conflicts of interest., (2022 The Japanese Association of Rehabilitation Medicine.)

Background: A method for assessing balance that differentiates between balance deficit can help guide effective interventions for preventing falls in older adults., Objective: This study aimed to clarify the relationship between balance control systems and falls, and to examine the ability of the Brief-Balance Evaluation Systems Test (BESTest) to evaluate balance deficits in older adults., Methods: Overall, 109 community-dwelling older adults participated in this study. The history of falls in the last year was investigated. Balance deficits were assessed using the Brief-BESTest, the functional reach test, the Timed up and Go Test, and the one leg balance test. We analyzed the difference between the fallers and non-fallers across two different age groups., Results: Among younger-older group participants (age < 75 years), there were no significant differences between fallers and non-fallers across all variables. Among older-older group participants (age ≥ 75 years), there were significant differences in the Brief-BESTest total ( p = .011; fallers, 13.5 versus non-fallers, 17.0) and section IV scores (postural responses of the Brief-BESTest; p = .026, 2.0 versus 5.0). There was no significant difference in other balance measurements., Conclusions: The postural responses assessed by the Brief-BESTest may serve important functions and may be associated with falls in older adults.

Aim: SARC-F, a sarcopenia screening tool, has limited use but may be beneficial for detecting sarcopenia in frail older people. This study aimed to clarify the validity of the SARC-F questionnaire in older people., Methods: In this validation study, 74 (36 men; age, 81.9 ± 6.7 years, 38 women; age, 83 ± 6.2 years) community-dwelling older people who attended a daycare facility participated in our study. Participants completed the SARC-F and SARC-calf circumference (SARC-CalF) questionnaires, and their body composition, walk speed and grip strength were measured. Sarcopenia was determined using the Asian Working Group for Sarcopenia criteria, and the participants were divided into non-sarcopenia and sarcopenia groups. SARC-F and SARC-CalF scores were evaluated using receiver operating characteristic curve analysis for sarcopenia considering the area under the curve. Internal consistency was evaluated using Cronbach's alpha., Results: The prevalence of sarcopenia, defined by physical characteristics, was 60.0% in men and 48.1% in women. The area under the curve of the SARC-F for sarcopenia was 0.703 (95% confidence interval [CI]: 0.585-0.821, P = 0.001). Cronbach's alpha was 0.81, and the internal consistency was high. SARC-F had lower sensitivity (0.47; 95% CI: 0.31-0.64) but higher specificity (0.78; 95% CI: 0.60-0.89) than the sensitivity and specificity of SARC-CalF, respectively, and the sensitivity of SARC-F was higher than that reported in previous studies., Conclusion: The SARC-F questionnaire is more sensitive in assessing sarcopenia in low-functioning populations and can be used as a screening tool for sarcopenia in long-term daycare facilities for older people rather than in community-based healthcare activities. Geriatr Gerontol Int 2022; 22: 889-893., (© 2022 Japan Geriatrics Society.)

Background: Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma., Methods: We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations., Results: This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival., Conclusion: Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

There is only one report of patients with developmental delay due to a 6q16.1 deletion that does not contain the SIM1 gene. A 3-year-old female showed strabismus, cleft soft palate, hypotonia at birth, and global developmental delay. Exome sequencing detected a de novo 6q16.1 deletion (chr6: 99282717-100062596) (hg19). The following genes were included in this region: POU3F2, FBXL4, FAXC, COQ3, PNISR, USP45, TSTD3, CCNC, and PRDM13., (© 2022. The Author(s).)

Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2 -associated neurodevelopmental phenotype in a patient cohort., Methods: We discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants., Results: We identified 12 unrelated individuals with five de novo missense variants in GNB2 , four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction., Conclusion: Missense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size., Methods: We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns)., Results: We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 "plausible" candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2., Conclusions: We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes., (© 2022. The Author(s).)

