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This study presents the development of a simple DNA extraction method and a novel PCR-RFLP protocol for genotyping the MALE STERILITY 4 (MS4) gene in Cryptomeria japonica as a proof of concept. Traditional CTAB-based DNA extraction methods, while effective, involve hazardous chemicals and require high-speed centrifugation, which are impractical in many field settings. Our approach utilizes a household dish detergent-based buffer, sodium chloride, and polyvinylpyrrolidone K-30 to extract DNA from C. japonica needle leaf tissues—without the need for liquid nitrogen. The simplicity of this method makes it more accessible and environmentally friendly. The extracted DNA was successfully used in PCR-RFLP analysis, targeting a single nucleotide polymorphism in the MS4 gene, demonstrating its efficacy for genotyping. The PCR-RFLP markers reliably discriminated between individual genotypes, confirming the practical application of our simple extraction method, even for conifers containing inhibitory substances. This technique is particularly advantageous for use in arboretums and field stations, where the use of hazardous chemicals, specialized equipment, and a draft chamber is limited. Our study contributes to genetic resource management by providing an easy, reliable, and safer method for DNA extraction and genetic analysis.

BackgroundIn patients with unresectable hilar malignant biliary obstruction (MBO), bilateral metal stent placement is recommended. However, treatment selection between partially stent-in-stent (SIS) and side-by-side (SBS) methods is still controversial.StudyClinical outcomes of bilateral metal stent placement by SBS and SIS methods for hilar MBO were retrospectively studied in four Japanese centers. While large-cell-type uncovered metal stents were placed above the papilla in SIS, braided-type uncovered metal stents were placed across the papilla in SBS.ResultsA total of 64 patients with hilar MBO (40 SIS and 24 SBS) were included in the analysis. Technical success rate was 100% in SIS and 96% in SBS. Functional success rate was 93% in SIS and 96% in SBS. Early adverse event rates were higher in SBS (46%) than in SIS (23%), though not statistically significant (P = 0.09). Post-procedure pancreatitis was exclusively observed in SBS group (29%). Recurrent biliary obstruction rates were 48% and 43%, and the median time to recurrent biliary obstruction was 169 and 205 days in SIS and SBS, respectively.ConclusionsOther than a trend to higher adverse event rates including post-procedure pancreatitis in SBS, clinical outcomes of SIS and SBS methods were comparable in patients with unresectable hilar MBO.

The association of physical activity with renal outcome and mortality in advanced chronic kidney disease (CKD; i.e., estimated glomerular filtration rate [eGFR] < 45 ml/min/1.73m 2 ) is poorly studied. We examined this association in patients with advanced CKD in Japan. We used the Rapid Assessment of Physical Activity to assess baseline physical activity and classify patients as active or inactive. CKD progression was defined as 40% decline in eGFR, eGFR < 10, or requiring dialysis or transplantation. Among the 1,808 eligible patients, after adjusting for possible confounders, hazard ratios (HRs) for poor renal outcome in the active group were 0.68 (95% CI, 0.44–1.04), 1.09 (0.86–1.38), and 1.01 (0.82–1.25) in CKD stage G3b, G4, and G5, respectively, suggesting a renal benefit of exercise in CKD stage G3b. Adjusted HRs for death were 0.79 (0.40–1.57), 0.55 (0.38–0.80), and 0.75 (0.44–1.26) in stage G3b, G4, and G5, respectively. While the adjusted HRs of death were 0.84 (0.52–1.38) and 0.60 (0.43–0.83) in diabetic and non-diabetic patients, suggesting that exercise may reduce mortality in non-diabetic patients. Our study suggests that exercise is associated with better survival in non-diabetic patients with CKD stage G3b-5, and better renal outcome in diabetic and non-diabetic CKD stage G3b.

