Search

Abstract Background Recent studies have suggested an increasing prevalence of intellectual disability diagnoses in some countries. Our aim was to describe the trend in the prevalence of intellectual disability diagnoses in Sweden and explore whether associated sociodemographic and perinatal factors can explain changes in the prevalence. Methods We used a register-based nationwide cohort of residents in Sweden born between 2001 and 2011. We calculated the prevalence of intellectual disability diagnoses by age 10 for each birth cohort and the prevalence ratios in relation to the baseline year 2011, overall and by severity of intellectual disability, and comorbidity of autism and attention-deficit/hyperactivity disorder. The prevalence ratios were stratified and adjusted for associated sociodemographic and perinatal factors. Results Among 1,096,800 individuals, 8,577 were diagnosed with intellectual disability by age 10. Among these, 3,949 (46%) and 2,768 (32%) were also diagnosed with autism and attention-deficit/hyperactivity disorder, respectively, and 4% were diagnosed with profound, 8% severe, 20% moderate, 52% mild, and 16% other/unspecific intellectual disability. The recorded age-10 prevalence of intellectual disability diagnoses increased from 0.64% (95% confidence interval 0.59–0.69%) in 2011 to 1.00% (0.94–1.06%) in 2021, corresponding to an annual prevalence ratio of 1.04 (1.04–1.05). The increase was, however, restricted to mild, moderate, and other/unspecific intellectual disability diagnoses, while the trends for profound and severe intellectual disability diagnoses were stable. The increasing trend was perhaps less pronounced among females and children with diagnosed attention-deficit/hyperactivity disorder, but independent of the co-occurrence of autism. The prevalence ratios did not change with stratification or adjustment for other associated demographic and perinatal factors. Conclusion The recorded prevalence of diagnosed mild and moderate intellectual disability among 10-year-olds in Sweden has increased over the recent decade. This increase could not be explained by changes in associated sociodemographic or perinatal factors, including birth weight, gestational age, and parental age, migration status, and education at the child’s birth. The increase instead may be due to changes in diagnostic practices in Sweden over time.

Background: Fatty acid-binding protein 4 (FABP4) is an adipokine that plays significant roles in the development of insulin resistance and atherosclerosis. High levels of soluble tumor necrosis factor receptors (TNFRs) including TNFR1 and TNFR2 are associated with renal dysfunction and increased mortality in patients with diabetes mellitus (DM). However, the association between circulating levels of FABP4 and TNFRs remains unclear. Methods: We investigated the associations of FABP4 with TNFRs and metabolic markers in Japanese patients with type 1 DM (T1DM, n = 76, men/women: 31/45) and type 2 DM (T2DM, n = 575, men/women: 312/263). Results: FABP4 concentration was positively correlated with levels of TNFR1 and TNFR2 in both patients with T1DM and those with T2DM. Multivariable regression analyses showed that there were independent associations of FABP4 concentration with body mass index (BMI) and estimated glomerular filtration rate (eGFR) after adjustment for age and sex in both patients with T1DM and those with T2DM. FABP4 concentration was independently associated with circulating levels of TNFR1 and TNFR2 after adjustment for the confounders in patients with T2DM but not in those with T1DM. Similarly, levels of TNFR1 and TNFR2 were independently associated with FABP4 concentration after adjustment for age, sex, systolic blood pressure, duration of DM and levels of eGFR, high-density lipoprotein cholesterol, and C-reactive protein in patients with T2DM but not in those with T1DM. Conclusion: FABP4 concentration is independently associated with levels of TNFRs in patients with DM, but the association is more evident in patients with T2DM than in those with T1DM.

Abstract In cancer genome analysis, identifying pathogenic alterations and assessing their effects on oncogenic processes is important. Although whole exome sequencing (WES) can effectively detect such changes, driver alterations could not be identified in 27.8% of the cases, according to a previous study. The objectives of the present study were to evaluate the utility of whole genome sequencing (WGS) and clarify its differences with WES in terms of driver alteration detection. For this purpose, WGS analysis was conducted on 177 driverless WES samples, selected from 5,480 fresh frozen samples derived from 5,140 Japanese patients with cancer. These samples were selected as primary tumor, both WES and transcriptome profiling were performed, estimated tumor content of ≥ 30%, and no driver alterations were identified by WES. WGS identified driver and likely driver alterations in 68.4 and 22.6% of the samples, respectively. The most frequent alteration type was oncogene amplification, followed by tumor suppressor gene deletion and small variants located outside the coding region. In the remaining 9.0% of samples, no such signals were identified; therefore, further investigations are required. The current study clearly demonstrated the role and utility of WGS in identifying genomic alterations that contribute to tumorigenesis.