[Purpose] This study aimed to assess fall-related risk factors among community-dwelling older adults during a period of voluntary self-isolation for preventing the spread of COVID-19. [Participants and Methods] This was a cross-sectional study. Survey questionnaire forms were distributed to 2,586 community-dwelling older adults in Takasaki City, Gunma Prefecture, Japan. Completed questionnaires were returned by mail. [Results] Of the 1,645 people who responded, 1,040 people aged 65 and over who did not apply for long-term care insurance and fully completed the questionnaire were included in this study. Since no in-person measurements were required, we utilized the Frailty Screening Index for the evaluations. We evaluated the relationship between questionnaire responses and fall rates among community-dwelling older adults. Among the results, "yes" responses to "Do you think you walk more slowly than before?" were identified as significantly associated with falls. [Conclusion] One must pay careful attention to subjectively assessing decreases in walking speed as a fall prevention measure during periods of self-restraint to prevent the spread of COVID-19 infection., (2022©by the Society of Physical Therapy Science. Published by IPEC Inc.)

GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: COVID-19 is a highly transmissible and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Algeria was also affected by the COVID-19, it was considered the third most affected country in Africa., Aim: The main aim of the study was to identify risk factors and the impact of risk factors on the incidence SARS-CoV-2 infection and the clinical course of the COVID-19, through a behavioral survey on a representative sample of the people who have been previously diagnosed with COVID-19., Materials and Methods: A partial cross-sectional study of 808 people from a population of both sexes, aged 1 to 90 years allowed the description of the epidemiological profile of patients in the city of Oum-El-Bouaghi in eastern Algeria., Results: The results of the study shows that the SASR-CoV-2 infection appears to be very strongly related to social and biological factor. The relationship between different BMI classes and the pandemic is confirmed by a significant difference (p., Competing Interests: The authors declare that they have no conflict of interest, (© National Institute of Public Health NIH – National Research Institute.)

Aim: This study aimed to clarify the construct validity of the Questionnaire for medical checkup of old-old (QMCOO)., Methods: In this cross-sectional study, questionnaires including the QMCOO were distributed to 1,953 older adults, and responses were returned by mail. We conducted an exploratory factor analysis (EFA) for the QMCOO among older participants (age ≥75 years) and extracted the relevant factors. Next, we structured the model for the QMCOO based on these factors and conducted a confirmatory factor analysis (CFA) using structural equation modeling. We conducted a CFA among young-older participants (age 65 to <75 years) for the same model., Results: Of the 1,110 (53.5%) adults who responded, data from the 994 respondents who provided complete answers were analyzed. Five factors were extracted from the results of the EFA: physical and mental condition, relationship with society, eating and smoking, chance for exercise, and cognitive function. The results of the CFA were as follows: comparative fit index (CFI) = 0.899, adjusted goodness of fit index (AGFI) = 0.965, root mean square error of approximation (RMSEA) = 0.034, and standardized root mean square residual (SRMR) = 0.040. Meanwhile, the results for young-older participants were as follows: CFI = 0.886, AGFI = 0.942, RMSEA = 0.035, and SRMR = 0.048., Conclusions: The QMCOO assessed health condition and was composed of multiple factors associated with frailty. The CFA results indicated that the model fit was good. The QMCOO showed sufficient structural validity. Therefore, the construct validity of the QMCOO was shown.