Background The clinical and economic impacts of intermediate care units (IMCUs) on intensive care unit (ICU)-discharged patients remain unclear due to inconsistent outcomes in previous studies. Under Japan’s National Health Insurance Scheme, ICUs are categorized by staffing intensity (high or low). Using a nationwide inpatient database in Japan, we evaluated the clinical outcomes and cost-effectiveness of IMCUs for ICU-discharged patients. Methods This retrospective observational study used a Japanese administrative database to identify patients admitted to the high-intensity ICU in hospitals with IMCUs between April 2020 and March 2023. Patients were categorized into the IMCU (IMCU group) and general ward (non-IMCU) groups. Propensity scores were estimated using a logistic regression model incorporating 14 variables, including patient demographics, and treatments received during ICU stay. One-to-one propensity score matching balanced baseline characteristics of each group. Clinical outcomes were compared between both groups, including in-hospital mortality, ICU readmission, length of ICU stay, length of hospital stay, and total medical costs. Surgical status and surgical area (e.g., cardiovascular) were considered in subgroup analyses. Data analyses were conducted using the chi-square test for categorical variables and t-test for continuous variables. Results Overall, 162,243 eligible patients were categorized into the IMCU (n = 21,548) and non-IMCU (n = 140,695) groups. Propensity score matching generated 18,220 pairs. The IMCU group had lower in-hospital mortality and ICU readmission rates than the non-IMCU group. However, total costs were higher in the IMCU group. Subgroup analyses revealed the IMCU group had significantly lower mortality and lower total costs than the non-IMCU group in the cardiovascular [open thoracotomy] surgery subgroup. Conclusions Discharge to an IMCU is associated with lower in-hospital mortality and ICU readmission rates compared to general ward discharge. High-risk subgroups, such as cardiovascular surgery patients, experienced cost-effective benefits from IMCU care. These findings highlight an association between IMCU admission and improved patient outcomes, suggesting a potential role in optimizing resource use in intensive care. Given the likelihood of selection bias in admission allocation, these findings should be interpretation with caution. Graphical abstract

An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLAST(CreERT2/+)/GLT1(flox/flox), iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.

Tablets and capsules are widely used forms of oral medication, but some patients experience difficulty handling them, which can reduce medication adherence and affect health outcomes. This study aimed to identify factors contributing to perceived handling difficulty, using data from harmo ® , a nationwide electronic medication notebook system. A questionnaire was distributed to adult users who had been prescribed oral medications, and the responses were linked with personal health records to analyze medication characteristics and patient backgrounds. Among the 1,230 respondents, 24% reported difficulty with small tablets or capsules. A size threshold was identified: a combined long and short diameter of 13.3 mm or less was most associated with handling problems (ROC-AUC = 0.834). Binomial logistic regression analysis revealed that difficulty in applying force with the hands (OR = 2.64), prescription of small tablets or capsules (OR = 2.52), and medical histories of hypertension (OR = 1.69) and osteoporosis (OR = 4.99) were significantly associated with reported difficulty. These results suggest that both the physical characteristics of formulations and individual patient factors influence medication usability. Our results provide evidence to inform more patient-centered approaches to oral formulation design and prescribing practices, ultimately supporting better adherence and medication safety.

Bullous pemphigoid (BP) is an autoimmune disease characterized by autoantibody-mediated activation of immune cells and subepidermal blister formation. Excess amounts of extracellular DNA are produced in BP, however, it remains unclear how extracellular DNA contributes to BP pathogenesis. Here we show a possible mechanism by which interleukin (IL)-26 binds to extracellular DNA released from neutrophils and eosinophils to support DNA sensing. Patients with BP exhibited high circulating levels of IL-26, forming IL-26 – DNA complexes in the upper dermis and inside the blisters. IL-26 – DNA complexes played a dual role in regulating local immunity and blister formation. First, they enhanced the production of inflammatory cytokines in monocytes and neutrophils. Second, and importantly, the complexes augmented the production and activity of proteases from co-cultured monocytes and neutrophils, which induced BP180 cleavage in keratinocytes and dermal-epidermal separation in a modified human cryosection model. Collectively, we propose a model in which IL-26 and extracellular DNA synergistically act on immune cells to enhance autoantibody-driven local immune responses and protease-mediated fragility of dermal-epidermal junction in BP.

Psoriasis is a chronic inflammatory disease that sometimes necessitates therapeutic intervention with biologics. Autoantibody production during treatment with tumor necrosis factor (TNF) inhibitors is a recognized phenomenon, however, the production of autoantibodies associated with antiphospholipid syndrome (APS) has not been comprehensively evaluated in patients with psoriasis. This study was conducted to assess the prevalence of APS-associated autoantibodies in patients with psoriasis treated with different biologics and to investigate the potential associations between autoantibody production and clinical or serological parameters. Patients with psoriasis undergoing biologics treatments were enrolled in this study, and were categorized based on the type of biologics administered, TNF, interleukin (IL)-17, or IL-23 inhibitors. Clinical and serological data were collected and analyzed in conjunction with data on APS autoantibodies. TNF inhibitors were associated with a higher frequency of APS autoantibodies compared to IL-17 and IL-23 inhibitors. Notably, the presence of APS autoantibodies correlated with concurrent arthritis and higher disease severity at treatment initiation in patients treated with TNF inhibitors. Elevated Psoriasis Area and Severity Index scores and anti-nuclear antibody titers higher than × 320 were predictors of APS autoantibody production. Despite the higher autoantibody rates, clinical symptoms of APS were absent in these patients. This study provides the first comprehensive evidence of an increased frequency of APS autoantibodies associated with TNF inhibitor treatment in patients with psoriasis. The observed association between APS autoantibody positivity and TNF inhibitor treatment or clinical parameters suggests a potential immunomodulatory interplay between autoimmunity and inflammation in the pathogenesis of psoriasis.