Abstract The analysis of cells frozen within the International Space Station (ISS) will provide crucial insights into the impact of the space environment on cellular functions and properties. The objective of this study was to develop a method for cryopreserving blood cells under the specific constraints of the ISS. In a ground experiment, mouse blood was directly mixed with a cryoprotectant and gradually frozen at −80 °C. Thawing the frozen blood sample resulted in the successful recovery of viable mononuclear cells when using a mixed solution of dimethylsulfoxide and hydroxyethyl starch as a cryoprotectant. In addition, we developed new freezing cases to minimize storage space utilization within the ISS freezer. Finally, we confirmed the recovery of major mononuclear immune cell subsets from the cryopreserved blood cells through a high dimensional analysis of flow cytometric data using 13 cell surface markers. Consequently, this ground study lays the foundation for the cryopreservation of viable blood cells on the ISS, enabling their analysis upon return to Earth. The application of this method in ISS studies will contribute to understanding the impact of space environments on human cells. Moreover, this method may find application in the cryopreservation of blood cells in situations where research facilities are inadequate.

To determine the characteristics of pediatric patients 0–19 years of age who died after onset of SARS-CoV-2 infection in Japan during January 1–September 30, 2022, we reviewed multiple sources. We identified 62 cases, collected detailed information from medical records and death certificates, and conducted interviews, resulting in 53 patients with detailed information for our study. Among 46 patients with internal causes of death (i.e., not external causes such as trauma), 15% were

Abstract Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666.

Among nonsteroidal anti-inflammatory drugs, ibuprofen, diclofenac, and celecoxib have been frequently used in multimodal analgesia. Recent studies challenge the conventional theory that they exhibit activity and toxicity by acting on cyclooxygenase selectively. We compared their membrane interactions that may be associated with analgesic and gastrointestinal toxic effects. Biomimetic membranes suspended in buffers of different pH were prepared with 1-palmitoyl-2-oleoylphosphatidylcholine, sphingomyelin, and cholesterol to mimic neuronal membranes and with 1,2-dipalmitoylphosphatidylcholine to mimic gastrointestinal mucosae. The membrane interactivity was determined by measuring fluorescence polarization. At pH 7.4, the drugs interacted with neuro-mimetic membranes to decrease membrane fluidity at pharmacokinetically-relevant 0.5–100 μM. Celecoxib was most potent, followed by ibuprofen and diclofenac. At pH 4.0 and 2.5, however, the drugs increased the fluidity of 1,2-dipalmitoylphosphatidylcholine membranes at 0.1–1 mM, corresponding to gastroduodenal lumen concentrations after administration. Their membrane fluidization was greater at gastric pH 2.5 than at duodenal pH 4.0. Low-micromolar ibuprofen, diclofenac, and celecoxib structure specifically decrease neuronal membrane fluidity, which hypothetically could affect signal transmission of nociceptive sensory neurons. Under gastroduodenal acidic conditions, high-micromolar ibuprofen, diclofenac, and celecoxib induce fluidity increases of membranous phosphatidylcholines that are hypothetically associated with gastrointestinal toxic effects, which would enhance acid permeability of protective mucosal membranes.

Abstract Background Interprofessional education (IPE) is essential for healthcare students to collaborate effectively in multidisciplinary teams. This study aimed to identify the effect of IPE programmes in nursing care and oral healthcare on dental and nursing students’ perceptions of interprofessional collaboration. Methods The study included 101 third-year dental and 98 fourth-year nursing students. The participants were divided into mixed-professional groups of four (2 dental and 2 nursing students). They participated in nursing care and oral healthcare training programmes that included student-on-student training and discussion groups. Questionnaires regarding perceptions of interprofessional collaboration were distributed to the participants before and after the programmes to compare the programmes before and after and between the dental and nursing students. The Wilcoxon signed-rank test and chi-square test were used to compare the data. Results Data from 79 dental students (42 males and 37 females) and 89 nursing students (4 males and 85 females) who completed both questionnaires were used for the comparisons. Perceptions of the differences between the approaches of different health professionals to nursing care, the roles of other professionals, and the need for multiprofessional collaboration improved significantly among both dental and nursing students after the programmes. Although the perception of their ability to communicate with unfamiliar or new people improved significantly only among the nursing students, other perceptions of their ability to communicate did not improve for either group. More dental students than nursing students chose nursing trainings as good programmes to participate in with other professional students, while more nursing students than dental students chose oral care trainings as good programmes. Many students commented that they learned about nursing and oral healthcare skills as well as the importance of teamwork and communication with other professionals. Seven students commented that they were more motivated to become dentists and nurses. Conclusions This study showed that IPE programmes for nursing care and oral healthcare might be effective at helping students understand other professionals and promoting multiprofessional collaboration. However, further studies are needed to develop IPE programmes to improve attitudes and abilities related to interprofessional communication skills.

Abstract Background Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Abstract The association between serum tumor necrosis factor receptor (TNFRs: TNFR1, TNFR2) levels and estimated glomerular filtration rate (eGFR) observed in patients with diabetes has not been comprehensively tested in healthy subjects with normal kidney function. It also remains unclear whether TNFR levels differ by age and sex, and between healthy subjects and diabetics. We measured serum TNFR levels in 413 healthy subjects and 292 patients with type 2 diabetes. In healthy subjects, TNFR levels did not differ between men and women. Additionally, TNFR2, but not TNFR1, levels increased with age. In multivariate analysis, TNFR1 was associated only with cystatin C-based eGFR (eGFR-CysC), whereas TNFR2 was associated with systolic blood pressure in addition to eGFR-CysC. Both TNFRs were associated with lower eGFR (eGFR-Cys

Abstract Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48 –/– mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.