Aim: This study aimed to investigate a method for scoring the questionnaire for medical checkup of old-old (QMCOO) and to clarify a cut-off score for the discrimination of frailty., Methods: Survey forms were distributed to 2,586 older adults. For old-old adults, the item characteristics of the QMCOO were indicated using the item response theory (IRT). A receiver operating characteristic (ROC) analysis was performed using the total score of the fitting model of QMCOO for suggesting a cut-off score to discriminate frailty. The cross-validity of the cut-off score was verified among young-old adults., Results: Among 1,680 adults who responded, data from 975 old-old and 421 young-old adults were analyzed. The method for scoring zero or one on each item in QMCOO conformed to the IRT model. The item discrimination and difficulty met the criteria. An ROC analysis showed that the area under the curve (AUC) and cut-off score for the discrimination of frailty were 0.871 and 4 points (sensitivity = 0.811, specificity = 0.766, positive likelihood ratio [LR+] = 3.469, and negative likelihood ratio [LR-] = 0.247), respectively. For young-old adults, the AUC and cut-off score were 0.874 and 4 points (sensitivity = 0.741, specificity = 0.817, LR+= 4.053, and LR- = 0.317), respectively., Conclusions: The method for scoring zero or one on each item of the QMCOO was valid. A cut-off score of 4 for the discrimination of frailty demonstrated the interpretability of the QMCOO, while the usefulness of the QMCOO in young-old adults demonstrated cross-validity.

Heterozygous variants in CLTC, which encode the clathrin heavy chain protein, cause neurodevelopmental delay of varying severity, and often accompanied by dysmorphic features, seizures, hypotonia, and ataxia. To date, 28 affected individuals with CLTC variants have been reported, although their phenotypes have not been fully elucidated. Here, we report three novel de novo CLTC (NM&#95;001288653.1) variants in three individuals with previously unreported clinical symptoms: c.3662&#95;3664del:p.(Leu1221del) in individual 1, c.2878T>C:p.(Trp960Arg) in individual 2, and c.2430+1G>T:p.(Glu769&#95;Lys810del) in individual 3. Consistent with previous reports, individuals with missense or small in-frame variants were more severely affected. Unreported symptoms included a brain defect (cystic lesions along the lateral ventricles of the brain in individuals 1 and 3), kidney findings (high-echogenic kidneys in individual 1 and agenesis of the left kidney and right vesicoureteral reflux in individual 3), respiratory abnormality (recurrent pneumonia in individual 1), and abnormal hematological findings (anemia in individual 1 and pancytopenia in individual 3). Of note, individual 1 even exhibited prenatal abnormality (fetal growth restriction, cystic brain lesions, high-echogenic kidneys, and a heart defect), suggesting that CLTC variants should be considered when abnormal prenatal findings in multiple organs are detected., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background and Purpose: Walking speed can be used to identify characteristics of frailty in older adults. It has a strong positive correlation with balance abilities. The Brief-Balance Evaluation Systems Test (Brief-BESTest) was developed to assess functions of the 6 balance control systems in a short time. However, for community-dwelling older adults, the relationship between walking speed and the Brief-BESTest needs to be clarified. Even the cutoff scores for each Brief-BESTest section should be indicated for physical therapists to effectively evaluate balance deficits. Our objective was to establish cutoff scores for individual Brief-BESTest sections, determine fast or slow walkers in community-dwelling older adults, and investigate the relationship between balance control systems and walking speed., Methods: In a cross-sectional study involving 55 participants 77 years and older, the Brief-BESTest was evaluated after grouping the participants based on their walking speeds in public community centers. We compared the age, history of falls, handgrip strength, quadriceps strength, appendicular skeletal muscle mass index, comfortable walking speeds, and the Brief-BESTest scores between the fast- and slow-walking groups by using the independent t test, Fisher exact test, or Mann-Whitney U test. We also determined the receiver operating characteristic curves, and calculated the cutoff, area under the curve (AUC), sensitivity, and specificity of each section., Results: All sections of the Brief-BESTest, except Section 1 (Biomechanical Constraints) were able to differentiate between fast and slow walkers in community-dwelling older women. Section VI (Stability in Gait) showed the highest AUC (0.83) and the cutoff score for the fast- and slow-walker groups was 3.0 points (sensitivity = 0.85, specificity = 0.81). Sections III, IV, and V (Anticipatory, Reactive, and Sensory Orientation, respectively) had moderate AUC (0.71-0.72). Sections I and II (Stability Limits) showed weak correlations with the walking speed., Conclusions: Three sections (III, anticipatory postural adjustments; IV, reactive postural responses; and VI, stability in gait) could differentiate between fast and slow walkers. Section VI was a particularly important balance function measurement that differentiated the walking speed with the highest accuracy. Therefore, it should be a primary focus when physical therapists treat community-dwelling older adults., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 APTA Geriatrics, An Academy of the American Physical Therapy Association.)