Understanding patient preference regarding taking tablet or capsule formulations plays a pivotal role in treatment efficacy and adherence. Therefore, these preferences should be taken into account when designing formulations and prescriptions. This study investigates the factors affecting patient preference in patients who have difficulties swallowing large tablets or capsules and aims to identify appropriate sizes for tablets and capsules. A robust data set was developed based on a questionnaire survey conducted from December 1, 2022, to December 7, 2022, using the harmo smartphone app operated by harmo Co, Ltd. The data set included patient input regarding their tablet and capsule preferences, personal health records (including dispensing history), and drug formulation information (available from package inserts). Based on the medication formulation information, 6 indices were set for each of the tablets or capsules that were considered difficult to swallow owing to their large size and concomitant tablets or capsules (used as controls). Receiver operating characteristic (ROC) analysis was used to evaluate the performance of each index. The index demonstrating the highest area under the curve of the ROC was selected as the best index to determine the tablet or capsule size that leads to swallowing difficulties. From the generated ROCs, the point with the highest discriminative performance that maximized the Youden index was identified, and the optimal threshold for each index was calculated. Multivariate logistic regression analysis was performed to identify the risk factors contributing to difficulty in swallowing oversized tablets or capsules. Additionally, decision tree analysis was performed to estimate the combined risk from several factors, using risk factors that were significant in the multivariate logistic regression analysis. This study analyzed 147 large tablets or capsules and 624 control tablets or capsules. The \"long diameter + short diameter + thickness\" index (with a 21.5 mm threshold) was identified as the best indicator for causing swallowing difficulties in patients. The multivariate logistic regression analysis (including 132 patients with swallowing difficulties and 1283 patients without) results identified the following contributory risk factors: aged <50 years (odds ratio [OR] 1.59, 95% CI 1.03-2.44), female (OR 2.54, 95% CI 1.70-3.78), dysphagia (OR 3.54, 95% CI 2.22-5.65), and taking large tablets or capsules (OR 9.74, 95% CI 5.19-18.29). The decision tree analysis results suggested an elevated risk of swallowing difficulties for patients with taking large tablets or capsules. This study identified the most appropriate index and threshold for indicating that a given tablet or capsule size will cause swallowing difficulties, as well as the contributory risk factors. Although some sampling biases (eg, only including smartphone users) may exist, our results can guide the design of patient-friendly formulations and prescriptions, promoting better medication adherence.

Background Japan has four types of intensive care units (ICUs) that are divided into two categories according to the management fee charged per day: ICU management fees 1 and 2 (ICU1/2) (equivalent to high-intensity staffing) and 3 and 4 (ICU3/4) (equivalent to low-intensity staffing). Although ICU1/2 charges a higher rate than ICU3/4, no cost-effectiveness analysis has been performed for ICU1/2. This study evaluated the clinical outcomes and cost-effectiveness of ICU1/2 compared with those of ICU3/4. Methods This retrospective observational study used a nationwide Japanese administrative database to identify patients admitted to ICUs between April 2020 and March 2021 and divided them into the ICU1/2 and ICU3/4 groups. The ICU mortality rates and in-hospital mortality rates were determined, and the incremental cost-effectiveness ratio (ICER) (Japanese Yen (JPY)/QALY), defined as the difference between quality-adjusted life year (QALY) and medical costs, was compared between ICU1/2 and ICU3/4. Data analysis was performed using the Chi-squared test; an ICER of < 5 million JPY/QALY was considered cost-effective. Results The ICU1/2 group ( n  = 71,412; 60.7%) had lower ICU mortality rates (ICU 1/2: 2.6% vs. ICU 3/4: 4.3%, p  < 0.001) and lower in-hospital mortality rates (ICU 1/2: 6.1% vs. ICU 3/4: 8.9%, p  < 0.001) than the ICU3/4 group ( n  = 46,330; 39.3%). The average cost per patient of ICU1/2 and ICU3/4 was 2,249,270 ± 1,955,953 JPY and 1,682,546 ± 1,588,928 JPY, respectively, with a difference of 566,724. The ICER was 718,659 JPY/QALY, which was below the cost-effectiveness threshold. Conclusions ICU1/2 is associated with lower ICU patient mortality than ICU3/4. Treatments under ICU1/2 are more cost-effective than those under ICU3/4, with an ICER of < 5 million JPY/QALY.