Abstract Although daily higher urinary sodium (Na) and potassium (K) excretion ratio is associated with the risk of cardiovascular disease in the general population, a low Na/K ratio is associated with renal dysfunction in critically ill patients. Thus, we retrospectively analyzed the impact of daily urinary Na and K excretion and their ratio on non-relapse mortality (NRM) and overall mortality in 172 adult single-unit cord blood transplantation (CBT) patients treated at our institution between 2007 and 2020. Multivariate analysis showed that a low urinary Na/K ratio at both 14 days (hazard ratio [HR], 4.82; 95% confidence interval [CI], 1.81–12.83; P = 0.001) and 28 days (HR, 4.47; 95% CI 1.32–15.12; P = 0.015) was significantly associated with higher NRM. Furthermore, a low urinary Na/K ratio at 28 days was significantly associated with higher overall mortality (HR, 2.38; 95% CI 1.15–4.91; P = 0.018). Patients with a low urinary Na/K ratio had decreased urine volume, more weight gain, experienced more grade III–IV acute graft-versus-host disease, and required corticosteroids by 28 days after CBT. These findings indicate that a low urinary Na/K ratio early after single-unit CBT is associated with poor NRM and survival in adults.

Abstract Oral lichen planus is a chronic inflammatory condition that adversely affects the oral mucosa; however, its etiology remains elusive. Consequently, therapeutic interventions for oral lichen planus are limited to symptomatic management. This study provides evidence of the accumulation of senescent mesenchymal cells, CD8 + T cells, and natural killer cells in patients with oral lichen planus. We profiled the patients’ tissues using the National Center for Biotechnology Information Gene Expression Omnibus database and found that senescence-related genes were upregulated in these tissues by gene set enrichment analysis. Immunohistochemical analysis showed increased senescent mesenchymal cells in the subepithelial layer of patients with oral lichen planus. Single-cell RNA-seq data retrieved from the Gene Expression Omnibus database of patients with oral lichen planus revealed that mesenchymal cells were marked by the upregulation of senescence-related genes. Cell-cell communication analysis using CellChat showed that senescent mesenchymal cells significantly influenced CD8 + T cells and natural killer cells via CXCL12-CXCR4 signaling, which is known to activate and recruit CD8 + T cells and NK cells. Finally, in vitro assays demonstrated that the secretion of senescence-associated factors from mesenchymal cells stimulated the activation of T cells and natural killer cells and promoted epithelial cell senescence and cytotoxicity. These findings suggest that the accumulation of mesenchymal cells with senescence-associated secretory phenotype may be a key driver of oral lichen planus pathogenesis.

Objectives: This study aimed to investigate the performance of oral assessment and health care education at nursing schools across Japan to identify problems and the need for oral health professional support. Methods: The participants were the academic staff in charge of oral health care education in the basic, adult, gerontological, and home nursing fields of 295 schools in Japan that offered a bachelor's degree in nursing. A questionnaire was sent to 1180 heads of the nursing fields of these schools. They were requested to have oral health care educators complete the survey; data on the performance of oral assessment and health care education and human resources allocated were collected through a questionnaire. Results: A total of 311 (26%) questionnaires were returned, 196 (63%) of which were completed by oral health care educators. Regarding the performance of oral assessment education, the majority (71%) of them spent less than 2 hours in teaching, and only 24.5% taught the usage of oral assessment tools. Regarding the performance of oral health care education, more than 90% spent less than 2 hours in lecture-based and practical oral health care education, respectively. Less than half taught the association of periodontal diseases with diabetes and cardiovascular diseases and use of fluoride for caries prevention in the lectures, and only approximately 30% taught the usage of an interspace brush or dental floss. Moreover, less than 10% of oral health professionals taught oral health care in lectures or practical oral health care. Conclusions: This study revealed problems associated with oral assessment and health care education in Japanese nursing schools. To address these, support from oral health care professionals is required. Further studies are also required to reveal problems in oral assessment and health care education in other nursing schools that do not offer a bachelor's degree programme in Japan and other countries.

This study aimed to clarify the effects of deep-sea pressure storage on the quality of whale meat, especially microbiological safety and physical properties, to examine the effectiveness of deep-sea storage for long-term aging of whale meat. Microbiological safety, physical properties, color and appearance, water content, water activity, and pH of whale meat were examined after storage in the deep sea at depths of 2200–6000 m (22–60 MPa) for 4 months. During storage under high pressure at a depth of >4000 m (40 MPa), the growth of aerobic bacteria was inhibited in whale meat. The toughness of whale meat stored in deep sea at a depth of >4000 m became significantly tender than that before deep-sea storage. Long-term storage of whale meat under high pressure and low-temperature conditions in the deep sea at a depth of >4000 m was clarified to improve the microbiological safety and tenderness of whale meat.