Background: Globally, lifestyles have changed to prevent the spread of coronavirus disease 2019 (COVID-19). Therefore, we aimed to understand health and lifestyle conditions associated with frailty transition over 6 months and devise a method for identifying frailty among community-dwelling older people during the COVID-19 pandemic., Method: This community-based prospective cohort study was conducted from May to July 2020 (baseline) and November 2020 to January 2021 (follow-up) in Japan, with 1,953 community-dwelling older people (≥65 years) at baseline. To identify transition from non-frailty at baseline to frailty at follow-up, the Frailty Screening Index was used. For predicting frailty transition, two self-reported questionnaires assessing health and lifestyle conditions were employed., Results: Overall, 706 individuals returned the baseline and follow-up questionnaires. Among the 492 non-frail older people at baseline, there was a 9.8% increase in frailty transition. The adjusted model for frailty transition by age, sex, multimorbidity, and living arrangements indicated that forgetfulness (odds ratio [OR] 2.74, 95% confidence interval [CI]: 1.00 to 7.51), falls in the past year (OR 2.26, 95% CI: 1.08 to 4.74), and subjective leg muscle weakness (OR 1.83, 95% CI: 1.05 to 3.21) were predictors of frailty transition. The combination of age ≥75 years and subjective leg muscle weakness showed moderate sensitivity, specificity, and % accuracy (0.688, 0.696, and 69.5%, respectively)., Conclusions: Approximately 10% of older people showed new transitions to frailty over 6 months during the COVID-19 pandemic. A combination of age and subjective leg muscle weakness is a feasible measure to optimally identify frailty transition., (Copyright © 2021. Published by Elsevier B.V.)

Rodent mast cells are classified into two major subsets, mucosal mast cells (MMCs) and connective tissue mast cells. MMCs arise from mast cell progenitors that are mobilized from the bone marrow to mucosal tissues in response to allergic inflammation or helminth infection. TGF-β is known as an inducer of MMC differentiation in mucosal tissues, but we have previously found that Notch receptor-mediated signaling also leads to the differentiation. Here, we examined the relationship between Notch and TGF-β signaling in MMC differentiation using mouse bone marrow-derived mast cells (BMMCs). We found that the coexistence of Notch and TGF-β signaling markedly upregulates the expression of MMC markers, mouse mast cell protease (mMCP)-1, mMCP-2, and αE integrin/CD103, more than Notch or TGF-β signaling alone, and that their signals act interdependently to induce these marker expressions. Notch and TGF-β-mediated transcription of MMC marker genes were both dependent on the TGF-β signaling transducer SMAD4. In addition, we also found that Notch signaling markedly upregulated mMCP-1 and mMCP-2 expression levels through epigenetic deregulation of the promoter regions of these genes, but did not affect the promoter of the CD103-encoding gene. Moreover, forced expression of the constitutively active Notch2 intracellular domain in BMMCs showed that Notch signaling promotes the nuclear localization of SMADs 3 and 4 and causes SMAD4-dependent gene transcription. These findings indicate that Notch and TGF-β signaling play interdependent roles in inducing the differentiation and maturation of MMCs. These roles may contribute to the rapid expansion of the number of MMCs during allergic mucosal inflammation., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Cerebellar ataxia is a genetically heterogeneous disorder. GEMIN5 encoding an RNA-binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss-of-function variants cause neurodevelopmental delay, hypotonia, and cerebellar ataxia. Here, whole-exome analysis revealed compound heterozygous GEMIN5 variants in two individuals from our cohort of 162 patients with cerebellar atrophy/hypoplasia. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G > A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both affected individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for null variants p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant models strongly suggest that biallelic loss-of-function variants in GEMIN5 cause cerebellar atrophy/hypoplasia., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: GGC repeat expansions in NOTCH2NLC are associated with neuronal intranuclear inclusion disease. Very recently, asymptomatic carriers with NOTCH2NLC repeat expansions were reported. In these asymptomatic individuals, the CpG island in NOTCH2NLC is hypermethylated, suggesting that two factors repeat length and DNA methylation status should be considered to evaluate pathogenicity. Long-read sequencing can be used to simultaneously profile genomic and epigenomic alterations. We analyzed four sporadic cases with NOTCH2NLC repeat expansion and their phenotypically normal parents. The native genomic DNA that retains base modification was sequenced on a per-trio basis using both PacBio and Oxford Nanopore long-read sequencing technologies. A custom workflow was developed to evaluate DNA modifications. With these two technologies combined, long-range DNA methylation information was integrated with complete repeat DNA sequences to investigate the genetic origins of expanded GGC repeats in these sporadic cases., Results: In all four families, asymptomatic fathers had longer expansions (median: 522, 390, 528 and 650 repeats) compared with their affected offspring (median: 93, 117, 162 and 140 repeats, respectively). These expansions are much longer than the disease-causing range previously reported (in general, 41-300 repeats). Repeat lengths were extremely variable in the father, suggesting somatic mosaicism. Instability is more frequent in alleles with uninterrupted pure GGCs. Single molecule epigenetic analysis revealed complex DNA methylation patterns and epigenetic heterogeneity. We identified an aberrant gain-of-methylation region (2.2 kb in size beyond the CpG island and GGC repeats) in asymptomatic fathers. This methylated region was unmethylated in the normal allele with bilateral transitional zones with both methylated and unmethylated CpG dinucleotides, which may be protected from methylation to ensure NOTCH2NLC expression., Conclusions: We clearly demonstrate that the four sporadic NOTCH2NLC-related cases are derived from the paternal GGC repeat contraction associated with demethylation. The entire genetic and epigenetic landscape of the NOTCH2NLC region was uncovered using the custom workflow of long-read sequence data, demonstrating the utility of this method for revealing epigenetic/mutational changes in repetitive elements, which are difficult to characterize by conventional short-read/bisulfite sequencing methods. Our approach should be useful for biomedical research, aiding the discovery of DNA methylation abnormalities through the entire genome., (© 2021. The Author(s).)

Aim: This study aims to clarify the construct and criterion-related validity of the Questionnaire for Older Senior Citizens (QO) during the COVID-19 pandemic., Methods: This cross-sectional study was conducted in Japan between November 11, 2020 and January 10, 2021. Of the 1645 (63.5%) older adults who responded, data from 900 participants were analyzed. First, we conducted an exploratory factor analysis (EFA) among older-older adults (aged ≥75 years) and extracted the factors. Next, we conducted a confirmatory factor analysis (CFA) using structural equation modeling. We also conducted this analysis among younger-older adults (aged ≥65 and <75 years) using the same model. Moreover, we compared each item of the QO with frailty status., Results: Results of the EFA revealed six factors: social conditions and lifestyle, subjective conditions, cognitive functions, physical activity, oral functions, and physical functions. The results of the CFA were as follows: comparative fit index (CFI) = 0.971, adjusted goodness of fit index (AGFI) = 0.978, root mean square error of approximation (RMSEA) = 0.018, and standardized root mean square residual (SRMR) = 0.030. The results among the younger-older adults were as follows: CFI = 0.880, AGFI = 0.940, RMSEA = 0.037, and SRMR = 0.048. Many QO items were significantly associated with frailty (P < 0.05)., Conclusions: Among the older-older adults group, the model used for the QO has sufficient suitability and construct validity; among the younger-older adults group, there also is sufficient questionnaire suitability. Moreover, the QO has criterion related validity with frailty. Geriatr Gerontol Int 2021; 21: 1018-1025., (© 2021 Japan Geriatrics Society.)

Purpose: To clarify the actual frail status over 6 months with the COVID-19 countermeasures., Methods: This prospective cohort study was conducted between the baseline assessment from May 11 to July 10 in 2020, and the follow-up assessment from November 11, 2020, to January 10, 2021, in Japan. The survey forms were distributed among 1953 community-dwelling older adults. Frailty status was assessed using the Frailty Screening Index., Results: In total, 702 older adults (35.2%) returned the survey forms, and 593 (mean age = 78.8 years, and 77.4% females) older adults without missing values for the survey forms were analyzed. Pre-frail and frail prevalence were 55.0 and 7.9% at the baseline, and 57.3 and 11.8% at the follow-up, respectively. Frailty transition that indicated transition from robust or pre-frail at the baseline to frail at the follow-up was 9.9%., Conclusion: Increase in frailty might indicate frailty related to implementation of COVID-19 countermeasures., (© 2021. European Geriatric Medicine Society.)

Introduction: Because of the countermeasures to prevent the spread of coronavirus disease 2019 (COVID-19) in Japan, it is easy to predict that the suspension of local activities and changes in lifestyle that lead to decreased activity will result in increased frailty and prefrailty rates in older adults., Objective: To clarify the actual frailty conditions and lifestyle changes among community-dwelling older adults affected by COVID-19 countermeasures in Japan., Methods: This cross-sectional study was conducted between May 8 and June 12, 2020. Self-reported questionnaires were distributed to 1,078 older adults aged ≥65 years. We used the frailty screening index to assess frailty status and developed the Questionnaire for Change of Life (QCL) to assess lifestyle changes, the amount of daily movement, leg muscle strength, meal size, worry or anxiety, and opportunities to talk to people. The differences in prevalence rates of frailty, prefrailty, and robustness between this study and the reference based on the Japanese meta-analysis were verified using the chi-square goodness of fit test. We compared each of the QCL results among the frailty, prefrailty, and robust groups using Fisher's exact test., Results: Of 680 older adults (63.1%) analyzed, 60 (8.8%) had frailty and 354 (52.1%) had prefrailty. There was a significant difference between the observed and expected prevalence based on the reference (p = 0.018). The frailty status was significantly associated with lifestyle changes. In participants with frailty, the amount of daily movement, leg muscle strength, and meal size significantly decreased (p < 0.001), whereas worry or anxiety significantly increased (p = 0.040). In contrast, regardless of the frailty status, opportunities to talk to people decreased., Conclusion: The prevalence of frailty and prefrailty might have increased due to the effects of COVID-19 countermeasures. Moreover, the lifestyle of community-dwelling older adults affected by COVID-19 countermeasures has changed. Lifestyle changes were more pronounced among older adults with frailty., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

[Purpose] We aimed to obtain new findings by investigating the relationship between the presence or absence of falls and the results from the Frailty Screening Index (FSI), which can be easily carried out. [Participants and Methods] A total of 780 community-dwelling older adults (age ≥65 years) were classified based on whether they had fallen in the past year as those who had fallen at least once (fall group), and those who had not (non-fall group). We compared the study groups using sub-items of the FSI to extract more specific fall-related factors. The FSI is a questionnaire that comprises five items with simple 'yes/no' responses. [Results] The following three out of five sub-items of the FSI were extracted as fall-related factors: 1) "no" to the question, "Do you do physical exercise, like walking, at least once a week?"; 2) "yes" to the question, "Do you think you walk slower than before?"; and 3) "yes" to the question, "Have you felt tired for no reason (in the past two weeks)?" [Conclusion] The study results suggest the significance of paying attention to participant responses to the sub-items on the FSI, instead of merely determining their frailty risk based on their total score., (2021©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Background: X-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The OTUD5 gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic OTUD5 variants, was recently reported as a new XLID with additional congenital anomalies., Methods: We investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing., Results: A hemizygous OTUD5 missense variant, c.878A>T, p.Asn293Ile [NM&#95;017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic OTUD5 variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations., Conclusions: Unlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense OTUD5 variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Saida, Fukuda, Scott, Sengoku, Ogata, Nicosia, Hernandez-Garcia, Lalani, Azamian, Streff, Liu, Dai, Mizuguchi, Miyatake, Asahina, Ogata, Miyake and Matsumoto.)

Conditions underlying balance impairment should be identified to improve knowledge regarding clinical interventions for frail older adults. This study aims to explore the relationship between balance functions and frailty by using the brief balance evaluation systems test (BESTest), which can assess biomechanical constraints, stability limits/verticality, anticipatory postural adjustments (APAs), reactive postural responses, sensory orientation and stability in gait. A total of 75 community-dwelling older women were included in this cross-sectional study. We evaluated frailty by using the Kihon checklist and assessed the participants' balance functions by using the Brief BESTest. We performed the Mann-Whitney U test and receiver operating characteristic curve analysis to compare each balance function between frail and nonfrail participants. Twenty-two of the 75 (29.3%) participants were included in the frailty group. We noted significant differences between the frailty and nonfrailty groups with regard to stability limit, APAs, sensory orientation, and stability in gait (P = 0.010, 0.001, 0.008 and <0.001, respectively). In terms of determining frailty and nonfrailty, APAs and stability in gait were moderately accurate (the area under the curve = 0.730 and 0.713, respectively). APAs showed the highest sensitivity (0.864), whereas stability limits, sensory orientation, and stability in gait showed the highest specificity (0.943, 0.849 and 0.868, respectively). Thus, frail and nonfrail older adults showed significantly different balance functions, such as stability limits, APAs, sensory orientation and stability in gait. The Brief BESTest is useful for evaluating balance functions in relation to frailty., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5 , encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Aim: This study aimed to clarify the association between frailty and changes in lifestyle and physical or psychological conditions among community-dwelling older adults affected by the coronavirus disease 2019 countermeasures in Japan., Methods: This cross-sectional study was carried out between 8 May and 12 June 2020 in Japan. Self-reported questionnaires were distributed among 1353 older adults. To assess frailty, we used the frailty screening index. To assess changes in lifestyle and physical or psychological conditions, we developed the Questionnaire for Change of Life (QCL), which comprised five items related to frailty. Cronbach's α was calculated as a measure of internal consistency of QCL. We compared the score for each item in the QCL between the frailty and non-frailty groups. Multiple logistic regression analysis was used to show the factors that affect frailty status., Results: In total, 856 older adults (63.3%) were analyzed. A total of 83 participants (9.7%) had frailty, and 755 participants (90.3%) had non-frailty. Cronbach's α for QCL was 0.552. We observed a significant decrease in daily movement, leg muscle strength and meal size among older adults with frailty compared with non-frailty (P < 0.001). Subjective leg muscle strength (odds ratio 3.257, 95% confidence interval 2.236-4.746) was negatively correlated with frailty., Conclusions: We suggest that each individual QCL item should be used in analyses involving the QCL. This report showed that subjective lifestyle changes affected by the coronavirus disease 2019 countermeasures were associated with frailty status. In particular, as older adults were aware of a decrease in their leg muscle strength, they were significantly more frail. Geriatr Gerontol Int 2021; 21: 39-42., (© 2020 Japan Geriatrics Society.)

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases., (© 2020 Wiley Periodicals LLC.)

Background: Immunization with various vaccines is considered desirable for children with idiopathic nephrotic syndrome (NS) because of their high risk of severe infections. Vaccinations may precipitate relapses of NS, but there is no available data regarding inactivated influenza (flu) virus vaccines., Methods: We retrospectively reviewed the medical records of children with NS who had received flu vaccines between 2002 and 2015. The day of flu vaccination was defined as day 0, and the period between the pre-vaccination and the post-vaccination days was defined as - X to + Y. The risk ratios and their 95% confidence intervals for NS relapse rate were estimated by generalized estimating equation (GEE) Poisson regression., Results: A total of 104 pediatric patients received 208 flu vaccines. The mean age at onset of NS was at 4.85 ± 3.87 years old. There were 261 NS relapses between days - 180 and + 180. Compared with the relapse rate in the - 180 to 0 interval (1.19 times/person-year), those in 0 to + 30 (1.23), + 31 to + 60 (1.58), + 61 to + 90 (1.41), + 91 to + 120 (1.41), and + 121 to + 180 (1.32) days groups were slightly increased, but without significance. Multivariate analysis using GEE Poisson regression also showed no significant increase in relapse rate in each day group compared with days - 180 to 0. Risk ratios for NS relapse were significantly higher in children who were treated with steroids at the first vaccination., Conclusions: Our results suggest that flu vaccines should not be avoided in children with NS based on the potential for NS relapses.

Introduction: Local activities that functioned to prevent frailty in the elderly have been suspended or reduced as a countermeasure against COVID-19. As a result, frailty rates are expected to increase, and frailty is expected to worsen as a secondary problem associated with COVID-19 countermeasures. Therefore, this study aims to determine the extent of frailty in the elderly associated with lifestyle changes implemented as COVID-19 countermeasures, to ascertain actual lifestyle changes and clarify the existence of Corona-Frailty. We will also conduct Corona-Frailty screening to verify the effect of support provided as feedback to supporters of the elderly., Methods and Analysis: The survey target area is Takasaki City, Gunma Prefecture, Japan. Phase I aims to verify the short-term effects of COVID-19. A questionnaire will be distributed to 465 community-dwelling elderly people, and responses will be obtained by post. Frailty will be evaluated using the Frailty Screening Index. Respondents who are frail and have had many changes in their lifestyle will be screened as high-risk people, and feedback will be provided to local supporters. The aim of Phase II will be to verify the long-term effects of COVID-19 and the effect of screening. A similar survey will be distributed twice after the first survey, once after 6 months and again after 1 year and the frailty rate will be tested. Furthermore, out of the subjects identified with frailty in Phase I, the progress of those who were screened and those who were not screened will be compared between groups., Ethics and Dissemination: This study has been approved by the Research Ethics Committee of the Takasaki University of Health and Welfare (approval number: 2009). The results of this study will be reported to the policymaker, presented at academic conferences and published in peer-reviewed journals., Trial Registration Number: UMIN000040335., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes.

Background: Despite advances in non-invasive vascular imaging, detection of renal artery stenosis via catheter angiography is the criterion standard for the diagnosis of renovascular hypertension (RVH). However, because of lack of evidence, the utility of various blood tests and imaging modalities remains unclear., Methods: We retrospectively analyzed the utility of blood tests (plasma renin activity [PRA], aldosterone, and renal vein renin [RVR] values) and imaging studies (computed tomography angiography [CTA], kidney ultrasonography [US]) by comparing them with catheter angiography. Ten pediatric patients with RVH at two institutions from January 2008 to December 2017 were recruited. The sensitivities for diagnosing RVH via imaging and blood tests (kidney [US], PRA, and aldosterone) were derived by examining patient records. Furthermore, the sensitivity and specificity of CT angiography were calculated by considering both the affected and non-affected renal arteries of the patients., Results: A high sensitivity for diagnosing RVH via kidney US (89%) and PRA (80%) was observed. The sensitivity and specificity of CTA were 100%, each. RVR sampling did not aid in the diagnosis of RVH; only two of six patients with unilateral RVH showed significant laterality of RVR boundary ratios. Renal scintigraphy facilitated detection of a non-functional kidney (split renal function <5%)., Conclusions: RVH in children could be diagnosed utilizing non-invasive blood and imaging tests, without catheter angiography. We recommend kidney length measurement along with measurement of PRA level, as a simple and highly useful screening test, followed by CTA as a diagnostic test., (© 2020 Japan Pediatric Society.)

RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole-exome and ultra-deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN-type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans., (© 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.)